Host-microbe interactions Why do some organisms cause disease while others do not? Pathogens cause disease evade immun

1. Host-microbe interactions Why do some organisms cause disease while others do not? Pathogens cause disease evade immune system cause tissue damage Other (most) organisms harmlessly colonize the body

2. Host-microbe relationships • Mutualism (symbiosis) beneficial to both • Organisms produce vitamins or other substances that benefit us • Commensalism- microbes benefit from us but don’t harm us • Parasitism (pathogenesis)

3. Normal flora (microbiota) • Microbiome- unique and adaptable • Primes immune system • Components of microbiome can be pathogenic (opportunistic) • Primary pathogens are not part of normal flora

4. Pathogenesis of infectious disease How does an organism cause disease? (impairment of function) What is the course of disease? How is disease spread? How is the organism shown to be pathogenic? Is it always pathogenic (primary pathogen) or only is susceptible people (opportunistic) How virulent is the infectious organism?

5. Contagious (communicable) diseases are easily spread Sometimes the infectious dose is very low (therefore easier to spread) Infectious dose can be calculated

6. General sequence of events in infectious disease Infection may be localized or systemic

7. Koch’s postulates • Microbe is present in all affected individuals • Isolated from sick individual and grown in pure culture • Introduce organism into new individual, who develops the same disease • Isolate the same organism from the new host • Not all organisms can be tested in this exact way (Koch was lucky)

8. Molecular postulates: virulence FACTORS can be identified Virulence factor is only in pathogenic strains If factor is mutated organism becomes less virulent; when transferred to a non- pathogenic organism, the organism becomes pathogenic Immune response to pathogenic factor should be protective

9. Mechanisms of pathogenicity Toxin production (endotoxin or exotoxin) toxins can be produced in body or ingested Colonization (usually GI or respiratory tract) Invasion of tissues (avoids immune system) Or some combination!

10. Adhesion can be a necessary first step • Adhesins bind to specific molecules on bacterial cell surface • N. gonorrhoeae in reproductive tract • Different strains of E. coli bind to different tissues; normally large intestine

11. Mechanisms of pathogenesis • Colonization- requires ability to obtain food and evade immune mechanisms • Antigenic variation • IgA proteases • Siderophores • Secretion of substances that enable them to permeate host cells

12. How do microbes invade body Skin- through lesions or vectors (bites) Many bacteria have developed ways to get through innate immune barriers or by crossing epithelia (cells specialized for engulfment and/or transport) Some bacteria hide inside host cells (e.g., Listeria)

13. Avoiding immune mechanisms Gram-positive organisms are not sensitive to complement-mediated lysis Some Gram-negatives use complement receptors or special glycosylation Avoiding phagocytosis capsules; complement inactivation streptococci, staphylococci Antigenic variation: mimicking host cells

14. Surviving phagocytosis: Shigella, Listeria, Salmonella

15. How do toxins damage host? (see table 16.1) Neurotoxins- interfere with transmission of nervous signal C. botulinum- prevents release of acetylcholine (flaccid) C. tetani- blocks inhibitory neurons spastic

16. Enterotoxins- oversecretion of fluids into intestine- E. coli; V. cholerae Cytotoxins B. anthracis, B. pertussis- oversecretion C. diphtheriae, E. coli O157:H7, S. dysenteriae inhibit protein synthesis All of the above are A-B toxins

17. Membrane-damaging toxins have different structure, directly attacking cell membranes Example: hemolytic bacteria (can lyse other membranes beside RBC membranes)

18. Superantigens break the rules of antigen specificity Recall that T cells recognize antigen “presented” to them by MHC Class II on APCs Superantigens bind differently; can activate may different T cells simultaneously Excess stimulation can cause nausea, vomiting and sometimes shock S. aureus toxin is well characterized

19. Most exotoxins are not heat-stable (except S. aureus superantigen) Many exotoxins have been isolated and are used (as toxoids) for vaccines Endotoxin is actually component of Gram- negatives (LPS), so cannot be isolated Damage is due to inflammatory response to it can be fatal Limulus amoebocyte assay is used to test for endotoxins

21. Thus immune response itself can contribute to disease Inflammation Autoimmune disease (cross-reactive antibodies) Immune complex disease (type III hypersensitivity) Possible genetic component to susceptibility (MHC haplotype)

22. Viral pathogenesis All viruses must live within cell; some can cause chronic or latent infections Viruses bind to specific receptors on cells and (in animals) are endocytosed May stick to one type of tissue or spread

23. Evasion of immune response by viruses • Suppress host protein expression (interferons) • Keep cell alive to prolong viral replication • “Hide” from immune response by suppression of MHC Class I

24. Specific examples: Many viruses have evolved mechanisms that neutralize specific immune functions Influenza, HIV- avoid interferons (HIV-infect regulatory T cells!) Block MHC Class I expression Form syncytia (cells fuse together) Antigenic variation

25. Fungal infections Nature’s saprophytes can damage living tissue Effect is strong in immunocompromised patients Toxins (aflatoxin) Hypersensitivities

26. Helminths and protozoa Depends on organism and host tissue (and whether receptors are present) Malnutrition Damage to colonized tissue; dysfunction associated with that Can suppress immune response

27. Study of pathogenesis involves: Identification of virulence factors Understanding host range of organisms Normal host response to organism and how pathogen deals with it Strategies for prevention and treatment