Evasion of Immunity 2

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Evasion of Immunity 2

• Immunity to specific parasites parasite immune
  evasion strategies.

Dr. Jo Hamilton Parasitology BS
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Introduction.

• In the last session we discussed vertebrate and
  invertebrate immunity. In this session we will
• Examine vertebrate and invertebrate immune
  responses to different groups of parasites.
• Explore the strategies that have evolved in
  parasites to overcome their hosts defences.

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Objectives and learning outcomes.

• By the end of this session students should be
• Familiar with vertebrate and invertebrate immune
  responses to different groups of parasites.
• Familiar with a range of strategies used by
  parasites to evade their hosts immune
  mechanisms.
• Able to give examples of parasites and link them
  to their immune evasion strategies.

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Introduction.

• Successful parasites have evolved strategies for
  survival development in both invertebrate and
  vertebrate hosts.

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Immunoparasitology (Parasite immunology).

• Host - susceptible if parasite survives.
• Host - insusceptible if parasite killed by innate
  immunity.
• E.g. Humans are insusceptible to the larval
  stages of bird schistosomes (e.g.
  Trichobilharzia). These parasites are quickly
  killed off, the associated inflammation itching
  is called cercarial dermatitis (or swimmers
  itch). In the natural duck host, larval stages
  develop into established infection with adult
  worms.

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Immunoparasitology (Parasite immunology).

• Spontaneous-cure occurs when parasite
  establishes itself but is eventually expelled,
  e.g., Nippostrongylus brasiliensis (the rat
  hookworm).
• The adult Nippostrongylus, releases protective
  antigens that are not stage specific to the
  adult. That is, the resulting antibodies
  recognise targets both on the adult worm and on
  the migrating infective larvae.
• Under conditions of trickle infection, possible
  to get persistent population of parasites in gut
  which are able to survive the adverse
  immunological conditions. Morphologically though
  these worms are stunted and appear to be less
  immunogenic than normal worms.

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Immunoparasitology (Parasite immunology).

• Parasites of major medical veterinary
  importance successfully adapted to innate
  acquired immune responses of host. E.g. malaria
  (Plasmodium spp.) Fasciola hepatica in sheep.
• Susceptibility of a host to a given parasite can
  depend genetic background, age, nutritional
  hormonal status etc. of an individual.

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Immunoparasitology (Parasite immunology).

• In nearly every case, immune response mounted to
  both protozoal and helminth infections.
• Evidence-
• (1) the prevalence of infection declines with
  age.
• (2) immunodepressed individuals quickly succumb
  to infection.
• (3) acquired immunity has been demonstrated in
  lab models.

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Immunopathology.

• Parasites can cause direct damage to host by
• Competing for nutrients (e.g. tapeworms).
• Disrupting tissues (e.g. Hydatid disease) or
  destroying cells (e.g. malaria, hookworm,
  schistosomiasis feeding on or causing
  destruction of cells anaemia).
• Mechanical blockage (e.g. Ascaris in intestine).
• However, severe disease often has a specific
  immune or inflammatory component.

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Immunopathology.

• Some examples include
• Cerebral malaria - TNF, IFN other
  proinflammatory cytokines in brain.
• Hepatosplenic schistosomiasis - anti-egg immune
  responses initiate hepatic fibrosis.
• Onchocerciasis - anti-microfilarial responses in
  eye blindness, perhaps inducing autoimmune
  response via cross-reactive antigens in eye
  microfilariae, this immune response is not
  protective as is against stage specific surface
  antigens, no cross-reaction with infective L3
  larvae.

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Immunopathology contd.

• Anaphylactic shock - rupture of hydatid cyst.
  Immediate hypersensitivity initiated by systemic
  release of parasite antigens reacting with IgE
  mast cells degranulation release of
  mediators, e.g. histamine.
• Nephropathy - immune complexes (parasite
  antigens, antibody complement) in kidney (e.g.
  malaria, schistosomiasis).

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Vertebrate Immune responses to Protozoan
parasites.

• Innate immune responses.
• In vertebrates, extracellular protozoa are
  eliminated by phagocytosis and complement
  activation.
• T cell responses.
• Extracellular protozoa - Th2 cytokines released
  for antibody production.
• Intracellular protozoa - Cytotoxic lymphocytes
  (CTLs) kill infected cells. Th1 cytokines
  produced to activate macrophages, CTLs DTH
  response also involved.

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Vertebrate Immune responses to Protozoan
parasites.

• Combination of innate and acquired immune
  responses.
• Antibody Complement, e.g. lysis of blood
  dwelling trypanosomes. Antibody / complement
  plus neutrophils or macrophages against malaria
  merozoites. Activated macrophages can be
  effective against many intracellular protozoa,
  e.g. Leishmania, Toxoplasma, Trypanosoma cruzi.
  CD8 cytotoxic T cells respond parasite infected
  host cells, e.g. Plasmodium infected liver cell.

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Vertebrate Immune responses to Protozoan
parasites.

• Acquired immune responses.
• Antibody responses.
• - Extracellular protozoa are eliminated by
  opsonization, complement activation and ADCC.
• - Intracellular protozoa are prevented from
  entering the host cells by a process of
  neutralisation e.g. neutralising antibody
  against malaria sporozoites, blocks cell
  receptor for entry into liver cells.

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Invertebrate Immune responses to Protozoan
parasites.

• Melanotic encapsulation.
• Malarial mosquito vector, Anopheles gambiae,
  melanotic encapsulation of young Plasmodium
  oocysts takes place. In general, the reactions
  set in motion by phenoloxidase activity result in
  chemical as well as physical protection, because
  oxidations leading to melanin formation also
  generate free radicals toxic quinone
  intermediate radicals.

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Vertebrate Immune responses to helminth
infections.

• Most helminths extracellular too large for
  phagocytosis.
• For the larger worms, e.g. some gastrointestinal
  nematodes host develops inflammation and
  hypersensitivity. Eosinophils IgE activated to
  initiate inflammatory response in the intestine
  or lungs to expel the worms. These histamine
  elicited reactions are similar to allergic
  reactions.

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Vertebrate Immune responses to helminth
infections.

• The acute response after previous exposure can
  involve an IgE and eosinophil mediated systemic
  inflammation which results in expulsion of the
  worms.

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Vertebrate Immune responses to helminth
infections.

• Chronic exposure to worm antigens can cause
  chronic inflammation
• Delayed type hypersensitivity (DTH), Th1 /
  activated macrophages which can result in
  granulomas.
• Th2 / B cell responses increase IgE, mast cells
  eosinophils activate inflammation.

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Vertebrate Immune responses to helminth
infections.

• Helminths commonly induce Th2 responses
  characterised by cytokine pattern with IL-4,
  IL-5, IL-6, IL-9, IL-13 eosinophils antibody
  responses including in particular, IgE.
• Characteristic ADCC (Antibody-dependent
  cell-mediated cytotoxicity) reactions i.e.
  killer cells (e.g. macrophages, neutrophils,
  eosinophils) directed against target parasite by
  specific antibody. E.g. Eosinophil killing of
  parasite larvae by IgE (or some IgG subclasses).

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Invertebrate immune responses to helminth
infections.

• Melanotic encapsulation. This mechanism is used
  to contain filarial larvae (nematodes) in
  mosquitoes.

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Parasite Immune Evasion Evasion strategies.

• Parasites need time in host to complete complex
  development, to sexually reproduce to ensure
  vector transmission.
• Chronic infections (from a few months to many
  years) are normal, therefore parasite needs to
  avoid immune elimination.
• Parasites have evolved immune evasion strategies.

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Protozoan immune evasion strategies.

• 1. Anatomical seclusion in the vertebrate host.
• Parasites may live intracellularly. By
  replicating inside host cell parasites avoid
  immune response.
• Plasmodium lives inside Red Blood Cells (RBCS)
  which have no nucleus, when infected not
  recognised by CTLs NK cells. Other stages of
  Plasmodium live inside liver cells.
• Leishmania parasites and Trypanosoma cruzi live
  inside macrophages.

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Protozoan immune evasion strategies.

• 2. Anatomical seclusion in the invertebrate host.
• Plasmodium ookinetes develop in serosal membrane
  are beyond reach of phagocytic cells
  (haemocytes).

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Protozoan immune evasion strategies.

• 3. Antigenic variation.
• In Plasmodium, different stages of the life cycle
  express different antigens. We will describe
  evasion strategies of Plasmodium in more detail
  in the next lecture.
• Antigenic variation also occurs in the
  extracellular protozoan, Giardia lamblia.

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Protozoan immune evasion strategies.

• 3. Antigenic variation contd.
• African Trypanosomes have one surface
  glycoprotein that covers the parasite.
• This protein is immunodominant for antibody
  responses.
• Trypanosomes have gene cassettes of variant
  surface glycoproteins (VSGs) which allow them to
  switch to different VSG.
• VSG is switched regularly. The effect of this is
  that host mounts immune response to current VSG
  but parasite is already switching VSG to another
  type which is not recognised by the host.

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Protozoan immune evasion strategies.

• 3. Antigenic variation contd.
• A parasite expressing the new VSG will escape
  antibody detection and replicate to continue the
  infection.
• This allows the parasite to survive for months or
  years.
• Up to 2000 genes involved in this process.

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Protozoan immune evasion strategies.

• 3. Antigenic variation contd.
• The fluctuations in parasitaemia in a patient
  with trypanosomiasis. Characteristic of both
  animal human trypanosomiasis.
• After each peak, the trypanosome population is
  antigenically different from that of earlier or
  later peaks.
• We will cover antigenic variation in the African
  trypanosomes in more detail in the next lecture.

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Protozoan immune evasion strategies.

• 4. Shedding or replacement of surface e.g.
  Entamoeba histolytica.
• 5. Immunosupression manipulation of the immune
  response e.g. Plasmodium.
• 6. Anti-immune mechanisms - Leishmania produce
  anti-oxidases to counter products of macrophage
  oxidative burst.

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Helminth immune evasion strategies.

• Helminth immune evasion mechanisms in the
  vertebrate host.
• 1. Large size. Difficult for immune system to
  eliminate large parasites. Primary response is
  inflammation to initiate expulsion, often worms
  are not eliminated.

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Helminth immune evasion strategies.

• Helminth immune evasion mechanisms in the
  vertebrate host.
• 2. Coating with host proteins. Tegument of
  cestode trematode worms, is able to adsorb host
  components, e.g. RBC Ags, thus giving the worm
  the immunological appearance of host tissue.
  Schistosomes take up host blood proteins, e.g.
  blood group antigens MHC class I II
  molecules, therefore, the worms are seen as
  self. We will describe schistosome evasion
  strategies in more detail in the next lecture.

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Helminth immune evasion strategies.

• Helminth immune evasion mechanisms in the
  vertebrate host.
• 3. Molecular mimicry. The parasite is able to
  mimic a host structure or function. E.g.
  schistosomes have E-selectin that may help in
  adhesion or invasion.
• 4. Anatomical seclusion - Uniquely, even one
  nematode worm larva does this Trichinella
  spiralis can live inside mammalian muscle cells
  for many years.
• 5. Shedding or replacement of surface e.g.
  trematodes, hookworms.

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Helminth immune evasion strategies.

• Helminth immune evasion mechanisms in the
  vertebrate host.
• 6. Immunosupression manipulation of the immune
  response. High burdens of nematode infection
  often carried with no outward sign of infection.
• Growing evidence that parasite secreted products
  include anti-inflammatory agents which act to
  suppress the recruitment and activation of
  effector leukocytes. E.g. a hookworm protein
  which binds the ß integrin CR3 inhibits
  neutrophil extravasation.

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Helminth immune evasion strategies.

• Helminth immune evasion mechanisms in the
  vertebrate host.
• 6. Immunosupression contd.
• There is other evidence of secreted products
  which block chemokine-receptor interactions, an
  acetylhydrolase from N. brasiliensis has been
  discovered which inactivates the pro-inflammatory
  molecule Platelet-activating Factor (PAF).

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Helminth immune evasion strategies.

• Helminth immune evasion mechanisms in the
  vertebrate 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. 

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Helminth immune evasion strategies.

• Helminth immune evasion mechanisms in the
  vertebrate host.
• 9. Production of parasite enzymes - Filarial
  parasites secrete a number of anti-oxidant
  enzymes such as glutathione peroxidase
  superoxide dismutase which most likely contribute
  to their observed resistance to
  antibody-dependent cellular cytotoxicity and
  oxidative stress.
• Genes for these enzymes cloned expressed with
  aim of producing effective vaccines.

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Helminth immune evasion strategies.

• Helminth immune evasion mechanisms in the
  vertebrate host.
• 9. Production of parasite enzymes contd -Many
  nematodes which colonise alimentary tract of host
  secrete acetylcholinesterases (AChEs), enzymes
  generally associated with termination of neuronal
  impulses via hydrolysis of acetylcholine at
  synapses and neuromuscular junctions. This
  unusual phenomenon has been known for some time,
  yet the physiological function of the enzymes
  remains undetermined.

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Helminth immune evasion strategies.

• Helminth immune evasion mechanisms in the
  invertebrate host.
• Anatomical seclusion Acanthocephala acanthors
  maintain host tissue layer around them. Acanthor
  only becomes melanised if developing larva dies.
• Molecular mimicry sporocysts of Schistosoma in
  the intermediate moluscan host produce surface
  molecules that are similar to molecules present
  in the haemolymph of the snail host. The parasite
  is thus seen as self.

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Helminth immune evasion strategies.

• Helminth immune evasion mechanisms in the
  invertebrate host.
• Immunosupression developing microfilariae of
  Brugia pahangi Dirofilaria immitis suppress the
  immune response of the mosquito.

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Hymentopteran immune evasion strategies.

• Hymentopteran immune evasion mechanisms in the
  invertebrate host.
• Anatomical seclusion. Many parasitic wasps lay
  eggs in ventral ganglion of insect or spider
  hosts thus avoiding action of phagocytic cells.
• Immunosupression. Some parasitic ichneumonid
  wasps lay eggs in larvae of lepdopterans. Eggs
  are not attacked by the immune system as long as
  they stay alive E.g. Nemeritis wasp lays eggs in
  the almond moth Ephesita.

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Evasion strategies of parasites of invertebrates.

• 1. Immature hosts. Many parasites take advantage
  of immature hosts in which there are less
  circulating haemocytes.
• 2. Incorporation of host antigen. This evasion
  strategy is used to make the parasite appear as
  self to the hosts immune system.
• E.g. The pedicellaria, tiny claw-like structures
  on surface of echinoderms. Used to prevent
  ectoparasites from settling. Mucous on the
  surface of these claws inhibits the biting
  response. Many ectoparasites coat themselves in
  mucous to prevent being bitten

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Evasion strategies of parasites of invertebrates.

• 2. Incorporation of host antigen contd.
• E.g. Clown fish produce mucous that does not
  contain sialic acid, this prevents them being
  stung by tentacles of sea anemone with which it
  lives. However, lack of sialic acid makes the
  fish more susceptible to bacterial infections.

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Evasion strategies of ectoparasites of
vertebrates.

• Ectoparasites also employ strategies to evade
  host defences whilst they are not immune
  evasion strategies they are worth briefly
  mentioning.
• Rapid feeding of blood-sucking insects to avoid
  host defensive movements.
• Use of hooks/claws e.g. claws on tarsi of head
  lice etc. used to hold on to hair allows
  parasite to survive grooming activities of host.

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Summary.

• By the end of this session you should be
• Familiar with vertebrate and invertebrate immune
  responses to different groups of parasites.
• Familiar with a range of strategies used by
  parasites to evade their hosts immune
  mechanisms.
• Able to give examples of these parasites and link
  them to their immune evasion strategies.

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Next session.

• We will
• Explore selected parasite immune evasion
  mechanisms in more detail.
• We will examine the immune evasion strategies of
  the schistosomes in both their intermediate and
  definitive hosts, Plasmodium, Trypanosoma cruzi
  the African trypanosomes.