Introduction to Host-Microbe Interactions

1. Introduction to Host-Microbe Interactions

2. Normal Flora • More bacterial than human cells in the body • provide some nutrients (vitamin K) • stimulate immune system, immunity can be cross-reactive against certain pathogens • Prevent colonization by potential pathogens (antibiotic-associated colitis, Clostridium difficile)

3. Potential Colonization Sites

4. Types of Pathogens • Primary Pathogens • Cause disease upon infection, not normally associated with host • Plague (Yersinia pestis), influenza virus • Opportunistic Pathogens • Cause disease under some circumstances, sometime members of normal flora • Pseudomonas, Candida albicans

5. Progression of Disease • Transmission: infectious dose from 10-106 organisms • Incubation period: few days (common cold)-weeks (hepatitis A)-months (rabies) • Convalescence: • Clearing (Strep throat, S. pyogenes) • Latency (Chicken pox, tuberculosis, cold sores)

7. Koch’s Postulates • Proposed by Robert Koch • Conclude that a microbe causes a particular disease • Must fulfill four postulates • 1. Microorganism must be present in every case of the disease • 2. Organism must be grown in pure culture from disease hosts • 3. Produce the same disease from the pure culture • 4. Organism recovered from experimentally infected hosts

8. Molecular Postulates • Describe virulence factors • Four postulates • 1. Virulence gene or its product must be present • 2. Virulence gene must transform a non-pathogen into a pathogen • 3. Virulence gene must be expressed during disease process • 4. Antibodies against gene products are protective

9. Establishing an Infection • 1. Encounter: • fecal-oral (cholera) • human-human (tuberculosis) • animal-human (rabies) • vector-borne (plague, lyme disease) • environmental contact (anthrax)

10. Establishing an Infection • 2. Adherence • Prevents early clearance • Often bind host tissues via pili • Specificity can determine host range of pathogen

13. Establishing an Infection • 3. Colonization: multiplication and maintainance • Competition with normal flora • Resist: • bile • stomach acid • peristalsis • skin secretions • IgA (mucosal antibodies) • compete with host for iron

14. Establishing an Infection • 4. Molecule Delivery • Affects target cell structure and host response

16. Invasion:Breaching Anatomical Barriers • Find new niche with few competitors • Gain access to rich nutrient supply • 1. Skin: tough barrier, rely on wounds or insect vectors • 2. Crossing mucous membrane (e.g. intestinal epithelial cells)

17. Zippering-model of invasion Tight ligand-receptor interactions direct uptake “one at a time” uptake

18. Ruffling method of invasion General induced cellular response Can lead to co-invasion of other bacteria in close proximity

19. M cell Invasion • M cells are a portal to the immune system • Important site of “antigen sampling” • Some pathogens use phagocytic nature of M cells to access deeper tissues by transcytosis

21. Avoiding the Host Defenses • 1. Hiding within host cells • Avoid exposure to host antibodies if remain intracellular • Access to rich source of nutrients

23. Cell-to-cell Spreading Shigella and Listeria species lyse out of vacuole -assemble actin at pole -actin propels them into neighboring cell “convergent evolution” “molecular mimicry”

24. Avoiding the Host Defenses • 2. Avoiding complement killing • Complement factors in blood serum can assemble into MAC “membrane attach complex” that are bactericidal • C3b is first component of complex to bind • Some bacteria bind factors that regulate C3b activity, prevent MAC assembly • “serum-resistance”

26. Avoiding the Host Defenses • 3. Avoiding phagocytosis • Innate immune cells engulf (phagocytose) and kill microorganisms with degradative enzymes • Block signaling molecule production or degrade them after production • C5a cleaved by C5a peptidase of Strep pyogenes (strep throat)

28. Avoiding the Host Defenses • 3. Avoiding phagocytosis • Capsule production on surface of bacteria: capsule leads to C3b inactivation-”serum resistance” • M protein of Streptococcus: also inactivates C3b • Fc receptors: bind antibodies and orient dangerous end away from bacteria • Found in Streptococcus (Protein G) and Staphylococcus (Protein A)

30. Survival Strategies within Phagocytes • A niche without competitors • Phagosomal escape: lyse out of vacuole and grow in cytoplasm of host cell • Shigella and Listeria

31. Survival Strategies within Phagocytes • Blocking lysosomal fusion: prevent delivery of degradative enzymes to bacterial compartment • Mycobacterium (tuberculosis) • Salmonella (food poisoning or typhoid fever) • Legionella (Legionnaire’s disease)

33. Survival Strategies within Phagocytes • Surviving lysosomal fusion: • Coxiella • Legionella

35. Avoiding Antibodies • 1. IgA protease: cleaves Ab’s found in mucosal secretions (Neisseria gonorrhoeae) • 2. Antigenic variation: turning pili On and Off, or switching to new pilus • 3. Mimicking the host: look like self-antigens • Streptococcus pyogenes has capsule of hyaluronic acid, also made by host tissues

36. Damage to Host (Disease) • 1. Exotoxins • May require prior colonization (cholera) • May cause food poisoning even in absence of organism • Botulism or Staphylococcus aureus toxin • Immune system often target toxin for neutralizing Ab’s • Vaccine against toxin • A-B toxins: A is catalytic subunit, B binds host cells

38. Damage to Host (Disease) • 2. Membrane-damaging toxins • Hemolysins • Cause cell-lysis: Streptolysin O • Phospholipases • Cleave lipids in membranes: Clostridium perfringens • Gas gangrene

39. Damage to Host (Disease) • 3. Superantigens • Hyperstimulate the immune system • 1/5 T cells stimulated rather than 1/10,000 • Fever, nausea, diarrhea, vomiting • Leads to shock • Organ failure, circulatory collapse • Cause of toxic shock syndrome (TSST) • Staphylococcus aureus and Streptococcus pyogenes

41. Damage to Host (Disease) • 4. Endotoxins (attached to cell) • LPS, in the outer leaflet of Gram negative bacteria • Lipid A is toxic if organisms enter bloodstream • Massive immune cell infiltration • Activation of coagulation • Intravenous fluids are screened for Lipid A

43. Damage due to the Immune System • Inflammation: bacterial meningitis • Neisseria meningitis • Antigen-Ab complexes • Settle in kidney or joints • Glomerulonephritis from S. pyogenes • Cross-reactive Ab’s • Ab’s against pathogen may cross-react with host tissues • Accute rheumatic fever, complication of Strep throat