Microbial Interference with Host Defenses

1. Medical Microbiology Microbial Interference with Host Defenses BIOL 533 Lecture 8

2. Overall Strategies • Defense against complement • Subversion of phagocytosis • Subversion of immune responses

3. General Aspects • Pathogen finds itself in hostile territory • Host fights back and usually—but not always—wins • Host’s defenses are interrelated and so are organism’s countermeasures

4. General Aspects • Given organism sometimes has numerous different virulence factors • Does not have to harm tissue to be called virulence factor, although many do • Have to determine precise role of each factor if a large number are involved • Not always sure in vitro situation is same as in disease state

5. Defense Against Complement • Overall strategies • Inhibit complement activation • Mask activating substances • Capsule • IgA antibodies • Cover up target of complement membrane attack complex

6. Defense Against Complement • Overall strategies, continued • Appropriate inhibitor to activation to surface • Inactivate complement chemotaxin C5a

7. Prevent Complement Activation • Masking surface components that activate by the alternative pathway • Capsules • Murein of S. aureus good activator, but is covered by capsule • Capsules rich in sialic acid of Group B streptococci and strains of E. coli

8. Prevent Complement Activation • IgA antibodies • Meningococci get coated with IgA antibody • Does not activate complement • Prevents other Ab that can activate from reaching surface of cell

9. Prevent Complement Activation • Cost of having capsule— antigenic • Elicits activation by primary pathway • Defend better against immediate defenses than later ones

10. Prevent Complement Activation • Cover up target of membrane attack complex (outer membrane) • Gram—, such as Salmonella or E. coli • Smooth strains with long ‘0’ antigen polysaccharide chain do not allow access of mac while rough strains (with little or no ‘0’ antigen) do • Correlates with pathogenicity

11. Subversion of Phagocytosis • Overall strategies • Inhibition of phagocyte recruitment • Microbial killing of phagocytes • Escape of ingestion

12. Subversion of Phagocytosis • Overall strategies, continued • Survival inside phagocytes • Escape into the cytoplasm • Inhibition of lysosome and phagosome fusion • Resistance to lysosomal enzymes • Inhibition of phagocyte oxidative pathway • Antibody effects (host counters)

13. Subversion of Phagocytosis • General aspects • Being inside cell is not necessarily bad for an organism • Powerful strategy is to grow within nonphagocytic cell • Shielded from antibodies and drugs

14. Subversion of Phagocytosis • Inhibition of phagocyte recruitment • Direct inhibition of neutrophil motility and chemotaxis • Bordetella pertussis produces toxins • Adenylate cyclase toxin • Increase cyclic AMP in neutrophils • Leads to paralysis • Pertussis toxin • Impairs migration of monocytes

15. Subversion of Phagocytosis • Microbial killing of phagocytes • Leukocidins (exotoxins) kill neutrophils and macrophages • Can work at distance or after ingestion • Typical producers are highly invasive bacteria • Pseudomonas, staphylococci, group A streptococci, gas gangrene clostridia

16. Subversion of Phagocytosis • Escaping ingestion • Naked capsule is effective (pneumococci) • Opsonized bacteria not as effective • Countering opsonization by complement components or Ab • Any mechanism inhibits • Activation of complement • Synthesis or activity of Ab

17. Subversion of Phagocytosis • Escaping ingestion, continued • Countering opsonization when antibodies are present • Staphylococci and streptococci • Make surface component (protein A) • Binds to IgG molecules by the wrong end (Fc region) • Cannot act as opsonins because Fc region not free to bind to Fc receptors on phagocytic cells • Not known if antiphagocytic defense is relevant to disease process

18. Subversion of Phagocytosis • Survival inside phagocytes • Escape into cytoplasm • Rickettsia (Rocky Mountain Spotted Fever) or trypanosomes of Chagas’ disease cross membrane of phagosome to enter cytoplasm • Since lysosomes do not secrete contents into cytoplasm, organism is safe • How they enter cytoplasm is not known for certain • Possess surface-bound phospholipase, which may weaken membrane

19. Subversion of Phagocytosis • Survival inside phagocytes, continued • Inhibition of lysosome and phagosome fusion • Examples—bacteria that cause: • Tuberculosis • Psittacosis • Legionnaire’s disease

20. Subversion of Phagocytosis • Mechanism of tuberculosis • Induced by complex glycolipids (sulfatides)—not certain • Facts: • Inhibition must be due to modification of phagosome membrane • Microorganism might contribute by compounds secreted or present on the surface

21. Subversion of Phagocytosis • Survival inside phagocytes, continued • Resistance to lysosomal enzymes—survive in phagolysosome (pH as low as 4) • Leishmania (protozoa)—resistance may be due to: • Resistant cell surfaces • Excretion of enzyme inhibitors

22. Subversion of Phagocytosis • Survival inside phagocytes, continued • Inhibition of phagocyte’s oxidative pathway • Bacillus of Legionnaire’s disease • Inhibits hexose-monophosphate shunt and oxygen consumption in neutrophils • Reduces respiratory burst for killing microbes • Staphylococci—produces catalase that degrades hydrogen peroxide necessary for oxidative killing

23. Subversion of Phagocytosis • Survival inside phagocytes, continued • Antibody effects: host counters parasite • Sometimes help host guard against microbial survival measures • Antibodies do not prevent entry into cells, but inhibit subsequent effects • Rickettsia coated with antibody cannot pass through membrane into cytoplasm • Antibodies against Legionnella prevent inhibition of phagolysosomal fusion

24. Subversion of Immune Response • Immunosuppression: general aspects • Host becomes susceptible to other infections and survival probability is lessened

25. Subversion of Immune Response • AIDS—infects T4 inducer-helper lymphocytes • Depletion of cells leads to collapse of immune system • Reduction in circulating lymphocytes • Impaired delayed hypersensitivity • Defective responses of T cells to Ag • Reduction in T-cell numbers cytotoxic for tumor cells and virus infected cells

26. Subversion of Immune Response • B cell function is also impaired • Reduced production of specific Ig • Increased chaotic production of nonspecific Ig

27. Subversion of Immune Response • Other immunosuppressive viruses: Measles • Tuberculosis more common after widespread measles outbreaks • Infected T cells in vitro do not die • Lose certain functions, including ability to mount delayed hypersensitivity response

28. Subversion of Immune Response • Infected B cells in vitro • Stop synthesizing and releasing Ig • Primary effect on B cells • Not secondary to action of virus on T cells or macrophage

29. Subversion of Immune Response • Other immunosuppressive viruses: Hepatitis B and influenza • Impair function of lymphoid cells without causing major structural damage • Immune suppression as a result of inhibition of synthesis of lymphokines • Leishmanias (protozoa)

30. Subversion of Immune Response • Leishmanias (protozoa)—when grown in macrophage • Suppress secretion of interleukin-1 • Important for initiating series of inflammatory and immunological reactions important for the eradication of the organism • Also explains T cell unresponsiveness • Suppresses capacity of macrophage to make class I and class II products of major histocompatibility locus (MHC) • Potential for marked suppression of cell-mediated immunity

31. Subversion of Immune Response • Final thoughts • Infection of lymphocytes is not immuno-suppressive in nature • Large number of organisms infect lymphoreticular tissues, but do not cause global disturbances to host immunity • Bacteria that cause typhoid fever or brucellosis live in lymph nodes for long period of time • Do not induce noticeable immune suppression

32. Subversion of Immune Response • Frequent changing of antigenic coats (antigenic variation) • Examples of bacteria, viruses, and protozoa • Trypanosomes (protozoa) • Gonococci • Borrelia (recurrent fever) • Influenza viruses

33. Subversion of Immune Response • Trypanosoma brucei (causative agent of sleeping sickness) • Infects blood of interstitial fluids of animals and man • Exposed to circulating Ab

34. Subversion of Immune Response • Trypanosoma brucei, continued • Covered with thick protein coat (variable surface glycoprotein) • Undergoes antigenic shifts during infection • Have several hundred genes that encode different antigens, but express only one at a time

35. Subversion of Immune Response • Trypanosoma brucei, continued • When antibodies against one type are made: • Number of parasites in blood drops • Soon replaced by new antigenic type • Can be many successive waves of antigenic changes in a single host • Protective immunity does not function well

36. Subversion of Immune Response • Gonococcus and its adhesin • Periodic change in • Pilin (protein fimbriae; attach to cells) • Major outer membrane proteins

37. Subversion of Immune Response • Antigenic variation among influenza viruses—major obstacle to effective vaccine (year after year) • Definitions • Antigenic drift—minor changes that occur every 2 to 3 years • Antigenic shift—major changes that occur about every 10 years

38. Subversion of Immune Response • Antigenic variation, continued • Mechanism involves two proteins • Hemagglutinin-binds to cell receptors • Neuraminidase-changes receptors

39. Subversion of Immune Response • Proteolysis of antibodies • Make extracellular proteases that inactivate secretory IgA antibody (major Ab type on human mucosal surfaces; subclasses I and II) • Cleave only subclass I at hinge region to leave complete by inactive peptide fragments • Examples: • Gonococci, meningococci, Haemophilus influenzae, and some pathogenic dental streptococci

40. Subversion of Immune Response • Proteolysis of antibodies, continued • Specificity of IgA1 proteases from different bacteria • Highly specific for subclass I • Biochemical and genetic differences that suggest property evolved independently • Presence in fluids and tissues • Active form in infected tissues and fluids

41. Subversion of Immune Response • Proteolysis of antibodies, continued • Possible relationship to pathogenicity; suggested, not proven • Nonpathogeic relatives lack these proteases • Fabulation (cleavage with Fab fragment attached) • Ag unavailable for binding with intact antibody molecules • May serve to protect some organisms against Ab

42. Subversion of Immune Response • Other viral survival strategies: general aspects • Chronic infection—evade host defenses longer

43. Subversion of Immune Response • Herpes infection • Do not usually enter extracellular fluid, but pass among cells through cytoplasmic bridges • Can also be latent (reside within nerve cells but do not multiply) • In these circumstances, not affect by antibodies, cell-mediated immunity, or interferon • Survive for long periods of time, then later reactivate (perhaps when defenses are lower)

44. Lecture 8 • Questions? • Comments? • Assignments...