Host-Pathogen Interactions

1. Host-Pathogen Interactions

2. Symbiosis • Commensual • Mutualistic • Parasitic

3. Normal microbiota • DYNAMIC! • Resident vs transient • Protective functions: • Block attachment • Consume nutrients • Produce antibiotics

4. Normal microbiota • Other beneficial functions? • Digestion and absorption of nutrients • Production of vitamins and fatty acids • Stimulation and regulation of the immune system

5. Normal microbiota • Can also become opportunistic pathogens • Injury to normal mucosal or skin surfaces • Antibiotic use

6. Colonization • 2 possible outcomes: • Symbiosis – commensual or mutualistic • Infection = parasitic symbiosis • Infection: • Subclinical vs infectious disease • Primary vs secondary infection • Opportunist vs primary pathogen

7. What determines outcome of infection? • Host defenses • Predisposing infection • Pathogenicity • Infectious dose

8. 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

9. 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

10. Exploitation of antigen sampling processes

11. Avoiding host defenses • Hide in cells • Avoid complement-mediated killing • Avoid phagocytosis • Survive in phagocytes • Avoid antibodies

12. 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

14. Surviving in phagocytes • Escape from phagosome • Block fusion of the phagosome and lysosome • Survive in the phagolysosome

15. Avoiding antibodies • IgA protease • Antigenic variation • Molecular mimicry

16. Disease: damage to host • Damage caused by bacterial exotoxins • Proteins synthesized by bacteria • Highly specific interactions with host cells • Highly immunogenic • Toxoids • Antitoxin

17. Disease: damage to host • Damage caused by the immune response • Inflammation • Immune complex deposition • Cross-reaction of antibodies with host tissues

18. 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

19. Types of exotoxins: structural/mechanistic classification • A-B toxins • Inhibit protein synthesis • Interfere with cell signaling systems • Membrane-damaging toxins • Superantigens

20. Diseases caused by A-B type exotoxins • Cytotoxins • Anthrax: Bacillus anthracis – lethal toxin, edema toxin (A-B toxins) • Pertussus (whooping cough): Bordetellapertussis – pertussis toxin (A-B toxin) • Diphtheria: Corynebacteriumdiphtheriae – diphtheria toxin • Hemolytic uremic syndrome: Escherichia coli O157:H7 • Bacillary dysentery: Shigelladysenteriae(and less severe forms caused by other Shigellaspecies)

21. Diseases caused by A-B type exotoxins • Enterotoxins • Cholera: Vibriocholerae • Traveler’s diarrhea: many possible etiologies, but most cases are caused by enterotoxigenic strains of Escherichia coli

22. Diseases caused by A-B type exotoxins • Neurotoxins • Botulism: • Clostridium botulinum • Tetanus: • Clostridium tetani

23. Diseases caused by membrane-damaging exotoxins • Gas gangrene: Clostridium perfingens • Strep throat: Streptococcus pyogenes • Abscesses – pyogenic bacteria (many)

24. Diseases caused by superantigens • Some foodborne intoxications • Toxic shock syndromes • Autoimmune disease, i.e. rheumatoid arthritis

25. Anthrax Etiologic agent: Bacillus anthracis Toxins: edema toxin (protective antigen + edema factor) and lethal toxin (protective antigen + lethal factor) Toxin type: A-B toxins B component of both = protective antigen A component of edema toxin = edema factor A component of lethal toxin = lethal factor Target cell: many cells, many mammals – receptor =highly conserved

26. Diphtheria Etiologic agent: Corynebacteriumdiphtheriae Toxin: diphtheria toxin Toxin type: A-B toxin Cell type with receptor: many human cells Toxin is encoded by a bacterial phage (virus)

27. Botulism Etiologic agent: Clostridium botulinum = G+ rod; obligate anaerobe; widespread Toxin: BoNTs Toxin type: A-B toxins Target cell: motor nerves at NM junction – people and dogs most suscecptible Effect: blocks release of acetylcholine = excitatory neurotransmitter → no nerve signal transmission → flaccid paralysis

28. Tetanus Etiologic agent: Clostridium tetani = G+ rod; obligate anaerobe; widespread Toxin: TeTx Toxin type: A-B toxin Target 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

29. Cholera Etiologic agent: Vibriocholerae Toxin: cholera toxin Toxin type: A-B toxin Cell type with receptor: human enterocytes Effect: secretion of Cl-; H2O and Na+ follow = severe watery diarrhea

30. 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.

31. 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

33. Viral pathogenesis • Binding to host cells • Invasion of host cells • Interference with host defenses • Regulation of apoptosis