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

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.

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

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.

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.

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.

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

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.

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).

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

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.

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.

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.

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.

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.

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.

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

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

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.

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

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.

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.

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.

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

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.

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

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”.

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.

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.

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. 

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?

Helminth immune evasion strategies – invert host. 1. Anatomical seclusion – Acanthocephala acanthors 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”.

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

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.

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.

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.

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.

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

Summary III. Helminths evade invertebrate immunity by: Anatomical seclusion. Molecular mimicry. Immunosupression.

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