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Host-Pathogen Interactions
Symbiosis
• Commensual• Mutualistic• Parasitic
Normal microbiota
• DYNAMIC!• Resident vs transient• Protective functions:– Block attachment– Consume nutrients– Produce antibiotics
Normal microbiota
• Other beneficial functions?– Digestion and
absorption of nutrients
– Production of vitamins and fatty acids
– Stimulation and regulation of the immune system
Normal microbiota
• Can also become opportunistic pathogens– Injury to normal mucosal
or skin surfaces– Antibiotic use
Colonization
• 2 possible outcomes:– Symbiosis – commensual or
mutualistic– Infection = parasitic symbiosis
• Infection:– Subclinical vs infectious
disease– Primary vs secondary
infection– Opportunist vs primary
pathogen
What determines outcome of infection?
• Host defenses• Predisposing infection• Pathogenicity• Infectious dose
Establishing infection• Adherence
– Pili, capsules, cell wall components – binding to receptors on host cells
• Colonization– Compete for iron, nutrients– Resist opsonization– Resist resident microbiota’s
antimicrobials
• Invasion/translocation – Type III secretion systems– Directed uptake– Exploitation of antigen sampling
processes
Type III Secretion System
• Pore-forming protein inserted in host cell membrane = type III translocon
• aka“injectisome” – bacterial proteins = virulence factors are injected into host cell cytoplasm
Exploitation of antigen sampling processes
Avoiding host defenses
• Hide in cells• Avoid complement-
mediated killing• Avoid phagocytosis• Survive in phagocytes• Avoid antibodies
Avoiding phagocytosis: Don’t get seen, don’t get recognized or don’t get caught– C5a peptidase– C3b binding sites:
capsules, M protein – Membrane damaging
toxins– Fc receptors
Surviving in phagocytes
• Escape from phagosome
• Block fusion of the phagosome and lysosome
• Survive in the phagolysosome
Avoiding antibodies
• IgA protease• Antigenic variation• Molecular mimicry
Disease: damage to host
• Damage caused by bacterial exotoxins– Proteins synthesized by
bacteria– Highly specific
interactions with host cells
– Highly immunogenic• Toxoids• Antitoxin
Disease: damage to host
• Damage caused by the immune response– Inflammation– Immune complex
deposition– Cross-reaction of
antibodies with host tissues
Types of exotoxins: functional/target tissue classification
• Enterotoxins: bind to receptors on enterocytes; alter function but do not kill target cells
• Neurotoxins: target cells in peripheral nervous system, interfere with nerve signal transduction (↑ or ↓)
• Cytotoxins: receptors may be present on a single cell type or many cell types; toxin is lethal to target cells
Types of exotoxins: structural/mechanistic classification
• A-B toxins– Inhibit protein
synthesis– Interfere with cell
signaling systems
• Membrane-damaging toxins
• Superantigens
Diseases caused by A-B type exotoxins
• Cytotoxins– Anthrax: Bacillus anthracis – lethal toxin,
edema toxin (A-B toxins)– Pertussus (whooping cough): Bordetella
pertussis – pertussis toxin (A-B toxin)– Diphtheria: Corynebacterium diphtheriae –
diphtheria toxin – Hemolytic uremic syndrome: Escherichia coli
O157:H7 – Bacillary dysentery: Shigella dysenteriae (and
less severe forms caused by other Shigella species)
Diseases caused by A-B type exotoxins
• Enterotoxins– Cholera: Vibrio cholerae– Traveler’s diarrhea:
many possible etiologies, but most cases are caused by enterotoxigenic strains of Escherichia coli
Diseases caused by A-B type exotoxins
• Neurotoxins– Botulism: – Clostridium botulinum– Tetanus: – Clostridium tetani
Diseases caused by membrane-damaging exotoxins
• Gas gangrene: Clostridium perfingens
• Strep throat: Streptococcus pyogenes
• Abscesses – pyogenic bacteria (many)
Diseases caused by superantigens
• Some foodborne intoxications
• Toxic shock syndromes• Autoimmune disease, i.e.
rheumatoid arthritis
AnthraxEtiologic agent: Bacillus anthracisToxins: edema toxin (protective antigen + edema factor) and lethal toxin
(protective antigen + lethal factor)Toxin type: A-B toxins
B component of both = protective antigenA component of edema toxin = edema factorA component of lethal toxin = lethal factor
Target cell: many cells, many mammals – receptor =highly conserved
Diphtheria
Etiologic agent: Corynebacterium diphtheriae
Toxin: diphtheria toxinToxin type: A-B toxinCell type with receptor:
many human cellsToxin is encoded by a
bacterial phage (virus)
BotulismEtiologic agent: Clostridium
botulinum = G+ rod; obligate anaerobe; widespread
Toxin: BoNTsToxin type: A-B toxinsTarget cell: motor nerves at NM
junction – people and dogs most suscecptible
Effect: blocks release of acetylcholine = excitatory neurotransmitter → no nerve signal transmission → flaccid paralysis
TetanusEtiologic agent: Clostridium tetani =
G+ rod; obligate anaerobe; widespread
Toxin: TeTxToxin type: A-B toxinTarget cell: spinal cord – receptors
are highly conserved but susceptibiltiy is variable; people & horses most susceptible
Effect: blocks release of GABA and glycine = inhibitory neurotransmitters → spastic or rigid paralysis
CholeraEtiologic agent: Vibrio
choleraeToxin: cholera toxinToxin type: A-B toxinCell type with receptor:
human enterocytesEffect: secretion of Cl-;
H2O and Na+ follow = severe watery diarrhea
Superantigens
• Bind directly to the outside of MHC-II molecules and the TCRs
• Activate many T4-lymphocytes
• A specific TCR is not required for activation.
Endotoxin
• Non-specific: triggers innate immune response; no antibody to endotoxin is produced
• Effect on cells is widespread
• A component of all (and only) Gram-negative bacteria
Viral pathogenesis
• Binding to host cells• Invasion of host cells• Interference with host
defenses• Regulation of apoptosis