Chapter 25Lecture Outline
Microbial Pathogenesis
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Overview
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 Pathogens: bacterial,
viral, and fungal agents of disease
Parasites: protozoans and worms causing disease
Definitions are typically used in microbial pathogenesis
Filaria Wucheria bancrofti causing elephantiasis.
Fungus Trichophyton rubrum causing athletes’s foot.
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Host-Pathogen Interactions: Definitions (1)
Colonization 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
Primary pathogens Have ability to penetrate host defenses and cause disease in a healthy
host Opportunistic pathogens
Cause disease only in compromised hosts 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) Virulence
Measure of degree or severity of disease Rate of lethal infections Lethal dose = LD50
Number of organisms to kill 50% of hosts
Infectious dose (for organisms that do not cause death) = ID50
Number of organisms to colonize 50% of hosts
Pathogenicity of organism Measure of ability to cause disease A function of infectivity and virulence
Determined by genetic makeup of organism
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Measurement of Virulence
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Infection Cycles
Transmission Entry
Colonization Invasion
Dissemination Exit
Adherence factors
ToxinsImmune evasion
Pathogenicity factors
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Transmission of Infections (1) Spread via direct contact
Example: common cold Indirect contact
Contact with fomites Inanimate objects Example: S. aureus infection
Via vectors Example: Mosquitoes (malaria) Reservoir for disease organism
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 Serve microbial attachment Human body expels invaders
Mucosa, dead skin constantly expelled Liquid expelled from bladder Coughing, cilia in lungs Expulsion of intestinal contents
Bacteria must adhere to host tissue Pili (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 Type I pili adhere to mannose
Grows from outer membrane New subunits added at base
E.g. uropathogenic E.coli
Type IV pili 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 bind to respiratory ciliated cells
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Toxins Subvert Host Function Exotoxins
SecretedTypically proteinsSpecific targets and effects
EndotoxinSame as lipopolysaccharidePart 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 synthesis Inhibition
2nd messenger pathway Disruption
Immune system Overstimulation (superantigens)
Proteases Degrade host proteins
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Mode of Action of Selected Exotoxins
Pore forming toxinsE.G: S. aureus alpha toxinTransmembrane, oligomeric, beta barrel pore
AB toxinB: mediates binding to hostA: subunit with toxic activity cleaving 28S rRNA in eukaryotic ribosomes
E. coli enterotoxigenic heat stable toxinStimulates guanylate cyclaseIncreases cGMP levelsAffects electrolyte flux, increases water efflux.
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ADP-Ribosylating Toxins
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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Cholera toxin Ribosylates to overactivate
adenylate cyclase cAMP activates ion transport,
water follows Uncontrollable diarrhea
Diphtheria toxin Ribosylates elongation factor 2 Blocks ribosome function, cell
dies Forms pseudomembrane over
trachea
ADP-Ribosylating Toxins
C. diphtheriae
V. cholerae
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ADP-Ribosylating ToxinsAnimation: 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 toengulf bacterium
Salmonella injects over 13 toxinsAlters fusion of vesicles in cellCauses diarrhea in host
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The Needle Complex of the Type III Secretion System
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
hostFacultative intracellular organismsObligate intracellular organisms
Change surface Inhibit immune defenses
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Surviving within the Host Outside host cell, how to avoid death?
Complement, antibodies bind pathogen and enhance uptake by phagocytes (opsonization)
Some pathogens secrete thick capsule Streptococcus pneumoniae, Neisseria meningitidis
Some pathogens make proteins to bind antibodies 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 fuses with acidic lysosome Some pathogens secrete proteins to prevent fusion
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 transductionDetect 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 Change of capsid alteration allows virus to re-infect
Creates novel epitopes Influenza virus antigenic drift
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
Influenza virus antigenic shift 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 QuizBacteria prevent being flushed from the intestine by means of
a. The Type II secretion system
b. Inhibition of immune system cells
c. Type IV pili and adhesins
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Concept QuizCholera toxin A subunit causes ADP-ribosylation of its target, and is an example of
a. A neurotoxin, which inhibits neural function
b. An enterotoxin, which disrupts function of the intestine
c. A cytotoxin, which kills infected host cells
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Concept QuizMost bacteria avoid the lysosome. One bacterium that welcomes lysosome acidity is
a. Shigella flexneri
b. Legionella pneumophila
c. Coxiella burnetii
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Concept QuizNew vaccines to influenza virus must be taken each year, because this virus undergoes
a. Antigenic drift
b. Binding to multiple receptors
c. Inhibition of p53 to allow unchecked growth
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