Chapter 25
Lecture Outline
Microbial Pathogenesis
Overview
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25.1 Host Pathogen Interactions
25.3 Virulence factors: Microbial attachment
25.4 Toxins: A way to subvert host cell function
25.5 Type III protein secretion and pathogenesis
25.6 Finding virulence genes with signature
tagged mutagenesis
25.7 Surviving within the host
25.8 Viral pathogenesis
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Pathogens and Parasites
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Pathogens: bacterial,
viral, and fungal agents
of disease
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Parasites: protozoans
and worms causing
disease

Definitions are typically
used in microbial
pathogenesis Microbiology: An Evolving Science
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Fungus Trichophyton rubrum
causing athletes’s foot.
Filaria Wucheria bancrofti
causing elephantiasis.
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Host-Pathogen Interactions:
Definitions (1)
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Colonization

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Presence of microbes on body surfaces
Infection

Entry and growth of pathogen or parasite
 Infection does not always cause disease
 Most infections removed by immune system
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Primary pathogens
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Have ability to penetrate host defenses and cause disease in a healthy
host
Opportunistic pathogens
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Cause disease only in compromised hosts
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Immune system defective
Break in tissue barrier allows organism access to new site
Loss of normal microbiota allows organism to bloom
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Host-Pathogen Interactions:
Definitions (2)
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Virulence
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Measure of degree or severity of disease
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Rate of lethal infections
Lethal dose = LD50
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Infectious dose (for organisms that do not cause death) = ID50
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Number of organisms to kill 50% of hosts
Number of organisms to colonize 50% of hosts
Pathogenicity of organism
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Measure of ability to cause disease
A function of infectivity and virulence
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Determined by genetic makeup of organism
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Measurement of Virulence
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Infection Cycles
Transmission
 Entry
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 Colonization
 Invasion
Dissemination
 Exit
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Adherence factors
Toxins
Immune evasion
Pathogenicity factors
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Transmission of Infections (1)
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Spread via direct contact
 Example:

common cold
Indirect contact
 Contact
with fomites
Inanimate objects
 Example: S. aureus infection
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
Via vectors
Example: Mosquitoes (malaria)
 Reservoir for disease organism
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
May not show disease symptoms
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Transmission of Infections (2)
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Port of Entries

Skin
 Hard
to penetrate (keratin)
 Requires usually lesion or injection

Mucosal surfaces
 Respiratory
tract
 Intestinal tract
 Urogenital tract

Exit site is usually same as entry site
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Adherence Factors
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
Serve microbial attachment
Human body expels invaders
 Mucosa,
dead skin constantly expelled
 Liquid expelled from bladder
 Coughing, cilia in lungs
 Expulsion of intestinal contents
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Bacteria must adhere to host tissue
 Pili
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(fimbriae)
Hollow fibrils with tips to bind to host cells
 Adhesins

surface proteins that bind to host cells
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Microbial Attachment via Pili
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Type I pili adhere to mannose
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Grows from outer membrane
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New subunits added at base
E.g. uropathogenic E.coli
Type IV pili
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Grow from inner membrane
Can grow and retract
Twitching motility
E.g. Neisseria gonorrhoeae
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Microbial Attachment via Adhesins

Streptococcus pyogenes uses M
protein to attach to respiratory
cells
B. pertussis uses pertactin and
filamentous hemagglutinin to
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bind to respiratory ciliated cells
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Toxins Subvert Host Function
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Exotoxins
 Secreted
 Typically
proteins
 Specific targets and effects

Endotoxin
 Same
as lipopolysaccharide
 Part of the outer membrane
 Activates host defense resulting in acute
inflammatory response including fever
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Exotoxins

Five target of protein exotoxins
 Cell

membrane
Leakage
 Protein

Inhibition
 2nd

synthesis
messenger pathway
Disruption
 Immune

system
Overstimulation (superantigens)
 Proteases

Degrade host proteins
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Mode of Action of Selected Exotoxins
Pore forming toxins
E.G: S. aureus alpha toxin
Transmembrane, oligomeric,
beta barrel pore
AB toxin
B: mediates binding to host
A: subunit with toxic activity
cleaving 28S rRNA in eukaryotic
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ribosomes
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E. coli enterotoxigenic heat stable
toxin
Stimulates guanylate cyclase
Increases cGMP levels
Affects electrolyte flux, increases
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water efflux.
ADP-Ribosylating Toxins
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Often AB toxins
Active toxin is an ADP-ribosyltransferase
Found among toxins that inhibit protein
synthesis (e.g. diphteria toxin) and among toxins
that disrupt 2nd messenger pathways (e.g.
cholera toxin)
ADP-ribosylated proteins may be inhibited or
activated
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ADP-Ribosylating Toxins
V. cholerae

Cholera toxin


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Ribosylates to overactivate
adenylate cyclase
cAMP activates ion transport,
water follows
Uncontrollable diarrhea
Diphtheria toxin


C. diphtheriae
Ribosylates elongation factor 2
Blocks ribosome function, cell
dies

Forms pseudomembrane over
trachea
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ADP-Ribosylating Toxins
Animation: Cholera Toxin Mode of Action
Click box to launch animation
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Type III Protein Secretion

Injects proteins directly into host cell
 “Hypodermic
needle” similar to base of flagellum!
 Genes on pathogenicity island

Injected proteins cause host to
engulf bacterium

Salmonella injects over 13 toxins
 Alters
fusion of vesicles in cell
 Causes diarrhea in host
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The Needle Complex
of the Type III
Secretion System
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
Proteins are directly
injected into host
cytoplasma
Apparatus is related to
flaggela assembly
proteins
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Immune Evasion
Prevent uptake
 Allow uptake but prevent degradation by
host

 Facultative
intracellular organisms
 Obligate intracellular organisms
Change surface
 Inhibit immune defenses

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Surviving within the Host
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Outside host cell, how to avoid death?
 Complement,
antibodies bind pathogen and
enhance uptake by phagocytes (opsonization)

Some pathogens secrete thick capsule


Some pathogens make proteins to bind antibodies

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Streptococcus pneumoniae, Neisseria meningitidis
Staphylococcus aureus cell wall Protein A
 Antibodies attach “upside down”
 Prevents opsonization
Some pathogens cause apoptosis (suicide) of
phagocytes
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Surviving within the Host

Once inside host cell, how to avoid death?
 Cell

ingests pathogens in phagosome
Some pathogens use hemolysin to break out

Shigella dysenteriae, Listeria monocytogenes
 Phagosome

Some pathogens secrete proteins to prevent fusion


fuses with acidic lysosome
Salmonella, Chlamydia, Mycobacterium
Some pathogens mature in acidic environment

Coxiella burnetii—Q fever
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How do Bacteria Recognize Host
Environment?
 Two-component
signal transduction
 Detect magnesium concentration, pH

Both low in host cell vacuole
 Quorum
sensing
Detect exotoxins made by other cells
 Delays toxin synthesis until many bacteria present


Possible pathway for preventing pathogen growth?
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Selected Viral Pathogenesis:
Immune Evasion
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Change of capsid alteration allows virus to re-infect

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Creates novel epitopes
Influenza virus antigenic drift
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Influenza virus antigenic shift
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Subtle changes in surface structure
RNA Polymerase does not correct replication errors
Frequent mutations in haemagglutinin gene
If allows virus to avoid immune system, virus spreads
New flu vaccine needed every year
Major changes in surface proteins
Infection of the immune system

HIV infects T helper cells

Central regulators of our adaptive immune system
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Concept Quiz
Bacteria prevent being flushed from the
intestine by means of
The Type II secretion system
b. Inhibition of immune system cells
c. Type IV pili and adhesins
a.
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Concept Quiz
Cholera toxin A subunit causes ADPribosylation of its target, and is an example
of
A neurotoxin, which inhibits neural
function
b. An enterotoxin, which disrupts function
of the intestine
c. A cytotoxin, which kills infected host
cells
a.
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Concept Quiz
Most bacteria avoid the lysosome. One
bacterium that welcomes lysosome acidity
is
Shigella flexneri
b. Legionella pneumophila
c. Coxiella burnetii
a.
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Concept Quiz
New vaccines to influenza virus must be
taken each year, because this virus
undergoes
Antigenic drift
b. Binding to multiple receptors
c. Inhibition of p53 to allow unchecked
growth
a.
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