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 Opportunistic 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 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