Evasion of Immunity 2

1. Evasion of Immunity 2 Jo Hamilton Parasitology BS31820 Immunity to specific parasites & parasite immune evasion strategies.

2. Objectives and learning outcomes. • Familiar with both vert & invert immune responses to a variety of parasites. • Familiar with range of strategies used by parasites to evade hosts’ immune mechanisms. • Able to give specific examples of parasites & their immune evasion strategies.

3. Introduction. • Successful parasites - strategies for survival & development in invert & vert hosts.

4. Immunoparasitology (Parasite immunology). • Host - susceptible - parasite survives. • Host - insusceptible - parasite killed by innate immunity. • E.g. Humans insusceptible to larval stages of bird schistosomes (e.g. Trichobilharzia). • But get cercarial dermatitis (‘swimmers itch’). • In duck host - established infection.

5. Immunoparasitology. • Spontaneous-cure - parasite establishes but eventually expelled, e.g., Nippostrongylus brasiliensis. • Adult Nippostrongylus, releases protective antigens - not stage specific. • Resulting antibodies recognise targets on both adult worm & migrating infective larvae.

6. Immunoparasitology. • Parasites successfully adapted to innate & acquired immune responses of host. • Many factors involved in host susceptibility • e.g. genetic background, age, nutritional & hormonal status of individual.

7. Immunoparasitology. • Immune response mounted to protozoal & helminth infections. • Evidence- • Prevalence infection declines with age. • Immunodepressed individuals quickly succumb. • Acquired immunity in lab models.

8. Immunopathology. Parasites damage host by: • Competing for nutrients (e.g. tapeworms). • Disrupting tissues (e.g. Hydatid disease). • Destroying cells (e.g. malaria, hookworm, schistosomiasis). • Mechanical blockage (e.g. Ascaris). • Severe disease often has immune / inflammatory component.

9. Immunopathology - examples. • Cerebral malaria - TNF, IFN & other proinflammatory cytokines in brain. • Hepatosplenic schistosomiasis - anti-egg immune responses – granuloma & fibrosis. • Onchocerciasis - anti-microfilarial responses in eye = blindness. • Anaphylactic shock – e.g. rupture of hydatid cyst. Immediate hypersensitivity by parasite antigens. • Nephropathy - immune complexes in kidney (e.g. malaria, schistosomiasis).

10. Vertebrate Immune responses to Protozoan parasites. 1. Innate immune responses. • Extracellular protozoa eliminated -phagocytosis & complement activation. • T cell responses. • Extracellularprotozoa - TH2 cytokines - ab production. • Intracellular protozoa – TC (cytotoxic lymphocytes) kill infected cells. • TH1 cytokines activate macrophages & TC.

11. Vertebrate Immune responses to Protozoan parasites. 2. Innate & acquired immune responses. • Antibody + Complement, e.g. lysis of blood dwelling trypanosomes. • Activated macrophages effective against intracellular protozoa, e.g. Leishmania, Toxoplasma, Trypanosoma cruzi. • CD8+ cytotoxic T cells kill parasite infected host cells, e.g. Plasmodium infected liver cell.

12. Vertebrate Immune responses to Protozoan parasites. 3. Acquired immune responses. • Antibody responses. - Extracellular protozoa - opsonization, complement activation & Antibody Dependent Cellular Cytotoxicity (ADCC). -Intracellular protozoa - neutralisation e.g. neutralising ab prevents malaria sporozoites entering liver cells.

13. Invertebrate Immune responses to Protozoan parasites. • Melanotic encapsulation. E.g. Plasmodium oocysts in Anopheles gambiae. • Initiated by phenoloxidase activity. • Chemical & physical protection - oxidations --- melanin formation generate free radicals & toxic quinone intermediates.

14. Vertebrate Immune responses to helminth infections. • Most extracellular & too large for phagocytosis. • Some gastrointestinal nematodes - host develops inflammation & hypersensitivity. • Eosinophils & IgE initiate inflammatory response in intestine / lungs. • Histamine elicited - similar to allergic reactions.

15. Vertebrate Immune responses to helminth infections. • Acute response - IgE & eosinophil mediated systemic inflammation = worm expulsion. • Chronic exposure = chronic inflammation: • DTH, Th1 / activated macrophages - granulomas. • Th2 / B cell responses increase IgE, mast cells & eosinophils = inflammation.

16. Vertebrate Immune responses to helminth infections. • Helminths induce Th2 responses - IL-4, IL-5, IL-6, IL-9, IL-13 & eosinophils & ab (IgE). • Characteristic ADCC reactions, i.e. killer cells directed against parasite by specific ab. • E.g. Eosinophil killing of parasite larvae by IgE.

17. Invertebrate immune responses to helminth infections. • Melanotic encapsulation.Used tocontain filarial larvae (nematodes) in mosquitoes.

18. Parasite Immune Evasion –Evasion strategies. • Parasites need time in host - development, reproduce & ensure vector transmission. • Chronic infections normal. • Parasites evolved variety immune evasion strategies.

19. Protozoan immune evasion strategies. 1. Anatomical seclusion in vertebrate host. • Parasites may live intracellularly - avoid host immune response. • E.g. Plasmodium inside RBC’s - when infected not recognised by TC & NK cells. Other stages Plasmodium inside liver cells. • Leishmania parasites & Trypanosoma cruzi inside macrophages.

20. Protozoan immune evasion strategies. 2. Anatomical seclusion in invertebrate host. • Plasmodium ookinetes in serosal membrane - beyond reach haemocytes.

21. Protozoan immune evasion strategies. 3. Antigenic variation. • In Plasmodium, different stages of life cycle express different antigens. • Antigenic variation also in extracellular protozoan, Giardia lamblia.

22. Protozoan immune evasion strategies. 3. Antigenic variation cont’d. • African trypanosomes -1 surface glycoprotein that covers parasite = VSG. • Immunodominant for ab responses. • Tryps have “gene cassettes” of VSG’s allowing regular switching to different VSG. • Host mounts immune response to current VSG but parasite already switching VSG to another type.

23. Protozoan immune evasion strategies. 3. Antigenic variation cont’d. • Parasite expressing new VSG escapes ab detection, replicates & continue infection. • Allows parasite survival - months / years. • Up to 2000 genes involved.

24. After Ross, P. (1910), Proc. Royal Soc. London, B82, 411 Protozoan immune evasion strategies. 3. Antigenic variation cont’d. • Parasitaemia fluctuates. • After each peak, tryp population antigenically different from that earlier / later peaks.

25. Protozoan immune evasion strategies. • 4. Shedding / replacement surface e.g. Entamoeba histolytica. • 5. Immunosupression – manipulation host immune response e.g. Plasmodium. • 6. Anti-immune mechanisms - Leishmania - anti-oxidases to counter macrophage oxidative burst.

26. Helminth immune evasion strategies – vert host. • Large size - difficult to eliminate. • Primary response – inflammation. • Often worms not eliminated.

27. Helminth immune evasion strategies vert host. • 2. Coating with host proteins. Tegument cestodes & trematodes adsorb host components, e.g. RBC ags. • Immunological appearance of host tissue. • E.g. Schistosomes - host blood proteins, (blood group ags & MHC class I & II). • Worms seen as “self”.

28. Helminth immune evasion strategies – vert host. • 3. Molecular mimicry. Parasite mimics host structure / function. E.g. schistosomes have E-selectin - adhesion / invasion. • 4. Anatomical seclusion - 1 nematode larva does this -Trichinella spiralis inside mammalian muscle cells. • 5. Shedding / replacement surface e.g. trematodes, hookworms.

29. Helminth immune evasion strategies – vert host. • 6. Immunosupression – manipulation of the immune response. High nematode burdens - apparently asymptomatic. • Parasite may secrete anti-inflammatory agents - suppress recruitment & activation effector leukocytes or block chemokine-receptor interactions. • E.g. hookworm protein binds ß integrin CR3 & inhibits neutrophil extravasation.

30. Helminth immune evasion strategies – vert host. • 7. Anti-immune mechanisms e.g. liver fluke larvae secretes enzyme that cleaves ab. • 8. Migration e.g. Hookworms - move about gut avoiding local inflammatory reactions. 

31. Helminth immune evasion strategies - vert host. • 9. Production of parasite enzymes - Filarial parasites secrete anti-oxidant enzymes • e.g. glutathione peroxidase & superoxide dismutase - resistance to ADCC & oxidative stress?

32. Helminth immune evasion strategies – invert host. • 1. Anatomical seclusion – Acanthocephalaacanthors maintain host tissue layer around them. Acanthor only melanized if larva dies. • 2. Molecular mimicry – Schistosoma sporocysts produce surface molecules similar to haemolymph molecules of snail host. Parasite seen as “self”.

33. Helminth immune evasion strategies – invert host. • 3. Immunosupression – developing microfilariae Brugia pahangi & Dirofilaria immitis suppress mosquito immune response.

34. Specific example -Hymentopteran immune evasion mechanisms in invert host. • 1. Anatomical seclusion.Parasitic wasps lay eggs in ventral ganglion insect / spider hosts - avoid phagocytosis. • 2. Immunosupression. Some parasitic ichneumonids lay eggs in lepidopteran larvae. • Eggs not attacked by immune system as long as alive.

35. Other evasion strategies of parasites of invertebrates. • 1. Immature hosts. Advantage- less circulating haemocytes. • 2. Incorporation of host antigen. Parasite appears as “self”. • E.g. Ectoparasites of echinoderms. Pedicellaria prevent ectoparasites from settling. • Mucus - inhibits pedicellaria response. • Ectoparasites coat themselves in mucus - prevents response.

36. Evasion strategies of parasites of invertebrates. • 2. Incorporation of host antigen cont’d. E.g. Clown fish produce mucus - no sialic acid - prevents stinging by tentacles of sea anemone. • But lack sialic acid - fish susceptible to bacterial infections.

37. Summary I. • Immunopathology – most severe parasitic pathology has immune/inflammatory component. • Protozoa evade vertebrate immunity by: • Anatomical seclusion. • Antigenic variation. • Surface shedding / replacement. • Immunosupression • Anti-immune mechanisms.

38. Summary II. • Protozoa evade invertebrate immunity by: • Anatomical seclusion. • Helminthsevade vertebrate immunity by: • Size. • Using host protein. • Molecular mimicry. • Anatomical seclusion. • Surface shedding / replacement. • Immunosupression. • Anti-immune mechanisms. • Migration. • Production enzymes.

39. Summary III. • Helminthsevade invertebrate immunity by: • Anatomical seclusion. • Molecular mimicry. • Immunosupression.

40. Next session. • Examine immune evasion strategies of: • Schistosomes (intermediate & definitive hosts). • The African trypanosomes.