Electron transport system

Содержание

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https://ecampusontario.pressbooks.pub/microbio/chapter/energy-matter-and-enzymes/ Energy, redox Reactions, and Enzymes

https://ecampusontario.pressbooks.pub/microbio/chapter/energy-matter-and-enzymes/

Energy, redox Reactions,
and Enzymes

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Lecture Overview Electron transport systems (ETS) or Electron Transport Chain: ETC)

Lecture Overview

Electron transport systems (ETS) or
Electron Transport Chain: ETC)
The proton

motive force
The respiratory ETS
ATP synthase
Anaerobic respiration
Lithotrophy
Phototrophy
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Introduction We have learned previously how microorganisms can catabolize nutrients and

Introduction

We have learned previously how microorganisms can catabolize nutrients and obtain

energy in the form of energy carriers
ATP and GTP can produce energy by hydrolysis and cleavage of the phosphate bond(s).
However, NADH and FABH2 need to be transformed into ATP.
Mot of the energy yield comes from successive redox (coupled reduction and oxidation) steps within an electron transport system (ETS).
The types of metabolisms that use an ETS include organotrophy (organic electron donors), lithotrophy (inorganic electron donors), and phototrophy (electrons are excited by light absorption).
Our focus will mainly be on ETS organotrophy.
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Flow of electrons Microbes transfer energy by moving electrons. Electrons move

Flow of electrons

Microbes transfer energy by moving electrons.
Electrons move from reduced

food molecules onto energy carriers, then onto membrane protein carriers, and then onto oxygen or oxidized minerals.
The electron transport system generates a “proton motive force” that drives protons across the membrane.
The Proton motive force stores energy to make ATP
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Energy transfer pathway Flow of electron from Donor to acceptor Reduced

Energy transfer pathway

Flow of electron from
Donor to acceptor

Reduced food

molecules

Energy carriers

Oxygen or Oxydized minerals

Cytochrome

e-

e-

e-


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Proton potential In each step of the ETS, a molecule becomes

Proton potential

In each step of the ETS, a molecule becomes

reduced (gains an electron), while the molecule donating the electron becomes oxidized (loses an electron).
Some of the energy from the electron transferred is stored across the membrane in the form of an electrochemical potential (voltage).
The potential is composed of the chemical concentration gradient of protons (H+ ions).
The proton potential drives ATP synthesis
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Electron transport system The electron transport system (ETS) or electron transport

Electron transport system


The electron transport system (ETS) or electron


transport chain (ETC) generates a proton motive
force that drives protons across the membrane
The proton motive force stores energy to
make ATP
A similar process occurs in mitochondria of
animals and photosynthetic membrane of plant
chloroplasts.
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The ETS is embedded in the membrane The ETS can convert

The ETS is embedded in the membrane
The ETS can

convert its energy into an ion
potential or electrochemical potential between
two compartments separated by a membrane
The ion potential is most commonly a proton
(H+) potential or proton motive force (PMF)
PMF drives essential cell processes such as
synthesis of ATP
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Complete redox reaction Basic principle: Combination of 2 redox couple e-


Complete redox reaction
Basic principle: Combination of 2 redox

couple
e- Acceptor : Reduction
e-Donor : Oxidation

Aerobic oxidation of NADH pairs a strong electron donor (NADH) with a strong electron acceptor O2.
NADH oxidation via the ETS provide the cell with a huge amount of potential energy.
To understand the energy gained in this system, please practice using the “electron tower”

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Cytochrome is a component of the ETS The ETS is composed

Cytochrome is a component of the ETS

The ETS is composed

of electron carriers (proteins and molecules that can accept and then donate electrons)
Cytochromes are important components of the ETS
Cytochromes are located in the inner membranes
Cytochromes can receive electrons (reduced state),
then donate electrons (oxidized state)
Reduction and oxidation of cytochomes are associated with a shift in light absorption (Fig.14.3)
The ETS is illustrated in Fig.14.4
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Light absorbance spectrum of a cytochrome. Cytochromes are colored proteins whose

Light absorbance spectrum of a cytochrome.

Cytochromes are colored proteins whose

absorbance spectrum shifts when there is a change in the redox state
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Electron transport system Each cytochrome molecule receives electrons from a stronger

Electron transport system

Each cytochrome molecule receives electrons from a stronger donor

and transfer them to a stronger electron acceptor.
This principle applies to all electron transport chain
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Summary of ETS The reduction potential E for a complex redox

Summary of ETS
The reduction potential E for a complex redox reaction

must be positive to yield energy for metabolism. The standard reduction potential Eo’ assumes all reactant concentration equal 1 M, at pH7
Concentrations of e- donors and e- acceptors in the environment influence the actual reduction potential E experienced by the cell
The ETS is embedded in a membrane that separate two compartments in order to maintain an ion gradient generated by ETS
The ETS is composed of protein complexes and cofactors. Protein complexes called oxidoreductases include cytochromes and noncytochrome proteins.
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Electron Transport Chain: Oxidative phosphorylation Excellent video on Electron Transport Chain:

Electron Transport Chain: Oxidative phosphorylation

Excellent video on Electron Transport Chain: Chemiosmotic

Theory.
Note that the author described the ETC in eukaryotes, but the basic principles are similar in organotrophs.

https://www.youtube.com/watch?v=LsRQ5_EmxJA

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The proton motive force The sequential transfer of e- from one

The proton motive force

The sequential transfer of e- from one ETS

protein to the next yield energy to pump ions (in most cases H+) across the membrane: Proton pump
Proton pumping generates a proton motive force , also called proton potential, which is composed of the H+ concentration difference as well as the charge difference across the membrane
The proton motive force (PMF) drives many different cell processes:
ATP synthesis as discussed previously under nutrient transports
Flagellar rotation (Bacteria swim using rotary motions powered by a proton current
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The transfer of H+ through a proton pump generates an electrochemical

The transfer of H+ through a proton pump generates an electrochemical

gradient of protons, called a proton motive force.

PMF drives the conversion of ADP to ATP through ATP synthase
This process is known as the chemiosmotic theory.

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Electrical Potential and pH Difference

Electrical Potential and pH Difference

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Rotation of flagella Uptake of nutrients Efflux of toxic drugs. Δp


Rotation of flagella
Uptake of nutrients
Efflux of toxic drugs.

Δp drives many cell

Functions


Processes driven by the proton motive force (Δp)

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Either pH difference or charge difference drives ATP synthesis.

Either pH difference or charge difference
drives ATP synthesis.

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The ETS components include enzymatic reactions Oxidoreductases catalyzes the removal of

The ETS components include enzymatic reactions
Oxidoreductases catalyzes the removal of

remove e- (oxidation of one substrate), and the donation of e- (reduction of another substrate)
Dehydrogenases: Oxidoreductases that accept e- from NADH or FADH2 are also called dehydrogenases because their reaction releases H+
Oxidases catalyzes the removal of remove e-
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A respiratory electron transport system includes at least 3 functional components

A respiratory electron transport system
includes at least 3 functional

components
1. An initial substrate oxidoreductase (or
dehydrogenase)
2. A mobile electron carrier
3. A terminal oxidase

Oxidoreductase Protein Complexes

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1. The substrate dehydrogenase receives a pair of electrons from an

1. The substrate dehydrogenase receives a pair of electrons from an

organic substrate, such as NADH, or an inorganic substrate, such as H2.
2. It donates the electrons ultimately to a mobile electron carrier, such as quinone.
Quinone picks up 2H+ from the solution and is
thus reduced to quinol. There are many
quinones, each with a different side chain; so for
simplicity they are collectively referred to as Q and
QH2.
3. The oxidation of NADH and reduction of Q is coupled to pumping 4H+ across the membrane
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Oxidoreductase Protein Complexes – 3 The oxidation of NADH and reduction

Oxidoreductase Protein Complexes – 3

The oxidation of NADH and reduction of

Q is coupled to pumping 4H+ across the membrane
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The Proton Potential Drives ATP Synthesis – 2

The Proton Potential Drives ATP Synthesis – 2

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Oxidoreductase Protein Complexes – 6

Oxidoreductase Protein Complexes – 6

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Oxidoreductase Protein Complexes – 7

Oxidoreductase Protein Complexes – 7

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Mitochondrial Electron Transport

Mitochondrial Electron Transport

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The Proton Potential Drives ATP Synthesis – 1 The F1Fo ATP

The Proton Potential Drives ATP Synthesis – 1

The F1Fo ATP synthase

is a highly conserved protein complex, made of two parts:
Fo: embedded in the membrane
Proton flow through the subunit causes its rotation in the membrane.
F1: protrudes in the cytoplasm
Rotation of the FO subunit causes the F1 γ subunit to turn, changing the conformation of the α and β subunits.
This conformational change catalyzes ATP synthesis.
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The Proton Potential Drives ATP Synthesis – 2

The Proton Potential Drives ATP Synthesis – 2

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Electron Transport Chain hhttp://www.youtube.com/watch?v=xbJ0nbzt5Kw&feature=related NDSU Virtual Cell Animations Project animation 'Cellular

Electron Transport Chain

hhttp://www.youtube.com/watch?v=xbJ0nbzt5Kw&feature=related
NDSU Virtual Cell Animations Project animation 'Cellular Respiration (Electron

Transport Chain)'. For more information please see http://vcell.ndsu.edu/animations
https://www.youtube.com/watch?v=3y1dO4nNaKY Gradients (ATP synthase)
NDSU Virtual Cell Animations Project animation 'Gradients (ATP Synthase)'. For more information please see http://vcell.ndsu.edu/animations
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Terminal electron acceptors In organotrophy or chemoorganotrophy: It is a form

Terminal electron acceptors

In organotrophy or chemoorganotrophy: It is a form of

metabolism in which organic molecules donate electrons, and the terminal electron acceptor is O2.
Alternative electron acceptor is Nitrate (NO3)
Some electron acceptors are organic molecules, such as fumarate (note that fumaric acid is a key chemical intermediate in the Krebs cycle)
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Oxidized forms of nitrogen - Nitrate is successively reduced as follows:

Oxidized forms of nitrogen - Nitrate is successively reduced as follows:
NO3– →

NO2– → NO → 1/2 N2O → 1/2 N2
- In general, any given species can carry out only one or two transformations in the series.

nitrite

nitric oxide

nitrous oxide

nitrate

nitrogen gas

Oxidized forms of sulfur - Sulfate is successively reduced by many bacteria as follows:
SO42– → SO32– → 1/2 S2O32– → S0 → H2S

sulfite

thiosulfate

sulfur

hydrogen sulfide

sulfate

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Anaerobic Respiration in Organotrophs Obligate aerobes are organisms that grow only

Anaerobic Respiration in Organotrophs

Obligate aerobes are organisms that grow only

using O2 as a terminal electron acceptor.
Include animals, plants, and many bacteria
Anaerobic respiration. Other prokaryotes use a wide range of terminal electron acceptors, including metals, oxidized ions of nitrogen, and sulfur.
This anaerobic respiration generally occurs in environments where oxygen is scarce
Wetland soil and the human digestive tract
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Anaerobic respiration is unique to prokaryotes. They usually possess alternative electron

Anaerobic respiration is unique to prokaryotes.
They usually possess alternative electron donors

and electron acceptors.

Electron Acceptors and Donors

Figure 14.18

FYI

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An important class of anaerobic respiration involves the reduction of metal

An important class of anaerobic respiration involves the reduction of metal

cations, or dissimilatory metal reduction.
In contrast to minerals reduced for the purpose of incorporation into cell components (assimilatory metal reduction)
The metals most commonly reduced through anaerobic respiration are:
Iron (Fe3+ → Fe2+)
Manganese (Mn4+ → Mn2+)

Dissimilatory Metal Reduction

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Dissimilatory Metal Reduction – 2 Anaerobic environments, such as the bottom

Dissimilatory Metal Reduction – 2

Anaerobic environments, such as the bottom of

a lake, offer a series of different electron acceptors.
As each successive terminal electron acceptor is used up, its reduced form appears; the next-best electron acceptor is then used, generally by a different microbe species.
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Chapter Summary Electron transport systems (ETS) consist of membrane-embedded proteins that

Chapter Summary

Electron transport systems (ETS) consist of membrane-embedded proteins that transfer

electrons from an initial electron donor to a TEA that leaves the cell.
The ETS complexes generate a proton motive force that can drive ATP synthesis and other cell functions.
Electron carriers contain metal ions and/or conjugated, double-bonded ring structures.
An ETS includes at least three functional components: - Substrate dehydrogenase, mobile electron carrier, and terminal oxidase
The F1Fo ATP synthase is a membrane-embedded protein complex. - Three protons drive each F1Fo cycle, synthesizing one molecule of ATP.
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BACTERIAL PATHOGENESIS Lecture 20 (Ch.25)

BACTERIAL PATHOGENESIS Lecture 20 (Ch.25)

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Chapter Overview Host-pathogen interactions How microbes attach to host cells How

Chapter Overview

Host-pathogen interactions
How microbes attach to host cells
How toxins subvert

host functions
How toxins and effectors are deployed
How pathogens survive within their hosts
Tools used to probe pathogenesis
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Introduction Mammals have elaborated physical, chemical, and immunological defenses that protect

Introduction

Mammals have elaborated physical, chemical, and immunological defenses that protect against

disease-causing microbes.
However, every fortress has its weakness.
Pathogenic microbes exploit those weaknesses, and the result is disease.
The fundamental question of microbial pathogenesis is this:
How an organism too small to be seen with the naked eye can kill a human a million times larger?
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The Language of Pathogenesis

The Language of Pathogenesis

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The Language of Pathogenesis – 1 By definition, a parasite is

The Language of Pathogenesis – 1

By definition, a parasite is an

organism that receives benefits at the expense of a host.
In practice, the term “parasite” refers to disease-causing protozoa and worms. Bacterial, viral, and fungal parasitic agents of disease are called pathogens.
Ectoparasites live on the surface of the host;
Endoparasites live inside the host’s body.
An infection occurs when a pathogen or parasite enters or begins to grow on a host. However, the term “infection” does not necessarily imply overt disease.
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The Language of Pathogenesis – 1 By definition, a parasite is

The Language of Pathogenesis – 1

By definition, a parasite is

an organism that receives benefits at the expense of a host.
In practice, the term “parasite” refers to disease-causing protozoa and worms. Bacterial, viral, and fungal parasitic agents of disease are called pathogens.
Ectoparasites live on the surface of the host;
Endoparasites live inside the host’s body.
An infection occurs when a pathogen or parasite enters or begins to grow on a host. However, the term “infection” does not necessarily imply overt disease.
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The Language of Pathogenesis – 3 Primary pathogens: cause disease in

The Language of Pathogenesis – 3

Primary pathogens: cause disease in healthy

hosts
For example: Shigella flexneri, the cause of bacillary dysentery
Opportunistic pathogens: cause disease only in compromised hosts or following entry into unprotected sites
For example: Pneumocystis jirovecii, the cause of life-threatening infections in AIDS patients
Some microbes even enter a latent state during infection, in which the infectious organism cannot be found by culture.
For example: herpesvirus, the cause of cold sores
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The Language of Pathogenesis – 2

The Language of Pathogenesis – 2

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The Language of Pathogenesis – 4 Pneumocytis jirovechi cysts in bronchoalveolar

The Language of Pathogenesis – 4

Pneumocytis jirovechi cysts in bronchoalveolar

materials
Cold sore produced by a reactivated herpesvirus hiding latent in nerve cells
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The Language of Pathogenesis – 5 Pathogenicity refers to an organism’s

The Language of Pathogenesis – 5

Pathogenicity refers to an organism’s

ability to cause disease. It is defined in terms of . . .
how easily an organism causes disease (infectivity)
how severe that disease is (virulence)
the specific genetic makeup of the pathogen
Virulence is a measure of the degree, or severity, of disease.
For example, Ebola is highly virulent, whereas rhinoviruses are not.
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The Language of Pathogenesis – 6 Virulence is measured by determining

The Language of Pathogenesis – 6

Virulence is measured by determining

the infectious dose (ID50, # required to cause infection, but not death, in 50% of hosts) and/or the lethal dose (LD50, # required to cause death in 50% of hosts).
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Immunopathogenesis It is often “friendly fire” by our immune system reacting

Immunopathogenesis

It is often “friendly fire” by our immune system reacting to

a pathogen that causes major tissue and organ damage.
The term immunopathogenesis applies when the immune response to a pathogen is a contributing cause of pathology and disease.
To fully understand any infectious disease, researchers must study both the pathogenic mechanisms of the pathogen and the disease symptoms caused by immunopathogenesis.
Ex. Lyme disease caused by the spirochete Borrelia burdorferi is associated with stimulates the production of strong inflammatory cytokines, including TNF alpha, IL-1
beta and IL-6.
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Infection Cycles

Infection Cycles

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Infection Cycles – 1 The infection cycle describes the route of

Infection Cycles – 1

The infection cycle describes the route of

transmission of an infectious organism.
Horizontal transmission: passage from one person or animal to another within the same generation
Can be direct (e.g., handshaking) or indirect (e.g., sharing contaminated objects)
Fomites: inanimate objects (e.g., doorknobs, hand towels, utensils)
Vehicles: ingested or inhaled materials (e.g., food, water, air)
Vertical transmission: passage from a mother to her fetus during pregnancy (transplacental) or birth (parturition)
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Infection Cycles – 3 Complex infection cycles often involve vectors as

Infection Cycles – 3

Complex infection cycles often involve vectors as intermediaries

(usually arthropods like mosquitoes, ticks, mites, or flies).
For example, a mosquito vector transfers the virus that causes yellow fever from infected to uninfected individuals.
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Infection Cycles – 4 A reservoir is an animal, bird, or

Infection Cycles – 4

A reservoir is an animal, bird, or arthropod

that normally harbors the pathogen, often without exhibiting disease.
In the case of yellow fever, the mosquito is not only the vector but the reservoir as well, because the insect can pass the virus to future generations of mosquitoes through vertical transmission.
The virus causing eastern equine encephalitis (EEE), however, uses birds as a reservoir.
Reservoirs are critically important for the survival of a pathogen and as a source of infection.
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Portals of Entry Infectious agents enter the body through one or

Portals of Entry

Infectious agents enter the body through one or more

portals of entry that are best suited to their mechanism of pathogenesis.
Mouth
Respiratory tract
Conjunctiva and mucous membranes
Wounds, injuries, and skin lesions
Parenteral route: direct injection into bloodstream (e.g., tick and mosquito bites, needle punctures)
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Effect of Infections on Microbiota A pathogen’s growth and the host’s

Effect of Infections on Microbiota

A pathogen’s growth and the host’s resulting

immune response also will affect the host’s normal microbiota.
Numerous mechanisms affect microbial competition and, ultimately, species diversity within the body.
Diarrhea reduces the overall numbers of gut microbiota.
Intestinal pathogens occupy host binding sites and alter available nutrients.
Inflammation can benefit pathogens more than normal microbiota.
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Bacteria can attach to surfaces in bulk, forming a biofilm. Biofilms

Bacteria can attach to surfaces in bulk, forming a biofilm.
Biofilms play

an important role in chronic infections by enabling persistent adherence and resistance to bacterial host defenses and antimicrobial agents.

Biofilms and Infections

Figure 25.15

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Virulence Factors

Virulence Factors

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To cause disease, all pathogens must . . . Enter a

To cause disease, all pathogens must . . .
Enter a host
Find

their unique niche
Avoid, circumvent, or subvert normal host defenses
Multiply
Transmit to a new susceptible host 
Pathogens employ virulence factors, encoded by virulence genes, to accomplish these goals.  Virulence factors include toxins, attachment proteins, capsules, and other devices.

Virulence Factors and How to Find Them – 1

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Virulence Factors and How to Find Them – 2 A suspected

Virulence Factors and How to Find Them – 2

A suspected virulence

gene can be confirmed as having a role in virulence or pathogenicity only if it fulfills a set of molecular Koch’s postulates.
The phenotype under study should be associated with pathogenic strains of a species.
Specific inactivation of the suspected virulence gene(s) should lead to a measurable loss in virulence or pathogenicity. The gene(s) should be isolated by molecular methods.
Reversion or replacement of the mutated gene should restore pathogenicity.
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Pathogenicity Islands – 1 Some virulence genes reside on plasmids or

Pathogenicity Islands – 1

Some virulence genes reside on plasmids or

in phage genomes.
Virulence genes in bacterial pathogens often are clustered into pathogenicity islands that encode virulence functions.
Most pathogenicity islands appear to have been horizontally transmitted via conjugation or transduction
Unique GC/AT ratio
Linkage to a tRNA gene
Association with genes homologous to phage/plasmid genes
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Pathogenicity Islands – 2

Pathogenicity Islands – 2

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Dangerous pathogens caught in the act of evolving include: Escherichia coli

Dangerous pathogens caught in the act of evolving include:
Escherichia coli O104:H4,

which caused a major European outbreak of hemolytic uremic syndrome
Streptococcus agalactiae and Staphylococcus aureus.
Streptococcus pyogenes (Group A Streptococcus)
Large-scale genome sequencing data have recently determined that epidemics are caused by clonal replacement events rather than by reemergence of preexisting clones.

Examples of Pathogen Evolution by Horizontal Gene Transfer – 1

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Examples of Pathogen Evolution by Horizontal Gene Transfer – 2

Examples of Pathogen Evolution by Horizontal Gene Transfer – 2

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Microbial Attachment

Microbial Attachment

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25.2 Microbial Attachment: First Contact – 1 The human body has

25.2 Microbial Attachment: First Contact – 1

The human body has many

ways to exclude pathogens. How do bacteria manage to stick around long enough to cause disease?
The first step toward infection is attachment, or adhesion.
Any microbial factor that promotes attachment is called an adhesin.
Viruses attach to host cells through their capsid or envelope proteins.
Bacteria use a variety of strategies, including pili (fimbriae) and other nonpilus proteins, to bind to specific host cell factors.
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Pili – 1 Many bacteria typically attach to specific host cells

Pili – 1

Many bacteria typically attach to specific host cells using

hairlike appendages called pili (fimbriae). [Note that fimbriae pili are not the same as conjugation, or sex pili used for gene transfer.]
Type I: adhere to carbohydrates on host membranes
Produce a static attachment to host cell
Grow from outer membrane of certain Gram-negative bacteria
Type IV: involved in “twitching motility”
Produce a dynamic attachment via assembly and disassembly
Grow from inner membrane of many Gram-negative bacteria
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Figure 25.12 Figure 25.13

Figure 25.12
Figure 25.13

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Nonpilus Adhesins – 3 Why are some people susceptible to certain

Nonpilus Adhesins – 3

Why are some people susceptible to certain infections,

whereas others are not?
Immunocompetence
Receptor availability
Pathogens rely on very specific surface structures (receptors) to recognize and attach to appropriate host cells.
Person-to-person differences in receptor structures are possible.
Example: HIV binds C-C chemokine receptor type 5 (CCR5); individuals with a CCR5 mutation are resistant to HIV infection!
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Bacteria also carry afimbriate adhesins that mediate binding to host tissues.

Bacteria also carry afimbriate adhesins that mediate binding to host tissues.

Nonpilus

Adhesins

Streptococcus pyogenes: M protein
Binds to fibronectin complement regulatory factor H
Bordetella pertussis: Pertactin
Binds to host cell integrin

Figure 25.14

A

B

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Microbial Toxins

Microbial Toxins

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25.3 Toxins Subvert Host Functions – 1 Bacterial toxins can be

25.3 Toxins Subvert Host Functions – 1

Bacterial toxins can be divided

into two main types.
1. Exotoxins
Proteins produced and secreted by various types of bacteria
Kill host cells and unlock their nutrients
2. Endotoxin
A part of lipopolysaccharide (LPS) of Gram-negative bacteria
Hyperactivate host immune systems to harmful levels
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Endotoxin (LPS) Is Made Only by Gram-Negative Bacteria – 2 Made

Endotoxin (LPS) Is Made Only by Gram-Negative Bacteria – 2

Made only

by Gram-negative bacteria
Present in lipopolysaccharide of outer membrane
Lipid A released as bacteria die
Causes massive cytokine release from host cells
Can trigger fever, shock, and death
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Categories of Microbial Exotoxins – 1 Microbial exotoxins fall into several

Categories of Microbial Exotoxins – 1

Microbial exotoxins fall into several

categories based on their mechanisms of action.

Plasma membrane disruption
Cytoskeleton alterations
Protein synthesis disruption
Cell cycle disruption
Signal transduction disruption
Cell-cell adherence
Vesicular traffic
Inhibit exocytosis
Superantigens

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Categories of Microbial Exotoxins – 2 Pore-forming toxins assemble in target

Categories of Microbial Exotoxins – 2

Pore-forming toxins assemble in target membranes

and cause leakage of compounds into and out of cells

Shiga toxin attaches to ganglioside Gb3, enters the cell, and cleaves 28SrRNA in eukaryotic ribosomes to stop translation

Enterotoxigenic E. coli heat-stable toxin affects cGNP production.The results is altered electrolyte transport: inhibition of Na+ uptake and stimulation of Cl- transport in response to the resulting electrolyte imbalance, water leaves the cell

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Membrane Disruption – 1 Some exotoxins disrupt host cell membranes by

Membrane Disruption – 1

Some exotoxins disrupt host cell membranes by forming

pores that cause leakage of cell constituents (host cell lysis).
Hemolysins lyse red blood cells (and sometimes other cells).
Leukocidins lyse white blood cells (leukocytes).
Some membrane-disrupting exotoxins function as both hemolysins and leukocidins.
Streptolysin S of Streptococcus pyogenes
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Membrane Disruption – 2 Two types of exotoxins disrupt host cell

Membrane Disruption – 2

Two types of exotoxins disrupt host cell membranes.
Pore-forming

proteins insert themselves into membranes by binding cholesterol and membrane receptors
Alpha toxin of Staphylococcus aureus
Panton-Valentine toxin of MRSA (see Special Topic 25.1)
Listeriolysin O of Listeria monocytogenes
Phospholipase enzymes hydrolyze phospholipids into fatty acids
Phospholipase C of Clostridium perfringens
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Microbial exotoxins fall into nine categories based on their mechanisms of

Microbial exotoxins fall into nine categories based on their mechanisms of

action:
Plasma membrane disruption
Cytoskeleton alterations
Protein synthesis disruption
Cell cycle disruption
Signal transduction disruption
Cell-cell adherence
Vesicle traffic
Exocytosis
Superantigens

Microbial Exotoxins

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25.5 Deploying Toxins and Effectors Many protein secretory systems evolved from,

25.5 Deploying Toxins and Effectors

Many protein secretory systems evolved from, and

bear structural resemblance to, other cellular structures that serve fundamental cellular functions.
The molecular processes that are evolutionarily related to secretion include:
Type IV pilus biogenesis (homologous to type II protein secretion)
Flagellar synthesis (homologous to type III protein secretion)
Conjugation (homologous to type IV protein secretion)
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Figure 25.16 Pore-forming toxins assemble in target membranes and cause leakage

Figure 25.16

Pore-forming toxins assemble in target membranes and cause leakage of

compounds into and out of cells

Shiga toxin attaches to ganglioside Gb3, enters the cell, and cleaves 28S rRNA in eukaryotic ribosomes to stop translation.

Enterotoxigenic Escherichia coli heat-stable toxin affects cGMP production. The result is altered electrolyte transport—inhibition of Na+ uptake and stimulation of Cl– transport. In response to the resulting electrolyte imbalance, water leaves the cell.

Microbial Exotoxins

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Membrane Disruption – 3 3D image of the pore complex, comprising

Membrane Disruption – 3

3D image of the pore complex, comprising 7

monomeric proteins.

Cross section showing the channel. Arrows indicate movement of fluids through the spore.

Blood agar plate inoculated with S aureus. The alpha toxin is secreted by the organism and diffuses away from the producing colony. It forms pores in the RBCs embedded in the agar, causing the cells to lyse, thus causing he clear area visible around each colony.

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Two-Subunit AB Exotoxins – 1 AB exotoxins consist of two subunits,

Two-Subunit AB Exotoxins – 1

AB exotoxins consist of two subunits, usually

called A and B, that work together to disrupt host cell functions.
“A” subunit: toxicity-associated factor
“B” subunit: binds host cell, delivers “A” subunit
AB5 exotoxins consist of five “B” subunits arranged in a ring with a single “A” subunit nestled in the center.
One major subclass of AB exotoxins includes an “A” subunit that has ADP-ribosyltransferase enzymatic activity
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Two-Subunit AB Exotoxins – 2 Typical AB toxin consists of an

Two-Subunit AB Exotoxins – 2

Typical AB toxin consists of an A

subunit and a pentameric B subunit joined noncovalently

Many AB toxins are ADP-ribosyltransferase enzymes that modify proteins structure and function

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Two-Subunit AB Exotoxins – 3 Cholera toxin is an AB5 exotoxin

Two-Subunit AB Exotoxins – 3

Cholera toxin is an AB5 exotoxin made

by Vibrio cholerae that disrupts the signaling functions of host cells.
The “B” subunits bind to intestinal cell membranes and trigger endocytosis of cholera toxin complex.
The “A” subunit ADP-ribosylates a host cell target that leads to a sharp increase in cAMP levels.
cAMP activates ion transporters that ultimately cause water to leave the cell, leading to watery stools (diarrhea).
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Two-Subunit AB Exotoxins – 4 Vibrio cholerae (SEM). Note the slight

Two-Subunit AB Exotoxins – 4

Vibrio cholerae (SEM). Note the slight curve

of the cell and the presence of a single polar flagellum

Brush border of intestine (TEM) V. cholerae binds to the fingerlike villi on the apical surface

V. cholerae, binding to the surface of a host cell (SEM). Note that V. cholerae does not invade the host cells

3D structure of cholera toxin, binding ganglioside GM1 on the intestinal cell surface

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Anthrax Toxin Made by Bacillus anthracis Two active toxins: Edema factor

Anthrax Toxin

Made by Bacillus anthracis
Two active toxins:
Edema factor (EF) raises

cAMP levels.
Causes fluid secretion, tissue swelling
Lethal factor (LF) cleaves protein kinases
Blocks immune system from attacking
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25.4 Deploying Toxins and Effectors – 1 Many protein secretory systems

25.4 Deploying Toxins and Effectors – 1

Many protein secretory systems evolved

from, and bear structural resemblance to, other cell structures that serve fundamental cell functions.
We will look at several secretion systems and the molecular processes with which they share an evolutionary history.
Type II secretion: homologous to type IV pilus biogenesis
Type III secretion: homologous to flagellar synthesis
Type IV secretion: homologous to conjugation
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Secretion Systems for Bacterial Toxins

Secretion Systems for Bacterial Toxins

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Type III Secretion Is an Injection Machine – 1 The type

Type III Secretion Is an Injection Machine – 1

The type III

secretion system (T3SS) is a reengineered flagellar synthesis mechanism that uses a molecular syringe to inject proteins from the bacterial cytoplasm directly into the host cell.
Secretion is normally triggered by cell-cell contact between host and bacterium.
T3SS genes usually are located within pathogenicity islands inherited via horizontal gene transfer.
Found in Salmonella, Yersinia, Shigella, and Escherichia species.
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Type II Secretion Resembles Type IV Pilus Assembly The type II

Type II Secretion Resembles Type IV Pilus Assembly

The type II secretion

system (T2SS) is a modification of the same system used for type I pilus biogenesis.
Secretion structures extend and retract, just like pili.
Proteins to be secreted first enter the periplasm, then they get folded and secreted via an outer membrane pore.
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Similar to Type IV pilus Modified for secreting proteins Can extend

Similar to Type IV pilus
Modified for secreting proteins
Can extend and

retract
Proteins to be secreted first make their way to the periplasm
Are then folded before secretion

Type II Secretion

Figure 25.24

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Type III Secretion Is an Injection Machine – 1 The type

Type III Secretion Is an Injection Machine – 1

The type III

secretion system (T3SS) is a reengineered flagellar synthesis mechanism that uses a molecular syringe to inject proteins from the bacterial cytoplasm directly into the host cell.
Secretion is normally triggered by cell-cell contact between host and bacterium.
T3SS genes usually are located within pathogenicity islands inherited via horizontal gene transfer.
Found in Salmonella, Yersinia, Shigella, and Escherichia species.
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Type III Secretion Is an Injection Machine – 2 The type

Type III Secretion Is an Injection Machine – 2

The type III

secretion complex from Salmonella enterica serovar Typhimurium type III injectisome. Unlike other secretion systems, the type III mechanism injects proteins directly from the bacterial cytoplasm into the host cytoplasm. The proteins in these systems are related to flagellar assembly proteins.
A. Purified needle complexes (TEM)
from S. Typhimurium.
B. Schematic representation of the S. Typhimurium needle complex and its putative components

C. Shigella invades a host cell ruffle produced as a result of its type III secretion system. Shigella flexneri (approx. 2 μm) entering the HeLa cell ruffle (SEM) formed by host actin rearrangements. (Hela cells are immortal cancer cell line). The ruffle engulfs the bacterium and eventually disassembles, internalizing the bacterium.

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Type III Secretion Is an Injection Machine – 4 Some microbes

Type III Secretion Is an Injection Machine – 4

Some microbes do

not rely solely on the natural array of host receptors for attachment.
Instead, these bacterial pathogens use a T3SS to insert their own receptors into target cells.
Bacteria inject Tir proteins into the host cell. These proteins act as receptors for the outer membrane protein intimin. Intimin binds to Tir to establish a strong attachment.
Used by enteropathogenic E. coli (EPEC) and enterohemor-rhagic E. coli (EHEC).
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Type III Secretion Is an Injection Machine – 5 A. Model

Type III Secretion Is an Injection Machine – 5

A. Model of

entropathogenic E. coli (EPEC) attachment and pedestal formation on intestinal cells. (1) EPEC attaches first, using type I pili. (2) Bound EPEC uses a T3SS to inject Tir protein into the host membrane and acts as a receptor for the EPEC surface intimin. (3) Tir also communicates through phosphorylation with other host factors that control actin filamentation and cytoskeleton formation. Actin polymerization raises the host membrane to produce a pedestal upon which EPEC sits. B. Pedestal formation (colorized SEM).
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Some microbes do not rely solely on the natural array of

Some microbes do not rely solely on the natural array of

host receptors for attachment.
Instead, these bacterial pathogens use a type III secretion system (T3SS) to insert their own receptors into target cells.
One such group of enterprising pathogens is enteropathogenic Escherichia coli (EPEC).

Figure 25.27

Type III Secretion System

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Type IV Secretion Resembles Conjugation Systems The type IV secretion system

Type IV Secretion Resembles Conjugation Systems

The type IV secretion system (T4SS)

is an evolutionary modification of a conjugation pilus that secretes proteins only, or proteins plus DNA.
The T4SS allows bacterial pathogens to secrete proteins directly from their cytoplasms or from their periplasms.
Found in Agrobacterium tumefaciens and Bordetella pertussis
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Use a molecular syringe to inject proteins from the bacterial cytoplasm

Use a molecular syringe to inject proteins from the bacterial cytoplasm

directly into host cell
Similar to flagellum
Genes usually located on pathogenicity island
Found in Salmonella, Yersinia, and Shigella

Type III Secretion

Figure 25.25

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Similar to conjugation pilus Modified to secrete proteins only, or proteins

Similar to conjugation pilus
Modified to secrete proteins only, or proteins plus

DNA
Can secrete proteins from cytoplasm or periplasm
Found in Agrobacterium tumefaciens and Bordetella pertussis

Type IV Secretion

Figure 25.29

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Various sensing systems act in concert to recognize any specific environmental

Various sensing systems act in concert to recognize any specific environmental

niche.
Two-component signal transduction systems
Detect magnesium concentration, pH
Both low in host cell vacuole
Detects exotoxins made by other cells
Delays toxin synthesis until many bacteria present
Possible pathway for preventing pathogen growth?

Where Am I?

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Cell ingests pathogens in phagosome. Some pathogens use hemolysin to break

Cell ingests pathogens in phagosome.
Some pathogens use hemolysin to break out.
Shigella

dysenteriae, Listeria monocytogenes
Phagosome fuses with acidic lysosome.
Some pathogens secrete proteins to prevent fusion.
Salmonella, Chlamydia, Mycobacterium, Legionella
Some pathogens mature in acidic environment.
Coxiella burnetii: causes Q fever

Intracellular Pathogens

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Chapter Summary A pathogen is any microbial agent of disease. Primary

Chapter Summary

A pathogen is any microbial agent of disease.
Primary pathogens cause

disease in normal hosts.
Opportunistic pathogens need immunocompromised host.
Infection cycles can be direct or indirect.
Virulence factors may be encoded by gene clusters on pathogenicity islands.
Acquired by horizontal transmission
Adhesins mediate bacterial attachment to host cells.
Type I pili: static attachment
Type IV pili: continually assembled and disassembled
Afrimbrial adhesins: pertactin and M protein
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CHAPTER 26 MICROBIAL DISEASES

CHAPTER 26

MICROBIAL DISEASES

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Chapter Overview Skin and soft-tissue infections Respiratory tract infections Gastrointestinal tract

Chapter Overview

Skin and soft-tissue infections
Respiratory tract infections
Gastrointestinal tract infections
Genitourinary tract infections
Cardiovascular

system infections
Central nervous system infections
Systemic infections
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Introduction Microbial diseases are with us daily and are major contributors

Introduction

Microbial diseases are with us daily and are major contributors to

global mortality.
The need for investigations into microbial disease mechanisms and the body’s ability to combat infectious agents have been heightened by:
The emergence of new pathogens, increasing drug resistance, and threats of bioterrorism
In addition, effective diagnostic algorithms are needed to quickly identify infectious diseases and prevent their spread.
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Characterizing and Diagnosing Microbial Diseases Microbial diseases may be classified based

Characterizing and Diagnosing Microbial Diseases

Microbial diseases may be classified based on

several criteria:
By organism
By organ system (used in this chapter)
By portal of entry
Each approach has clear benefits and pitfalls.
Pathogens can be divided into four main groups based on their route of infection:
Food-borne, airborne, blood-borne, and sexually transmitted
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Zoonotic Diseases Francisella tularensis Diarrheal disease of the travellers Tularemia Coxiella burnetii Q fever

Zoonotic Diseases

Francisella tularensis
Diarrheal disease of the travellers
Tularemia
Coxiella burnetii
Q

fever
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Many infectious diseases display similar symptoms, making diagnosis difficult. Thus, knowledge

Many infectious diseases display similar symptoms, making diagnosis difficult.
Thus, knowledge of

a patient’s history is vital:
Travel information: diarrheal diseases
Hobbies: hunters and tularemia (Francisella tularensis)
Occupation: farmers and Q fever (Coxiella burnetii)
Both tularemia and Q fever are zoonotic diseases.

Figure 26.1

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Skin and Soft-Tissue Infections Staphylococcus aureus Streptococcus pyogenes, also called Group

Skin and Soft-Tissue Infections

Staphylococcus aureus
Streptococcus pyogenes, also called Group A Streptococcus

(GAS)
Lancefield groups
Lancefield grouping is a serological method for classifying streptococci into one of 20 groups (designated by a letter) based on the presence of polysaccharide and teichoic acid antigens in the bacterial cell wall (Lancefield 1933). The technique is now performed using commercial latex agglutination test kits, which allow rapid detection of clinically important streptococcal groups. Some streptococci, for example S. pneumoniae, have not been assigned to a group because their antigen extracts fail to react with group antisera. With the exception of S. pneumoniae all the equine streptococci belong to Lancefield group C.
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Lancefield groups Lancefield grouping is a serological method for classifying streptococci

Lancefield groups

Lancefield grouping is a serological method for classifying streptococci into one of 20 groups

(designated by a letter) based on the presence of polysaccharide and teichoic acid antigens in the bacterial cell wall (Lancefield 1933).
The technique is now performed using commercial latex agglutination test kits, which allow rapid detection of clinically important streptococcal groups.
Some streptococci, for example S. pneumoniae, have not been assigned to a group because their antigen extracts fail to react with group antisera. With the exception of S. pneumoniae all the equine streptococci belong to Lancefield group C.
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Skin and soft-tissue infections Skin and soft-tissue infections Staphylococcus aureus Streptococcus pyogenes Beta hemolytic

Skin and soft-tissue infections

Skin and soft-tissue infections
Staphylococcus aureus Streptococcus pyogenes

Beta hemolytic

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26.2 Skin and Soft-Tissue Infections Staphylococcus aureus Boils: walled off from

26.2 Skin and Soft-Tissue Infections

Staphylococcus aureus
Boils: walled off from body with

fibrin
Can produce toxic shock superantigen
MRSA: methicillin-resistant S. aureus
Major cause of nosocomial infections (in hospitals)
Some strains make exfoliative toxin (scalded skin syndrome)

Figure 26.2

Boils

Scalded skin

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Streptococcus pyogenes Best known for causing sore throats and immunological sequelae,

Streptococcus pyogenes
Best known for causing sore throats and immunological sequelae, such

as rheumatic fever
Also necrotizing fasciitis (“flesh-eating” disease)
And a less aggressive but similar skin infection called cellulitis
Many virulence factors are encoded by prophages

Figure 26.3

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S. pyogenes Necrotizing fasciitis can spread so rapidly that patients often

S. pyogenes

Necrotizing fasciitis can spread so rapidly that patients often must

get surgery done very quickly. Antibiotics are given through a needle into a vein (IV antibiotics) to try to stop the infection. When the bacteria have killed too much tissue and reduced blood flow, multiple surgeries are necessary.

Impetigo is a common and highly contagious skin infection that mainly affects infants and children. Impetigo usually appears as red sores on the face, especially around a child's nose and mouth, and on hands and feet. The sores burst and develop honey-colored crusts.

Cellulitis is a common, potentially serious bacterial skin infection. The affected skin appears swollen and red and is typically painful and warm to the touch.
Cellulitis usually affects the skin on the lower legs, but it can occur in the face, arms and other areas.

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Respiratory Tract Infection Bordetella pertussis Steptococcus pneumoniae Mycobacterium tuberculosis Pneumocystis Jirovecci

Respiratory Tract Infection

Bordetella pertussis
Steptococcus pneumoniae
Mycobacterium tuberculosis
Pneumocystis Jirovecci

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26.3 Respiratory Tract Infections The mucociliary escalator is primary respiratory defense.

26.3 Respiratory Tract Infections

The mucociliary escalator is primary respiratory defense.
Bordetella pertussis

(cause of whooping cough) inhibits it by binding to lung cilia.
https://www.youtube.com/watch?v=HMdrhwEnY6M Introduction to Mucociliary Transport Video Microscopy
Pneumonia is a disease, not a specific infection.
Caused by many different microbes
Streptococcus pneumoniae is the main bacterium:
Has capsule that prevents phagocytosis
Can invade the bloodstream (bacteremia) and the covering of the brain (meningitis)
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Figure 26.5 A B C Pneumonia caused by S. pneumoniae

Figure 26.5

A

B

C

Pneumonia caused by S. pneumoniae

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Mycobacterium tuberculosis An acid-fast bacillus An ancient and reemerging pathogen Forms

Mycobacterium tuberculosis
An acid-fast bacillus
An ancient and reemerging pathogen
Forms calcified tubercles

in the lung
Can disseminate through the bloodstream

Figure 26.7

Has high mortality rate due to multidrug-resistant strains and high susceptibility of HIV patients

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Gastrointestinal Tract Infection Salmonella enterica serovar Thyphimurium Campylobacter enteritis Campilobacter jejuni

Gastrointestinal Tract Infection

Salmonella enterica serovar Thyphimurium
Campylobacter enteritis
Campilobacter jejuni
Shigella dysenteriae
Vibrio cholerae
Helicbacter pylori
Enteroinvasive

E. coli (EIEC)
Other E. coli remain outside epithelial cells:
EHEC, ETEC, EAEC, and E coli 057:H7
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Gastrointestinal Tract Infections The main symptoms of gastroenteritis are watery diarrhea

Gastrointestinal Tract Infections
The main symptoms of gastroenteritis are watery diarrhea and

vomiting. The most frequent causes of self-limiting diarrheal disease include
Salmonella enterica serovar Typhimurium and
Bacteria of the genus Campylobacter, such as C. enteritis is common cause of intestinal infection
A more severe form of gastroenteritis is called dysentery (diarrhea with passage of blood or mucus)
Bacterial dysentery: Shigella species, including S. dysenteriae
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Remarkably, Staphylococcus aureus causes gastrointestinal disease without ever producing infection. Some

Remarkably, Staphylococcus aureus causes gastrointestinal disease without ever producing infection.
Some strains

can secrete enterotoxins into tainted foods such as pies, turkey dressing, or potato salad, causing food poisoning
The most important treatment for diarrhea is rehydration therapy
Antibiotics are often inappropriate when treating diarrhea
Ineffective against viruses; bacterial gastroenteritis resolves spontaneously
In some cases, antibiotic treatment can actually trigger gastrointestinal disease.
Example: clindamycin can kill competing bacteria, thus allowing Clostridium difficile to thrive
Causes pseudomembranous enterocolitis
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Pseudomembranous colitis refers to swelling or inflammation of the large intestine

Pseudomembranous colitis refers to swelling or inflammation of the large intestine

(colon) due to an overgrowth of Clostridium difficile (C. difficile) bacteria. This infection is a common cause of diarrhea after antibiotic use.
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Enterobacterial toxin-producing strains Inject toxin via type III secretion Bacteria invade

Enterobacterial toxin-producing strains

Inject toxin via type III secretion
Bacteria invade

epithelial mucosa.
Salmonella
Shigella, enteroinvasive Escherichia coli (EIEC)
Produce Shiga toxin
Blocks host protein synthesis, damages endothelia
Capillary damage, loss of blood, clots
Bacteria remaining outside epithelial cells
E. coli: EHEC (O157:H7), ETEC, EAEC
Entero-hemorrhagic, -toxigenic, -aggregative
O157 = serotype of LPS; H7 = serotype of flagella
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Other bacterial agents of gastrointestinal disease Campylobacter jejuni Most frequent bacterial

Other bacterial agents of gastrointestinal disease
Campylobacter jejuni
Most frequent bacterial cause of

diarrhea
Vibrio cholerae: cholera
Helicobacter pylori: gastric ulcers

Secretes urease: urea → NH4+
Neutralizes stomach acid
Burrows into protective mucous layer
Associated with gastric cancer

Figure 26.8

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Genitourinary tract infections Uropathogenic E. coli (UPEC)

Genitourinary tract infections

Uropathogenic E. coli (UPEC)

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26.5 Genitourinary Tract Infections The urinary tract includes the kidneys, ureters,

26.5 Genitourinary Tract Infections

The urinary tract includes the kidneys, ureters, urinary

bladder, and urethra.
Active infection of the urinary tract occurs in one of three basic ways:
Infection from the urethra to the bladder
Descending infection from the kidneys
Ascending infection to the kidney
Most UTIs are caused by Gram-negative rods from the GI tract.
Only 5% are caused by Gram-positive bacteria and fungi.
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The urinary system

The urinary system

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Uropathogenic strains of Escherichia coli (UPEC) Cause about 75% of UTIs

Uropathogenic strains of Escherichia coli (UPEC)
Cause about 75% of UTIs
Invade

the bladder up from the urethra
Have P-type pili, with a terminal receptor for the P antigen
Have five unique pathogenicity islands

Figure 26.10

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Sexually Transmitted Diseases Syphilis by Treponema pallidum Chlamydia trachomatis Chlamydia pneumoniae

Sexually Transmitted Diseases

Syphilis by Treponema pallidum
Chlamydia trachomatis
Chlamydia pneumoniae

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Sexually Transmitted Diseases Syphilis Caused by the spirochete Treponema pallidum Primary

Sexually Transmitted Diseases

Syphilis
Caused by the spirochete Treponema pallidum
Primary syphilis: chancre at

site of infection
Secondary syphilis: generalized rash
Tertiary syphilis: effects on heart and CNS

Figure 26.11

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Chlamydia Most frequently reported STD in the United States Caused by

Chlamydia
Most frequently reported STD in the United States
Caused by unusual Gram-negative

bacteria
Chlamydia trachomatis
Chlamydia pneumoniae
Obligate intracellular pathogens
Both cause STDs, as well as pneumonia and trachoma of the eye
Left untreated, infection can cause serious health problems in both females and males
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Trachoma Trachoma is a bacterial infection that affects the eyes. It

Trachoma

Trachoma is a bacterial infection that affects the eyes. It is

caused by the bacterium Chlamydia trachomatis. Trachoma is contagious, spreading through contact with the eyes, eyelids, and nose or throat secretions of infected people. It can also be passed on by handling infected items, such as handkerchiefs.
At first, trachoma may cause mild itching and irritation of your eyes and eyelids. Then you may notice swollen eyelids and pus draining from the eyes. Untreated trachoma can lead to blindness.
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Figure 26.12 Elementary bodies are the infective form. They enter eukaryotic

Figure 26.12

Elementary bodies are the infective form. They enter eukaryotic cells

by endocytosis or phagocytosis
They differentiate into reticulate bodies, which are the replicative form.
The reticulate bodies differentiate into elemental bodies that are released
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Gonorrhea Caused by the Gram-negative diplococcus Neisseria gonorrhoeae Over the decades,

Gonorrhea
Caused by the Gram-negative diplococcus Neisseria gonorrhoeae
Over the decades, it has

incrementally developed resistance to antibiotics used in its treatment
Most infected men exhibit symptoms, whereas most women are asymptomatic.
Binds to CD4+ T cells, inhibiting T-cell activation

Figure 26.13

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Central Nervous System Infections Meningitis Infection of membrane surrounding brain Some

Central Nervous System Infections

Meningitis
Infection of membrane surrounding brain
Some bacteria cross blood-brain

barrier
Streptococcus pneumoniae
Haemophilus influenzae
Neisseria meningitidis
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Neisseria meningitidis Has thick capsule and type IV pili Dangerous if

Neisseria meningitidis
Has thick capsule and type IV pili
Dangerous if it gets

into the bloodstream
Crosses from capillary into cerebrospinal fluid
Once in meninges, it is very difficult to treat
Effective vaccine to capsule components

Figure 26.16

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Clostridium toxins C. botulinum: botulism toxin (“Botox”) Anaerobe, grows in canned

Clostridium toxins
C. botulinum: botulism toxin (“Botox”)
Anaerobe, grows in canned food
Spores survive

unless autoclaved
Toxin blocks the release of acetylcholine
Causes flaccid paralysis
C. tetani: tetanus toxin
Anaerobe, grows in puncture wounds
Blood flow interrupted; tissue becomes anaerobic
Toxin blocks release of GABA, a primary inhibitory transmitter for the central nervous system. Its function is to reduce neuronal excitability
By inhibiting nerve transmission
Causes spastic paralysis
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Cardiovascular Diseases Infections of the cardiovascular system include: Endocarditis: inflammation of

Cardiovascular Diseases

Infections of the cardiovascular system include:
Endocarditis: inflammation of the heart’s

inner lining
Septicemia: presence of microbes in the blood
Bacteremia: presence of bacteria in the blood
Can develop from a local infection situated anywhere in the body
Caused by Gram-positives, Gram-negatives, aerobes, and anaerobes
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Bacterial Endocarditis Bacterial causes are usually viridans streptococci from the oral

Bacterial Endocarditis
Bacterial causes are usually viridans streptococci from the oral microbiota:

Streptococcus mutans
Enters the bloodstream following a dental procedure

Grows on damaged heart valves
Forms biofilm
Difficult to treat

Figure 26.21

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Systemic Infections Septicemia disseminating throughout body Plague Caused by the bacterium

Systemic Infections

Septicemia disseminating throughout body
Plague
Caused by the bacterium Yersinia pestis
Bite of

flea introduces organism
Moves to lymph nodes: bubonic plague
Moves to bloodstream: septicemic plague
Inhaled: pneumonic plague
Highly infectious
Virulence factors inhibit phagocytosis
Type III secretion system injects virulence proteins
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Zoonotic disease A zoonosis is another name for zoonotic disease. This

Zoonotic disease

A zoonosis is another name for zoonotic disease. This type

of disease passes from an animal or insect to a human. Some don’t make the animal sick but will sicken a human.
Zoonotic diseases range from minor short-term
illness to a major life-changing illness. Certain
ones can even cause death.
Zoonosis include those caused by a virus, bacteria, fungus, and parasites.
Zoonotic diseases spread by mosquitos and ticks are some of the most serious of these diseases
(Healthline)
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Lyme disease Caused by Borrelia burgdorferi, a spirochete Transmitted by ticks

Lyme disease
Caused by Borrelia burgdorferi, a spirochete
Transmitted by ticks
Bacterium can travel

to any part of the body
Has three stages:
Stage 1: a bull’s-eye rash (erythema migrans)
Stage 2: joint, muscle, and nerve pain
Stage 3: arthritis, with WBCs in the joint fluid
Treatment with antibiotics is recommended for all stages
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Figure 26.25

Figure 26.25

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Immunization Vaccines are typically given in childhood Most are administered as

Immunization

Vaccines are typically given in childhood
Most are administered as multiple booster

doses
Except influenza: new vaccine every year
Serious side effects are very rare
Herd immunity
Vaccinating a large percentage of a community effectively conveys herd immunity by interrupting transmission of contagious diseases
Example: gardasil—human papillomavirus vaccine
Only works for diseases spread person to person
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Chapter Summary Pathogens can be classified as food-borne, airborne, blood-borne, or

Chapter Summary

Pathogens can be classified as food-borne, airborne, blood-borne, or sexually-transmitted.


Patients histories are vital in diagnosing diseases.
Skin and soft-tissue infections include: - Boils; scalded skin syndrome (Staphylococcus aureus) - Necrotizing fasciitis (Streptococcus pyogenes) - Measles: rubella and rubeola (viral infections)
Respiratory tract infections include pneumonia (caused by a variety of organisms) and tuberculosis.
The main causes of GI tract infections include: - Bacteria: EHEC, Salmonella, Shigella, H. pylori - Protozoa: Entamoeba, Cryptosporidium, Giardia - Viruses: rotavirus (single greatest cause of gastroenteritis)
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Chapter Summary The main cause of UTIs is uropathogenic Escherichia coli

Chapter Summary
The main cause of UTIs is uropathogenic Escherichia coli (UPEC)
Sexually

transmitted diseases include: - Syphilis, gonorrhea; chlamydia (bacterial diseases) - Trichomoniasis (protozoan disease), AIDS (viral disease)
Pathogens that cause CNS infections include: - Neisseria meningitidis (meningitis), Clostridium botulinum toxin (flaccid paralysis), C. tetanus toxin (spastic paralysis)
Cardiovascular system infections include:
- Septicemia, endocarditis, malaria
Pathogens that cause systemic infections include: - Yersinia pestis (plague), Borrelia burgdorferi (Lyme disease)
Herd immunity can protect unimmunized people.
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Viral diseases Paramyxovirus Herpes virus Togavirus Influenza virus and rhinovirus Rotavirus

Viral diseases

Paramyxovirus
Herpes virus
Togavirus
Influenza virus and rhinovirus
Rotavirus
Hepatitis virus
Human immunodeficiency virus

FYI

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Viral Diseases Causing Skin Rashes Viruses cause a maculopapular skin rash.

Viral Diseases Causing Skin Rashes

Viruses cause a maculopapular skin rash.
Usually infect

through respiratory tract
Paramyxovirus: rubeola (“measles”)
Herpes virus: chickenpox, shingles
Togavirus: rubella (“German measles”)

Figure 26.4

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Viral Diseases of the Lung Numerous viruses can cause lung infections

Viral Diseases of the Lung

Numerous viruses can cause lung infections
Influenza virus

and rhinovirus
SARS (severe acute respiratory syndrome)
Respiratory syncytial virus (RSV)
A negative-sense, single-stranded RNA, enveloped virus
The most common cause of pneumonia among infants and children under 1 year of age
Remains localized in the lung
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Gastroenteritis caused by viruses Rotavirus is the single greatest cause of

Gastroenteritis caused by viruses
Rotavirus is the single greatest cause of gastroenteritis
Double-stranded

RNA viruses
Highly infectious, spreading by the fecal-oral route
Endemic around the globe; affects all age groups
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Hepatitis Viruses Hepatitis is a term meaning inflammation of the liver.

Hepatitis Viruses

Hepatitis is a term meaning inflammation of the liver.
Caused by

several blood-borne viruses, including:
HAV: hepatitis A—picornavirus (ssRNA)
HBV: hepatitis B—hepadnavirus (dsDNA)
HCV: hepatitis C—flavivirus (ssRNA)

Figure 26.26

Viral infections
Adenovirus
Enteroviruses

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Viral endocarditis Association between enterovirus endomyocardial infection and late severe cardiac

Viral endocarditis

Association between enterovirus endomyocardial infection and late severe cardiac events

in some adult patients receiving heart transplants.
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Figure 26.14 ACQUIRED IMMUNODEFICIENCY SYNDROME (AIDS) Human Immunodeficiency Virus

Figure 26.14

ACQUIRED IMMUNODEFICIENCY SYNDROME (AIDS)

Human Immunodeficiency Virus

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Acquired immunodeficiency syndrome HIV: a lentiviral retrovirus Attacks CD4+ T cells,

Acquired immunodeficiency syndrome
HIV: a lentiviral retrovirus
Attacks CD4+ T cells, glial cells
First

stage: AIDS-related complex
Fever, headache, rash
Second stage: AIDS
Depletion of T cells
Opportunistic infections
Oral candidiasis
Pneumocystosis
Third stage: AIDS-related dementia
Fourth stage: rare cancers
Kaposi’s sarcoma via herpes virus type 8
infection
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Fungal Diseases Most fungi are not dangerous: Mild fungal skin diseases

Fungal Diseases

Most fungi are not dangerous: Mild fungal skin diseases can

look like a rash and are very common. Ex. Trichophyton rubrum (ectopathogen) causes Athtete’s foot.
Fungal diseases in the lungs are often similar to other illnesses such as the flu or tuberculosis.
Blastomyces dermatitidis can cause skin, and bone lesions, and metastatic or disseminating lesions in the lung, causing acute pneumonia
Some fungal diseases like fungal meningitis and bloodstream infections are less common than skin and lung infections but can be deadly. It can be caused by Candida albicans, Cryptococcus neoformans and Histoplasma.
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Blastomyces dermatitidis Dimorphic fungus found in the soil Infection usually associated

Blastomyces dermatitidis
Dimorphic fungus found in the soil
Infection usually associated with

occupational and recreational activities
Does not usually cause an increase in WBCs
Can cause metastatic lesions

Figure 26.6

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Pathogenic Monocellular Eukaryotes Amoeba Entamoeba Cryptosporidium Naegleria Acanthamoba Giarda lamblia Trichomonas

Pathogenic Monocellular Eukaryotes

Amoeba
Entamoeba
Cryptosporidium
Naegleria
Acanthamoba
Giarda lamblia
Trichomonas

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Pathogenic Ameba Unicellular eukaryotic organism Entamoeba histolytica causes amebic dysentery Which

Pathogenic Ameba

Unicellular eukaryotic organism
Entamoeba histolytica causes amebic dysentery
Which is a more

severe form of gastroenteritis,
e.g. diarrhea with passage of blood or mucus.
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Entamoeba Cryptosporidium Naegleria Acanthamoeba Giardia lamblia attaches to the intestinal wall Figure 26.9 Protozoal infections

Entamoeba
Cryptosporidium
Naegleria
Acanthamoeba
Giardia lamblia attaches to the intestinal wall

Figure 26.9

Protozoal infections

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Trichomoniasis ~ 2–3 million infections per year in the United States

Trichomoniasis
~ 2–3 million infections per year in the United States
Caused by

Trichomonas vaginalis, a flagellated protozoan
No cyst; transmitted via trophozoite stage

Reservoirs are the male urethra and female vagina
Feeds on bacteria in the vagina
pH increases
Treated with metronidazole

Figure
26.15

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Figure 26.23

Figure 26.23

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Prions Proteinaceous infectious particles Cause spongiform encephalopathies Improperly folded proteins form

Prions

Proteinaceous infectious particles
Cause spongiform encephalopathies
Improperly folded proteins form aggregates that damage

the brain
Most mammals suffer from these diseases

Figure 26.20

A

B

C

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Malaria Causes 1–3 million deaths per year. Four protozoan Plasmodium species:

Malaria

Causes 1–3 million deaths per year.
Four protozoan Plasmodium species: P. falciparum,

P. malariae, P. vivax, and P. ovale.

P. falciparum is the most deadly of all.
Infects liver, red blood cells (RBCs).
New merozoites are released every 48–72 hours.
Many parasites are killed in each generation.
Others switch protein placed on RBC surface.
60 var genes encode different surface proteins; thus parasite constantly eludes immune system.
Chloroquine resistance is a problem.

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Antimicrobial Chemotherapy and Discovery Lecture 22 (Ch. 27)

Antimicrobial Chemotherapy
and Discovery
Lecture 22 (Ch. 27)

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Chapter Overview The golden age of antibiotic discovery Basic concepts of

Chapter Overview

The golden age of antibiotic discovery
Basic concepts of antimicrobial

therapy
Measuring drug susceptibility
Mechanisms of action
Challenges of drug resistance
The future of drug discovery
Antiviral agents
Antifungal agents
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Introduction The discovery of antibiotics about 80 years ago has played

Introduction

The discovery of antibiotics about 80 years ago has played a

major role in increasing life expectancy throughout the world.
From 45 to 50 years (prior to 1918) to nearly 79 years now
But antibiotics may soon become useless.
Their overuse and misuse have led to the development of antibiotic-resistant strains
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The Golden Age of Antibiotic Discovery Antibiotics are compounds produced by

The Golden Age of Antibiotic Discovery

Antibiotics are compounds produced by

one microbe that adversely affect other microbes.
The modern antibiotic revolution began in 1928 with the discovery of penicillin by Alexander Fleming.
A contaminating mold had inhibited the growth of Staphylococcus aureus colonies on a plate.
The mold was identified as Penicillium notatum.
Penicillin was purified in the early 1940s by Howard Florey and Ernst Chain.
Has saved millions of lives since!
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Figure 27.1

Figure 27.1

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Gerhard Domagk (1930s) Discovered sulfa drugs Inactive until converted by the

Gerhard Domagk (1930s)
Discovered sulfa drugs
Inactive until converted by the body

to active agents
Analogs of PABA (Para-aminobenzoic acid), a precursor of a vitamin needed for DNA synthesis

Selman Waksman (1940s)
Discovered streptomycin
Antibiotic produced by an actinomycete bacterium found in the soil
Streptomyces griseus

Figure 27.2

A

B

C

D

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Fundamentals of Antimicrobial Therapy Antibiotics comprise mostly of chemotherapeutic agents used

Fundamentals of Antimicrobial Therapy

Antibiotics comprise mostly of chemotherapeutic agents used to

treat microbial diseases.
The term “antibiotic” originally referred to any compound produced by one microbial species that could kill or inhibit the growth of other microbes.
Today the term “antibiotic” is also used for synthetic chemotherapeutic agents, such as sulfonamides, that are clinically useful but chemically synthesized.
Many natural and synthetic compounds affect microbial growth, but their utility in a clinical setting is dictated by certain key characteristics.
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Antibiotic must affect target organism. But it must not affect humans.

Antibiotic must affect target organism.
But it must not affect humans.
Many have

side effects at high concentration.
Chloramphenicol interferes with our ribosomes.
At high levels, it interferes with RBC development.
Some may cause allergic response.
Antibiotics are foreign substances in our bodies.
Drug should affect microbial physiology.
That does not exist, or is greatly modified, in humans
Peptidoglycan
Differences in ribosome structure
Biochemical pathway missing in humans

Antibiotics Exhibit Selective Toxicity

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Broad spectrum Effective against many species Narrow spectrum Effective against few

Broad spectrum
Effective against many species
Narrow spectrum
Effective against few or a single

species
Source of antibiotics
Most discovered as natural products
Often modified by artificial means to:
Increase efficacy
Decrease toxicity to humans

Antimicrobials Have a Limited Spectrum of Activity

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Bactericidal antibiotics kill target organisms. Many drugs only affect growing cells.

Bactericidal antibiotics kill target organisms.
Many drugs only affect growing cells.
Inhibitors of

cell wall synthesis
Only effective if organism is building new cell wall
Example: penicillin
Bacteriostatic antibiotics prevent growth of organisms.
Cannot kill organism
Immune system removes intruding microbe

Antibiotics Are Classified as Bacteriostatic or Bactericidal

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Measuring Drug Susceptibility One critical decision a clinician must make when

Measuring Drug Susceptibility

One critical decision a clinician must make when treating

an infection is which antibiotic to prescribe for the patient.
There are several factors to consider, including:
The relative effectiveness of different antibiotics on the organism causing the infection
The average attainable tissue levels of each drug
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The MIC is the lowest concentration that prevents growth Varies for

The MIC is the lowest concentration that prevents growth
Varies for different

bacterial species
Test by diluting antibiotic

Minimal Inhibitory Concentration

Lowest concentration with no growth: MIC
May still have living (but nongrowing) organisms
Plate liquid without antibiotic: Do colonies form?
No colonies: minimal lethal concentration (MLC)
MLC always lower than MIC

Figure 27.3

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The time required to evaluate antibiotic effectiveness can be reduced by

The time required to evaluate antibiotic effectiveness can be reduced by

using a strip test that avoids the need for dilutions.
The MIC is the point at which the elliptical zone of inhibition intersects with the strip.

Minimal Inhibitory Concentration

Figure 27.4

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Clinical labs can receive up to 100 or more isolates in

Clinical labs can receive up to 100 or more isolates in

one day, so individual MIC determinations are impractical.
The Kirby-Bauer assay tests strain sensitivity to multiple antibiotics.
Uses a series of round filter paper disks impregnated with different antibiotics.
A dispenser delivers up to 12 disks simultaneously to the surface of an agar plate covered by a bacterial lawn.
During incubation, the drugs diffuse away from the disks into the surrounding agar and inhibit growth of the lawn.
Size of cleared zones reflects relative sensitivity

Kirby-Bauer Disk Susceptibility Test

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The following are standardizations used to make the test reproducible and

The following are standardizations used to make the test reproducible and

easier:
Size of the agar plate: 150 mm
Depth of the media
Media composition: Mueller-Hinton agar
The number of organisms spread on the agar plate
Size of the disks: 6 mm
Concentrations of antibiotics in the disks
Incubation temperature: 37oC

Kirby-Bauer Disk Susceptibility Test

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Figure 27.5

Figure 27.5

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Peptidoglycan synthesis is rather complex. However, it may be summarized in

Peptidoglycan synthesis is rather complex.
However, it may be summarized in these

four steps:
1. Precursors are made in the cytoplasm.
UDP-NAG and UDP-NAM-peptide
2. They are carried across the cell membrane by a lipid carrier: bactoprenol.
The carrier is then recycled.
3. The precursors are polymerized to the existing cell wall structure by transglycosylases.
4. The peptide side chains are cross-linked by transpeptidases.

Cell Wall Antibiotics

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Figure 27.7

Figure 27.7

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Figure 27.7

Figure 27.7

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Penicillins, cephalosporins The beta-lactam ring chemically resembles the D-Ala-D-Ala piece of

Penicillins, cephalosporins
The beta-lactam ring chemically resembles the D-Ala-D-Ala piece of peptidoglycan.
This

molecular mimicry allows the drug to bind transpeptidase and transglycosylase (which is why the proteins are called penicillin-binding proteins).
Thus, preventing their activities and halting synthesis of the chain
R groups can be modified to generate a number of semisynthetic drugs.

Beta-Lactam Antibiotics

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Other Antibiotics That Inhibit Synthesis of the Cell Wall Vancomycin: binds


Other Antibiotics That Inhibit Synthesis of the Cell Wall

Vancomycin: binds ends

of peptides
Prevents action of transglycosylases and transpeptidases
Same step as penicillin, but different activity
Cycloserine: inhibits formation of the D-ala-D-ala dipeptide precursor
Bacitracin: blocks the lipid carrier
Disaccharide subunits do not reach periplasm
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Gramicidin Cyclic peptide produced by Bacillus brevis Forms a cation channel,

Gramicidin
Cyclic peptide produced by Bacillus brevis
Forms a cation channel, through which

ions leak

Drugs That Disrupt Cell Membranes

Polymyxin
Produced by Bacillus polymyxa
Destroys cell membrane, just like a detergent
Used only topically

Figure
27.11

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Quinolones: nalidixic acid, ciprofloxacin Block bacterial DNA gyrase, and so prevent

Quinolones: nalidixic acid, ciprofloxacin
Block bacterial DNA gyrase, and so prevent DNA

replication
Metronizadole
Nontoxic, unless metabolized by anaerobe ferredoxin
Sulfa drugs
Analogs of PABA, a precursor of folic acid
Needed for DNA synthesis
Supplied in our diet, thus no folic acid synthesis to inhibit

Drugs That Affect DNA Synthesis and Integrity

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Figure 27.12 A C B

Figure
27.12

A

C

B

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Antibiotics that inhibit transcription are bactericidal and most active against growing

Antibiotics that inhibit transcription are bactericidal and most active against growing

bacteria
Rifampin
Binds to the beta subunit of RNA polymerase
Prevents the elongation step of transcription
Actinomycin D
Prevents the initiation step of transcription
Binds to DNA from any source
Thus, not selectively toxic

RNA Synthesis Inhibitors

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Figure 27.14

Figure 27.14

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Drugs that affect the 30S subunit Aminoglycosides cause the translational misreading

Drugs that affect the 30S subunit
Aminoglycosides cause the translational misreading of

mRNA
Are bactericidal
Include streptomycin
Tetracyclines: block the binding of charged tRNAs to the A site of the ribosome
Are bacteriostatic
Include doxycycline

Protein Synthesis Inhibitors

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Drugs that affect the 50S subunit Macrolides: inhibit translocation Lincosamides: inhibit

Drugs that affect the 50S subunit
Macrolides: inhibit translocation
Lincosamides: inhibit translocation
Chloramphenicol: inhibits

peptidyl transferase activity
Oxazolidinones: prevent formation of the 70S ribosome initiation complex
Streptogramins
Streptogramin A: blocks tRNA binding
Streptogramin B: blocks translocation

Protein Synthesis Inhibitors

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Challenges of Drug Resistance Antibiotics are considered secondary metabolites because they

Challenges of Drug Resistance

Antibiotics are considered secondary metabolites because they often

have no apparent primary use in the producing organism.
Not essential for survival
But enhance ability to survive competition
Microbes prevent self-destruction by means of various antibiotic resistance mechanisms.
Example: make enzymes to disable antibiotics
Genes encoding some of these drug-resistance mechanisms have been transferred to pathogens.
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Antibiotic resistance is a growing problem worldwide Antibiotics are overused Overprescribed;

Antibiotic resistance is a growing problem worldwide
Antibiotics are overused
Overprescribed; used in

farm animal feed
This exerts selective pressure for drug-resistant strains
Streptococcus pneumoniae
Acinetobacter baumanii
Resistant to multiple drugs
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There are four basic forms of antibiotic resistance Figure 27.18

There are four basic forms of antibiotic resistance

Figure 27.18

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Modify the target so that it no longer binds the antibiotic.

Modify the target so that it no longer binds the antibiotic.

Antibiotic-Resistance

Mechanisms

Destroy the antibiotic before it gets into cell.
The beta-lactamase enzyme specifically destroys penicillins.

Mutations in ribosomal proteins confer resistance to streptomycin.

Figure
27.19

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Add modifying groups that inactivate the antibiotic. Three classes of enzymes

Add modifying groups that inactivate the antibiotic.
Three classes of enzymes are

used to modify and inactivate the aminoglycoside antibiotics.

Antibiotic Resistance Mechanisms

Pump the antibiotic out of the cell.
Specific and nonspecific transport proteins
Similar strategy is used in cancer cells.

Figure 27.21

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How Does Drug Resistance Develop? De novo antibiotic resistance develops through

How Does Drug Resistance Develop?

De novo antibiotic resistance develops through gene

duplication and/or mutations.
Can be acquired via horizontal gene transfer:
Conjugation
Transduction
Transformation
Recently, multidrug resistance has also been attributed to the presence of integrons.
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Integrons Integrons are genetic mechanisms that allow bacteria to adapt and

Integrons

Integrons are genetic mechanisms that allow bacteria to adapt and

evolve rapidly through the stockpiling and expression of new genes. These genes are embedded in a specific genetic structure called gene cassette that generally carries one promoterless open reading frame together with a recombination site.
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The Future of Drug Discovery Evolutionary pressure is constant. Requires constant

The Future of Drug Discovery

Evolutionary pressure is constant.
Requires constant search for

new antibiotics
The modern drug discovery process is outlined as such:
Identify new targets using genomics.
Design compounds to inhibit targets.
Alter compound structure to optimize MIC.
Determine spectrum of compound.
Narrow or broad?
Determine pharmaceutical properties.
Not toxic to animals; persistence in body
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Antibiotics from the sea The hero marine bacteria, Planctomycetes, naturally produce

Antibiotics from the sea

The hero marine bacteria, Planctomycetes, naturally produce antibiotic compounds

to fight against other bacteria. Thanks to Jogler's lab work, a whopping 79 new cultures of Planctomycetes could pave the way for a new source of antibiotics and help those who suffer from antibiotic-resistant infections.Dec 13, 2019
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Potential targets for rational antimicrobial drug design include proteins expressed only

Potential targets for rational antimicrobial drug design include proteins expressed only

in vivo or proteins expressed both in vivo and in vitro.
Candidate antimicrobial compounds can be designed to bind and inhibit the active site of a known enzyme
Combinatorial chemistry is used to make random combinations of compounds that can be tested for enzyme inhibitory activity and antimicrobial activity.
Intriguing ideas that may lead to novel antimicrobial therapies include:
Nanotubes to poke holes in bacterial cell membranes
Molecules that “cork” the type III secretion apparatus
Interfering with the quorum-sensing mechanisms
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Methods to Identify Drug-Resistant Pathogens The proportion of antibiotic-resistant infections has

Methods to Identify Drug-Resistant Pathogens

The proportion of antibiotic-resistant infections has doubled

since 2002, rising from 5.2% to 11% of all infections.
The faster a clinical lab can identify a pathogen’s antibiotic susceptibility, the more quickly a clinician can prescribe an appropriate narrow-spectrum antibiotic.
Traditional MIC tests take up to 3 days to complete; using automated methods cuts this down to 2 days.
Multiplex PCR platforms can detect pathogen-specific or drug resistance gene DNA sequences within an hour.
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Evolving, and Sharing, Drug Resistance Genes De novo antibiotic resistance develops

Evolving, and Sharing, Drug Resistance Genes

De novo antibiotic resistance develops through

gene duplication and/or mutations.
Antibiotic resistance also can be acquired via horizontal gene transfer (conjugation, transduction, and transformation ).
A study in 2015 found that antibiotic-resistant microbes occur naturally in uncontacted Amazon communities.
Recently, multidrug resistance has been attributed to the presence of highly-mobile gene expression elements called integrons.
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How Did We Get into This Mess? – 2 Another proposed

How Did We Get into This Mess? – 2

Another proposed source

of antibiotic resistance is the widespread practice of adding antibiotics to animal feed.
Giving animals subtherapeutic doses of antibiotics in their food makes for larger, and therefore more profitable, animals.
Some estimates suggest that 80% of all antibiotics used in the United States (up until 2017) were fed to healthy livestock.
Feeding growth-promoting antibiotics to cattle can stimulate the spread of pathogenicity genes between bacteria.
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How Did We Get into This Mess? – 3 Many of

How Did We Get into This Mess? – 3

Many of these

situations have conspired to produce incredibly dangerous bacteria resistant to almost every antibiotic known.
ESKAPE pathogens
Term coined by the Infectious Diseases Society of America
Six highly resistant bacterial species that collectively cause about two-thirds of all U.S. nosocomial infections
Enterococcus faecium Acinetobacter baumannii Staphylococcus aureus Pseudomonas aeruginosa Klebsiella pneumoniae Enterobacter sp.
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How Did We Get into This Mess? – 4

How Did We Get into This Mess? – 4

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How Did We Get into This Mess? – 5 When should

How Did We Get into This Mess? – 5

When should antimicrobials

be used? Antibiotic stewardships are coordinated interventions that improve and measure antibiotic use.
Do not use antibiotics to treat viral infections.
Do not use an antibiotic if a patient’s microbiome includes a strain that is resistant to the drug.
Know which antibiotic resistant strains are prevalent in the community or hospital before prescribing.
Consider how long the patient needs to take the antibiotic.
De-escalate antibiotic usage whenever possible.
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Biofilms, Persisters, and the Mystery of Antibiotic Tolerance Why do some

Biofilms, Persisters, and the Mystery of Antibiotic Tolerance

Why do some infections

return after bactericidal antibiotic treatment is discontinued?
A subpopulation of dormant organisms, called persister cells, often arises within a population of antibiotic-susceptible bacteria.
The stalled metabolism of persisters renders them tolerant to bactericidal antibiotics during treatment.
Persister cells can be found in any biofilm or population of late-exponential-phase cells.
Tolerance provides antibiotic resistance at the price of not growing.
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Fighting Resistance and Finding New Drugs – 1 The prudent use

Fighting Resistance and Finding New Drugs – 1

The prudent use of

current antibiotics and innovative strategies for finding new ones hopefully will enable us to continue to control evolving pathogens.
Directly countering drug resistance
Dummy target compounds inactivate resistance enzymes (e.g., clavulanic acid)
Alter antibiotic’s structure so that it sterically hinders access of bacterial modifying enzymes
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Fighting Resistance and Finding New Drugs – 2 Finding new antibiotics

Fighting Resistance and Finding New Drugs – 2

Finding new antibiotics
Brute-force screening

of microbes, plants, and animals
Combinatorial chemistry
Genome sequence analysis to identify potential bacterial molecular targets
Photosensitive chemicals
Interfering with quorum-sensing mechanisms
CRISPR-based strategies for reversing antibiotic resistance
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Fighting Resistance and Finding New Drugs – 3 Antipersister and antibiofilm

Fighting Resistance and Finding New Drugs – 3

Antipersister and antibiofilm approaches
Kill

persisters directly
Prevent persister formation
Interfere with biofilm formation
Induce biofilm dispersal
The progression of these strategies has been slow because the road to FDA approval, though necessary for safety reasons, is long (8 to 10 years) and expensive, and it can discourage some companies from investing in antibiotic discovery.
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Introduction to the Immune System The Innate and Adaptive Immunity

Introduction to the Immune System

The Innate and Adaptive Immunity

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What is the immune system? The immune system is a system

What is the immune system?

The immune system is a system of

defense to protect the body against foreign invaders (foreign antigens)
Exterior defense: Physiological barriers, chemical barriers, mechanical barriers, microbiological barriers
Interior defense or systemic defense:
Immune cells and soluble factors

dust

pollen

dander

bacteria

fungi

Foreign invaders

spores

protozoa

virusess

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Exterior Defense

Exterior Defense

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Interior or Systemic defense In the body there are cells and

Interior or Systemic defense

In the body there are cells and soluble

factors that deal with foreign antigens, which have come into the body.
In humans and higher vertebrates there are two lines of internal defense, and distinct cells and soluble factors are involved in each type of immunity, and hence they are divided into:
1. Cells and factors of the innate immunity
2. Cells and soluble factors of the adaptive immunity
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Components of the immune system The immune system is composed of

Components of the immune system

The immune system is composed of

specialized organs, tissues, cells and soluble factors that work in concert in order to mount an adequate immunological response.
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Components of the Immune System The immune system is composed of

Components of the Immune System

The immune system is composed of lymphoid

organs, tissues, cells and soluble factors.
Organs of the immune system and their functions
Primary lymphoid organ: The thymus is a bilobed organ where immature T cells (also called progenitor T cells) undergo maturation
Secondary lymphoid organs include the spleen and lymph nodes. These organs contain B cells, T cells and macrophages.
The spleen is the largest secondary lymphoid organ where antigens from the blood are trapped
Lymph nodes are encapsulated organs that are located at the junction of lymphatic vessels
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The Bone Marrow The bone marrow consists of connective tissue that

The Bone Marrow

The bone marrow consists of connective tissue that is

contained in the cavity of most bones in the body.
There are two types of bone marrow:
Yellow marrow rich in fat cells
Red marrow containing developing blood cells. Red bone marrow is primarily a site of development of all blood cells from a common precursor, the hematopoietic stem cell by a process called hematopoiesis.
All blood cell types mature in the bone marrow except for the progenitor T cells, which undergo maturation in the thymus.
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The Thymus The thymus is an encapsulated bilobed organ that is

The Thymus

The thymus is an encapsulated bilobed organ that is located

in the thoracic cavity, between the chest bone and the heart. The thymus contains lobules, which are organized into 2 regions: a cortex and a medulla. The cortex contains immature T cells, whereas mature T cells can be found in the medulla. T cell maturation occurs in the cortical medullary region. It is noteworthy that only around 10 % of the progenitor T cells could reach maturation, indicating that around 90% of progenitor T cells are eliminated during the maturation process. The thymus increases in size after birth, reaching its largest size at puberty, after which time it progressively decreases in size with age. Thymic involution is associated with reduced thymopoiesis and immunosenescence.  
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The thymus The thymus is a bilobed organ that is divided

The thymus

The thymus is a bilobed organ that is divided

into lobules. Immature thymocytes are localized in the vortex, and T cell maturation occurs in the cortical medullary region
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The lymph nodes The lymph nodes are small encapsulated organs that

The lymph nodes

The lymph nodes are small encapsulated organs that are

located at major junctions of lymphatic vessels. The lymph node is organized into 3 regions, including the cortex or B cell zone that contains resting B cells in primary follicles and proliferating B cells in germinal centers, the paracortex or T cell zone, and the medulla, where T, B cells, and macrophages can be found.
Lymph nodes are irrigated by both the blood circulatory system and the lymphatic system. Blood enters the lymph node via the artery to the arterioles and comes out through the venules and vein.
The lymph comes into the lymph node via the afferent vessels or ducts, and out via the efferent duct. Therefore, lymph nodes trap antigens from both the blood circulatory and lymphatic systems.
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Lymph nodes Afferent duct Efferent duct Proliferating B cells in T

Lymph nodes

Afferent duct

Efferent duct

Proliferating B cells in

T cell zone

B cell

zone

High endothelial venule (HEV)

Lymph nodes are encapsulated organs where antigens in both the blood and the lymph are trapped and where immune cells (B and T cells, macrophages, dendritic cells and follicular dendritic cells) are located and ready to interact with each other in order to mount an adequate immunological response

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The Spleen The spleen is the largest encapsulated secondary lymphoid organ.

The Spleen

The spleen is the largest encapsulated secondary lymphoid organ. In

humans, the spleen is located below the rib cage and to the left of the abdomen. The spleen contains two regions that are designated as the red pulp and white pulp.
 The red pulp contains worn out red blood cells that are destined for destruction, hence it is referred to as a cemetery for RBCs. The process of removing worn out and dead RBCs is called hemocatharsis, meaning cleansing of the blood. The white pulp is rich in white blood cells and it forms a sheath around the central arteriole. The sheath is designated as periarteriolar lymphoid sheath (PALS), which is a tissue rich in T cells (mostly CD4+ T cells and CD8+ T cells, and in smaller numbers B cells that are located in follicles and germinal centers, and macrophages that are located in the marginal zone. .
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The spleen The spleen is the largest secondary lymphoid organ, in

The spleen

The spleen is the largest secondary lymphoid organ, in

which antigens in the blood are trapped Blood circulation gets into the spleen via the artery and arterioles and come out via venules and the vein, and hence the spleen serves as a trap of foreign antigens that are coming from the blood circulation
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Tissues Blood circulation Hematopoiesis All blood cells are derived from a

Tissues

Blood circulation

Hematopoiesis
All blood cells are derived from a common precursor, the

hematopoietic stem cell via three lineages of differentiation: The lymphoid lineage, the myeloid lineage, and the erythrocyte/megakaryocyte lineage

Erythrocyte and Megakaryocyte lineage

Myeloid lineage

Lymphoid lineage

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Non-Immune cells: Erythrocytes & Megakaryocytes. Erythrocytes, also referred to as red

Non-Immune cells: Erythrocytes & Megakaryocytes.   Erythrocytes, also referred to as red blood

cells (RBCs) are the most abundant cells in peripheral blood. RBCs do not have a nucleus. These cells are not immune cells, but they play a role in the binding and removal of immune complexes from the blood circulation. Megakaryocytes are large cells (at least 20 X larger than the RBCs). These cells are the precursors to platelets, and around 4000 platelets can be generated by the fragmentation of one megakaryocyte. Platelets are necessary for blood clotting, and they also play an important role in the inflammatory response.

Erythrocytes or Red blood cells

Megakaryocyte

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Monocytes are the largest white blood cells, which constitutes 3–7% of

Monocytes are the largest white blood cells, which constitutes 3–7% of

the leukocytes in the circulating blood. They are characterized by a kidney-shaped nucleus, grey cytoplasm and small red-blue granules upon staining by the Giemsa stain. Pictures of monocytes and macrophages are available at. Monocytes can leave the blood circulation and differentiate into tissue macrophages and dendritic cells.

Cells of the myeloid lineage

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Macrophages Macrophages are larger than the monocytes, with larger cytoplasm t

Macrophages

Macrophages are larger than the monocytes, with larger cytoplasm t hat

is heavily vacuolated. Macrophages assume different shapes and are given different names based on their location. Ex., Alveolar macrophages in the lung, peritoneal macrophages, Kupffer cells that are resident macrophages in the liver, brain microglia (resident macrophages in the brain), spleen sinus macrophages, lymph node sinus macrophages, Kidney intraglomerular mesangial cells…etc. Macrophages display abundant dendrites when exposed to bacteria (Fig.2.7A). Macrophages have the ability to perform phagocytosis of foreign antigens, and hence like the neutrophils, they are designated as “professional”phagocytes.
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Monocyte-Derived Dendritic cells Monocyte-Derived Dendritic cells belong to a heterogeneous population

Monocyte-Derived Dendritic cells

Monocyte-Derived Dendritic cells belong to a heterogeneous population of

professional antigen-presenting cells (APCs).
Monocyte-derived DCs (mDCs), which are also called myeloid DCs are the best understood types of DCs.
The mDCs are characterized by a change in morphology depending on their stages of maturation and/or activities, such as the presence of dendrites in culture and tissues and with sheet-like projections when exposed to viruses

Dendritic cell exposed to virus

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Polymorphonuclear granulocytes Neutrophils (50-70% of leukocytes) have a multilobed nucleus and

Polymorphonuclear granulocytes

Neutrophils (50-70% of leukocytes) have a multilobed nucleus and

cytoplasmic granules that are small and stained in pale blue with the neutral Giemsa stain.
The primary function of neutrophils is to perform phagocytosis of foreign antigens in the blood circulation.
These cells will also respond to chemotactic factors and chemokines generated at the site of injury and/or inflammation. The chemokine CXCL8 produced by activated macrophages facilitate neutrophil extravasation, and the chemotactic factor complement C5a direct them to the site of the infection
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Eosinophils (>0-5% of leukocytes) have a bilobed nucleus and cytoplasmic granules

Eosinophils (>0-5% of leukocytes) have a bilobed nucleus and cytoplasmic granules

that are stained in red with the acidic dye eosin. They are pro-inflammatory white blood cells, which play a role in the immune defense against small parasites, such as helminth worms.
Basophils (>0-2% of leukocytes) have a bilobed nucleus and cytoplasmic granules stained in blue with the basic dye Alcian blue. Basophils are also involved in the immune response to parasitic infection.

Eosinophil

Basophil

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Mast Cells Mast cells are only found in tissues, in both

Mast Cells

Mast cells are only found in tissues, in both connective

tissue (Connective tissue mast cells or CTMCs) and mucosa (mucosa-associated mast cells or MMCs).
Mast cells show some similar morphological characteristics to basophils, such as the presence of a blue cytoplasm with deep purple granules by histochemical staining method using combined Alcian Blue-Safranin O.
A direct precursor to mast cells has not yet been identified.

Inactive mast cell

Degranulated mast cell

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Cells of the innate immunity Neutrophil Eosinophil Basophil Monocyte Mast cell Dendritic cell Macrophage

Cells of the innate immunity

Neutrophil Eosinophil Basophil Monocyte

Mast cell

Dendritic cell Macrophage
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Recap Cells of the innate immunity Polymorphonuclear granulocytes (Neutrophils, Eosinophils and

Recap

Cells of the innate immunity
Polymorphonuclear granulocytes (Neutrophils, Eosinophils and Basophils)
Monocytes that

differentiate into tissue Macrophages and Denditic cells
Mast cells in connective tissue and mucosa-associated tissues
Natural Killer cells (NK cells).
Note: Megakaryocytes and Erythrocytes are not immune cells, but they do contribute to the immune system, Megakaryocytes being precursors to platelets, and Erythrocytes help in the removal of immune complexes from the blood circulatory system.
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Cells of the Adaptive Immunity

Cells of the Adaptive Immunity

Слайд 245

Cells of the adaptive immunity

Cells of the adaptive immunity

Слайд 246

Clonal selection of B cell by antigen and differentiation into plasma cells producing antibodies

Clonal selection of B cell by antigen and differentiation into plasma

cells producing antibodies
Слайд 247

T-helper cell and B-cell Interaction

T-helper cell and B-cell Interaction

Слайд 248

The Killing Action of Cytotoxic T Cells

The Killing Action of Cytotoxic T Cells

Слайд 249

Recap The cells of the adaptive immunity include B and T

Recap

The cells of the adaptive immunity include B and T cells


B cells which differentiate into plasma cells producing antibodies
T cells which include
TCR-1 T cells
TCR-2 T cells, which are divided into
CD4+ T helper cells by producing cytokines
CD8+ Cytotoxic T cells which kill infected cells by induction of apoptosis
Слайд 250

The Immune Responses

The Immune Responses

Слайд 251

Lecture contents The systemic Immunological response to foreign antigens involves two

Lecture contents

The systemic Immunological response to foreign antigens involves two lines

of defense
First line of defense
Involves cells and soluble factors of the innate immunity
Immediate response
Second line of defense
Delayed response
Specific response
Interaction between innate and adaptive components
Слайд 252

Innate Immunity or First Line of Defense The importance of the

Innate Immunity or First Line of Defense

The importance of the innate

immunity is the readiness of innate immune cells and soluble factors in the elimination of foreign antigens and infected cells.
Our focus is on the following:
1. Phagocytosis of foreign antigens by neutrophils and macrophages.
The inflammatory response to an infection and/or injury.
Lysis of Gram-negative bacteria ny the complement system.
Detection and killing of infected or transformed cells by NK cells.
Antimicrobial factors.
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Phagocytosis Neutrophils and macrophages are professional phagocytic cells Macrophages are the

Phagocytosis

Neutrophils and macrophages are professional phagocytic cells
Macrophages are the main phagocytes

in tissues.
Neutrophils are the main phagocytes in the blood circulatory system and, when called by macrophages, they extravasate and migrate to the site of an infection and/or inflammation.
The next slide will show the main four steps in phagocytosis
Слайд 254

Phagocytosis Macrophages and neutrophils are referred to as professional phagocytic cells

Phagocytosis

Macrophages and neutrophils are referred to as professional phagocytic cells or

phagocytes.
Phagocytosis is facilitated by the coating of the antigen with opsonins, such as antibodies or complement component C3b
Слайд 255

Steps in phagocytosis Step 1 Binding of bacterium by surface receptors

Steps in phagocytosis

Step 1
Binding of bacterium by surface receptors on phagocytes.

Ex. CD14 binding LPS on gram-negative bacteria, and receptors for opsonins which are proteins that can bind both to bacteria and the corresponding receptors on phagocytes, thus facilitating phagocytosis. Examples of opsonins include antibodies and the complement component C3b.
Step 2
Internalization of the bacterium is facilitated by the cross-linking of the bacterium and the phagocyte.
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Step 3 Internalization of the bacterium in a phagosome Step 4

Step 3
Internalization of the bacterium in a phagosome
Step 4
Fusion of the

lysosome with the phagosome, thus forming a
phagolysosome, where the bacterium is destroyed by up to 40 acidic
lysosomal enzymes, such as lysozyme digesting peptidoglycan cell wall,
hydrolytic enzymes or acid hydrolases such as nucleases, proteases,
lipases, phosphatase, etc., and protein such as lactoferrin that binds iron
and deprive iron-dependent bacteria.
Oxygen-dependent killing of bacteria. The bacterium is also destroyed by reactive oxygen species (ROS), such as superoxide anion (O2−), hydrogen peroxide (H2O2), and hydroxyl radical (HO•), consist of radical and non-radical oxygen species formed by the partial reduction of oxygen. Cellular ROS are generated endogenously as in the process of mitochondrial oxidative phosphorylation,
Слайд 257

Killing of bacteria in the phagolysosome

Killing of bacteria in the phagolysosome

Слайд 258

The beneficial acute inflammatory response

The beneficial acute inflammatory response

Слайд 259

Inflammation The five cardinal signs of inflammation Redness Heat Pain Swelling

Inflammation

The five cardinal signs of inflammation
Redness
Heat
Pain
Swelling
Loss of function
Question: What can

cause these signs?
Слайд 260

The Inflammatory Response Beneficial acute inflammatory response to injury and infection

The Inflammatory Response

Beneficial acute inflammatory response to injury and infection
Macrophages performing

phagocytosis of bacteria
Activated macrophages producing cytokines to activate other immune cells in tissue, to mobilize circulatory neutrophils and platelets, to induce fever by pyrogens, etc.
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The 5 signs of inflammation Redness resulted from vasodilation caused by

The 5 signs of inflammation
Redness resulted from vasodilation caused by histamine

and prostaglandin produced by mast cells.
Swelling resulted from exudates caused by vasodilation and smooth muscle contraction.
Heat resulted from the effect of pyrogens (produced by activated macrophages: IL-1 beta and IL-6 on the hypothalamus.
Pain resulted from the stimulation of nerve ending by bradykinin and prostaglandin.
Loss of function caused by disruption of tissue structure.
Слайд 262

Neutrophil undergoing NETosis Neutrophils can extravasate (get out of blood vessel)

Neutrophil undergoing NETosis

Neutrophils can extravasate (get out of blood vessel) in

response to the chemokine CXCL8 produced by macrophage and the chemotactic factor C5a from complement activation.
CXCL8 induces the expression of adhesion molecules on neutrophils (LFA-I) and on endothelial cells (ICAM-I).
C5a is a chemotactic factor that attracts neutrophils to the site of the infection/inflammation.
Neutrophils do not recirculate, and they die by apoptosis or NETosis at the site of the infection/inflammation.
Слайд 263

Functions of the complement system The them more attractive to phagocytic

Functions of the complement system

The them more attractive to phagocytic

cells such as macrophages (a process known as opsonization). Some complement components also promote inflammation by stimulating cells to release histamine and by attracting phagocytic cells to the site of infection.

Lysis of foreign cells for the insertion of on of membrane attack complexes (MAC) into the membrane of Gram- bacteria
Production of reactive proteins:
C3b: Opsonin
C3a and C5a at low concentration: chemotactic factors
C3a and C5a at higher concentration, are anaphylatoxins
that bind to their respective receptors on mast cells,
triggering the release of factors of anaphylaxis

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Complement activation The complement system is composed of over 30 heat-labile

Complement activation

The complement system is composed of over 30 heat-labile

proteins that are produced mainly by the liver. These proteins
circulate in the blood and extracellular fluid in an inactivated
state until a complement component encounters a foreign cell,
leasing to a sequence of enzymatic reaction on the surface of
the foreign cell, such as E. coli (Gram- bacteria).
Complement activation occurs by three pathways:
The Alternative pathway which is also called the properdin pathway
The Lectin pathway
The Classical pathway
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Initiation or Activation of the Complement The Alternative pathway is initiated

Initiation or Activation of the Complement

The Alternative pathway is initiated by

the binding of a fluid phase C3 convertase that consists of iC3 associated with Factor Bb (iC3Bb), which cleaves complement C3 into 2 fragments C3a and C3b that binds to the bacterial surface, followed by the formation of the C3 convertase C3bBb on bacterial surface. Binding of the protein properdin to C3bBb extends the half life of this C3 convertase .
The Lectin pathway is initiated by the binding of a Mannan-binding lectin (MBL) complex to mannose residues on the bacterial surface. Mannan-binding lectin complex consists of one molecule of Mannan-binding lectin associated with two molecule of MBL associated serine protease 1 (MBL-SP1) and two molecule of MBL-associated serine protease 2 (MBL-SP2), which results in the activation of a serine protease. Cleavage of complement C4 and C2 by this enzyme results in the formation of C4bC2b (C4b2b), which is a C3 convertase.
The Classical pathway is initiated by the binding of antibodies of the IgG and IgM classes to the bacterial surface, which is followed by the binding of C1 complex (C1q associated with two C1r and two C1s to the antibodies), which results in the activation of a serine protease. Like in the Lectin pathway, cleavage of complement C4 and C2 by this enzyme results in the formation of C4bC2b (C4b2b), which is a C3 convertase.
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Formation of C5 convertase and MAC Formation of C5 convertase. This

Formation of C5 convertase and MAC

Formation of C5 convertase. This step

is similar in the three pathways: C3 convertase cleaves C3 into C3a and C3b fragments. Binding of C3b to C3 convertase results in the formation of C5 convertase: C3bBb3b in the Alternative pathway, and C4b2b3b in the Lectin and Classical pathways.
Formation of the membrane attack complex (MAC). This step is identical in all three pathways. C5 convertase cleaves C5 into two fragments C5a and C5b, which gets associated sequentially with C6, C7 and C8, forming the complex C5b678 which inserts into the membrane of the bacteria. Finally, C9 binds to C8 of C5b678, followed by C9 polymerization (C5b678(C9)n in the membrane of the bacteria, thus creating a channel or pore, leading to bacterial lysis.
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Membrane attack complex https://www.youtube.com/watch?v=vbWYz9XDtLw The Classical Pathway of the complement system MAC

Membrane attack complex

https://www.youtube.com/watch?v=vbWYz9XDtLw
The Classical Pathway of the complement system

MAC

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Antimicrobial soluble factors Alpha and beta defensins Alpha-2 macroglobulins Lysozyme Polyamines Kinins Pentrexins

Antimicrobial soluble factors Alpha and beta defensins Alpha-2 macroglobulins Lysozyme Polyamines Kinins Pentrexins

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Antimicrobial Factors Antimicrobial factors include: Antimicrobial peptides: Alpha and beta defensins

Antimicrobial Factors

Antimicrobial factors include:
Antimicrobial peptides: Alpha and beta defensins that disrupt

microbial membranes.
Alpha-2 macroglobulin inhibits potentially damaging proteases
Pentraxins: Pentameric plasma proteins of the innate immunity that bind microorganisms and host phagocytes, thus facilitating phagocytosis.
Lysozyme: Enzyme digesting bacterial cell wall.
Polyamines: Molecules causing the sequestration of lipoteichoic acid of Gram+ bacteria.
Kinins: plasma proteins of the blood coagulation with antifungal and anti bacterial properties.
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Natural Killer Cells NK cells have the natural (or innate) ability

Natural Killer Cells

NK cells have the natural (or innate) ability to

detect and kill infected, stressed out and abnormal cells, such as virus- or bacteria-infected cells, or cancer cells. NK cells are derived from the lymphoid lineage, but they do not have the characteristics of the cells of the adaptive immunity, hence they are considered as members of the innate immunity. A distinctive feature in NK cells is the expression of inhibitory receptors and activating receptors.
The killer inhibitory receptors that recognize MHC-I expressed on cells in the body contain a region designated as Immunoreceptor Tyrosine-based Inhibition Motif (ITIM) in their cytoplasmic tail.
In contrast NK cells have the activating receptors, such as NKG2D that binds to MICA and MICB that are expressed by cells that are under stress, such as tumor cells or infected cells. The activating receptors contain a region in their cytoplasmic tail designated as Immunoreceptor Tyrosine-based Activation Motif (ITAM)
Слайд 271

Cells of the Lymphoid lineage B lymphocytes or B cells. These

Cells of the Lymphoid lineage

B lymphocytes or B cells. These cells

express B cell receptors for antigens (BCRs), which are membrane-associated surface immunoglobulins (Igs) or antibodies (Abs).
The surface Abs expressed by naïve mature B cells (mature B cells that have not yet encountered the corresponding antigens) are of the IgM and IgD classes. There are around 105 surface immunoglobulins on naïve B cells.
Upon binding antigen B cell get activated and proliferate, and the cells generated undergo differentiation into effector cells, which are in this case antibody forming cells or plasma cells, and memory B cells as described previously.
Слайд 272

Cytokines Produced by Macrophages in the Inflammatory Response Killing of cancer

Cytokines Produced by Macrophages in the Inflammatory Response

Killing of cancer cells,

virus or bacteria-infected cells by causing these cells to undergo apoptosis, similarly to cytotoxic T cells (described in later slides)
Слайд 273

Function of NK cells NK cell has inhibitory receptors that bind

Function of NK cells

NK cell has inhibitory receptors that bind

to body cell expressing MHC-I. This is a mechanism to prevent the killing of body cell by NK cells.
Some cancer cells that fail at expressing MHC-I are killed by NK cells.
Cancer cells are also killed by NK cells if they are coated by antibodies to cancer antigens. This process is called ADCC (Antibody-Dependent Cellular Cytotoxicity).
Слайд 274

Слайд 275

The adaptive immune response

The adaptive immune response

Слайд 276

The Adaptive Immunity The Adaptive Immunity is also called Acquired Immunity.

The Adaptive Immunity

The Adaptive Immunity is also called Acquired Immunity. This

form of immunity is characterized by specificity in binding antigen and memory in response upon subsequent encounter with the same antigen.
The cells of the acquired immunity are the B cells and T cells. Common characteristics between these cells are their high specificity in the recognition of antigens. Only a few cells can recognize a given antigen, and these cells get activated and then proliferate and differentiate into effector cells and memory cells
Our focus is on B cells, T helper cells (Th), and cytotoxic T (Tc) cells. The effector B cells are plasma cells that produce specific antibodies against the antigen, whereas the effector Th cells produce cytokines that activate other immune cells, and effector Tc specifically kill altered or infected cells in the body. While B cell receptor (BCR) can bind antigen directly, TCR-2 of Th can only bind antigen peptide in association with MHC class II, and TCR-2 of Tc can only bind antigen peptide in association with MHC-I.
Слайд 277

B lymphocytes As illustrated, there is a repertoire of B cells

B lymphocytes
As illustrated, there is a repertoire of B cells that

differ from each other in antigen binding specificity. BCRs consist of cell surface antibody molecules that are represented in different colors.
A. Clonal selection by antigen
Clonal activation
Clonal proliferation and differentiation into plasma cells and memory cells
Secondary immune response is mediated by activation of memory cell which responds much faster and at much higher levels compared to the initial B cell

A B C D

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T Lymphocytes or T cells. These cells are cells of the

T Lymphocytes or T cells.
These cells are cells of the

adaptive cell-mediated immunity.
There are two types of T cells, which differ in T cell receptors for
antigen (abbreviated as TCRs): These cells include the TCR-1 T
cells and TCR-2 T cells based on the type of TCRs.
TCR-1 is a dimer composed of a γ and a δ chains and, like BCR, it can bind directly foreign antigen. These cells do not have the characteristics of cells of the adaptive immunity, and hence will not be addressed in this lecture.
TCR-2 is a dimer composed of a α and a β chains. TCR-2 T cells cannot bind directly antigens and they are divided into two groups of cells based on the presence of CD4 (example Th cells) or CD8 (example Tc cells) surface molecules.
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CD4+ T cells, also called CD4 T cells include T helper

CD4+ T cells, also called CD4 T cells include T helper

cells (Th), follicular T helper cells (Tfh), and regulatory T cells or Tregs. We will focus first on Th cells. As mentioned above, these cells cannot bind directly protein antigens, but only foreign antigen peptide that is associated with MHC class II molecule (abbreviated as Agp:MHC-II complex) that are expressed on antigen-presenting cells (APCs : Macrophages, B cells and Dendritic cells). TCR-2 T cells undergo clonal selection upon binding the corresponding Agp:MHC complexes, they get activated and undergo clonal proliferation and differentiation into effector cells that can carry out their specific functions, and memory cells.
CD8+ T cells that are also referred to as cytotoxic T lymphocytes (CTLs) bind to Agp:MHC-I complex that are expressed on infected or altered cells in the body and kill these cells by the induction of apoptosis.  
Слайд 280

Elimination of infected body cells Elimination of extracellular antigens Functions of

Elimination of infected body cells

Elimination of extracellular antigens

Functions of T-helper (Th)

cells vs cytotoxic T (Tc) cells
Слайд 281

Killing of Target cells by Cytotoxic T cells Tc recognizes target

Killing of Target cells by Cytotoxic T cells

Tc recognizes target cell

by TCR-2 of Tc binding to Agp:MHC-I complex that are expressed on the surface of the host infected cells
Activated Tc expresses perforin molecules, which polymerize in the target cell membrane and create a polyperforin channel through which serine protease granzymes are transferred from Tc to the target cells
Granzymes induce the apoptosis of the target cell.
Слайд 282

Слайд 283

Antigen Processing & Presentation There are two pathways of antigen processing

Antigen Processing & Presentation

There are two pathways of antigen processing and

presentation.
The exogenous or endocytic pathway
The protein antigen is extracellular.
Endocytosis of extracellular antigen.
Processing in an endosome by proteases into antigen peptides.
Association of peptide antigen (Agp) in association with MHC-II.
Presentation of Agp: MHC-II complex on the antigen processing .
cell (APC: dendritic cells, B cells & macrophages) to cognate
CD4+ helper T cell.
Слайд 284

2. The endogenous or cytosolic pathway of antigen processing. The foreign

2. The endogenous or cytosolic pathway of antigen processing.
The foreign or

worn-out protein antigen is inside of a host cell.
Processing of the protein antigen occurs in the proteasome in the cytoplasm
Antigen peptides enter the RER through the membrane-associated TAP1 and TAP2.
The antigen peptide is loaded onto the antigen loading complex (which is composed of MHC-I associated with calreticulin, ERP57, and Tapasin which bins to TAP-1 and TAP-2
The Agp: MHC-I complex is transported by the Golgi apparatus to the cell surface.
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Endocytic or exogenous pathway of antigen and presentation to Th cells

Endocytic or exogenous pathway of antigen and presentation to Th cells


Only Antigen Presenting cells (APCs) can present antigen peptide:MHC-II comlex to Th cells. APCs include
Macrophages, B cells and dendritic cells

Endogenous pathway of antigen and presentation to Th cells
All cells in the body can process intracellular antigen for presentation to Tc

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