Evasion of immunity 3'

1
Evasion of immunity 3.

• Specific examples of parasite immune evasion
  strategies.

Jo Hamilton Parasitology BS31820
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Objectives and learning outcomes.

• Immune evasion strategies of schistosomes in vert
  host combination 6 strategies.
• Immune evasion strategies of schistosomes in
  invert host 1 main strategy?
• Immune evasion strategies of African trypanosomes
  1 main strategy.

3

• Hostparasite relationship - subtle interplay
  between parasite survival host defence.

4
Introduction to parasite immune evasion
strategies.

• Parasites - same/similar immune
• signalling molecules / molecular mimicry
• escape host immunosurveillance.
• Ensures host immunocompatibility.
• Bidirectional communication between parasites
  hosts.
• Includes reninangiotensin, opioid opiate
  systems.

5
Parasite immune evasion mechanisms.

• 2 main mechanisms
• Express appropriate antigens
• Rapid antigen turnover - e.g. antigenic
  variation.
• Express epitopes similar to host molecules
• molecular mimicry.
• Modify host immune response
• Directly using own molecules.
• Indirectly - deregulate host effector cells.

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Schisto immune evasion mechanisms - vert host.

• Induction of 'blocking antibodies
• Schistosomula surface glycoproteins share CHO
  epitopes with polysaccharides in parasite egg.
• Egg ags induce T cell-independent ab responses.
• IgM IgG2 (in human) - cannot mediate eosinophil
  killing of schistosomula.
• Block' schistosomula killing by IgE other IgG
  subclasses.
• Response induced by eggs, protects incoming
  larvae.

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Schisto immune evasion mechanisms - vert host.

• Tegument
• Tegument larval adult worms direct contact
  with host immune system.
• Surrounds worm interacts with host.
• Immune evasion organ unique to trematodes.

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Schisto tegument contd.

• Immune evasion features of tegument
• Double lipid bilayer - outer layer rapidly
  replaced.
• Outer lipid bilayer few antigens - membrane
  proteins in inner bilayer.
• Adsorbs host serum glycoprotein ligands RBC
  ags. e.g. MHC class I, complement IgG seen as
  self.

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Schisto tegument contd.

• Experimental evidence?
• First demonstrated 1960s by Smithers Terry in
  Schistosoma mansoni.
• Possible surgically transfer adult schistosomes
  from one host to another.

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Schisto tegument contd.

• Transferred worms from mouse to monkey
  initially no egg-production.
• After 6 weeks worms recovered resumed
  egg-laying.

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Schisto tegument contd.

• Monkey immunized with whole mouse antigen
  preparation.
• Worms transferred mouse to monkey.
• Destroyed by monkeys immune system.

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Schisto tegument contd.

• Demonstrated
• Schistosomes from different hosts -antigenically
  different.
• Schistosomes antigenically similar to host came
  from.

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Schisto tegument contd.

• Further experiments
• Fluorescent anti-mouse abs demonstrated
  schistosomes from mice take up incorporate
  mouse antigen into tegument.
• Ag tightly bound but replaceable.
• Schistosome tegument half life 2 - 3 hours.

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Schisto tegument contd.

• Only certain components hosts blood system
  incorporated into schistosome surface.
• Blood group ags - A, B, Lewis X H factors.
• MHC antigens.
• M, N, S, Rhesus Duffy factors are not.
• Part of tegument not stuck on outside.

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Schisto immune evasion mechanisms - vert host.

• Anti-immune response mechanismse.g. Proteolytic
  cleavage host abs.

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Schisto immune evasion mechanisms in vert host.

• Immunosuppresion / immunomodulation
• Parasite survives, grow mature using external
  / or self-molecules.
• Opioid neuropeptides in mammalian immune response
  nervous signalling.
• Conserved in free-living inverts.
• Involved in parasitism?

17
Schisto immune evasion mechanisms - vert host.

• Proopiomelanocortin (POMC)-derived peptides,
  reninangiotensin system (RAS) elements
  morphine-like substances demonstrated in S.
  mansoni.
• Implicated in host interactions?

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Schisto immune evasion mechanisms - vert host.

• Proopiomelanocortin (POMC) derived peptides
• e.g. adrenocorticotropic hormone (ACTH),
  melanostimulating hormone (MSH) endorphins (E).
• Identified in S. mansoni cercariae,
  schistosomula, adult worms miracidia.
• Related sequences in parasite genome.

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Schisto immune evasion mechanisms - vert host.

• Functional significance?
• ACTH endorphins found after in vitro incubation
  of adult S. mansoni - de novo synthesis
  release.
• Conversion ACTH into MSH in verts.
• These enzymes present in both Schistosoma in
  Biomphalaria glabrata.
• MSH inhibits immunocytes.
• ACTH MSH help parasite avoid host effector
  cells?

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Schisto immune evasion mechanisms - vert host.

• How?
• Host IFN IL-2 decrease during schistosomiasis
  adults oviposition.
• Result of recruitment Th2 cells reduction Th1
  populations?
• ACTH decreases IFN production by T cells.
• Schisto adults may produce ACTH convert it to
  MSH-like molecules evade many host effector
  mechanisms?

21
Schisto immune evasion mechanisms - vert host.

• Reninangiotensin system (RAS).
• Identification of RAS in parasites.
• In leeches - renin, angiotensin-converting
  (ACE)-like enzymes, angiotensins.
• RAS involved in diminishing inflammation.
• Possible that operational in schistosomes.

22
Schisto immune evasion mechanisms in vert host.

• Morphine - codeine like molecules.
• Schistosoma synthesize morphine-like molecule.
• Morphine - immune down regulator immobilises
  immunocytes.
• Codeine-like material rapidly converted to
  morphine. Presence of positive feedback loop.
• Suggests parasite uses morphine for immune escape
  evasion.

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Schisto immune evasion mechanisms - vert host.

• Molecular mimicry.
• Ags common to both vert invert schistosome
  hosts.
• Parasite expression of host proteins e.g.
  alpha-2-macroglobulin, immunoglobulin receptors,
  MHC class I II antigens etc. - diversity
  structures involved.

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Schistosome immune evasion mechanisms vert
host.

• Mimicry avoids immune detection.
• Acquisition active / passive / both?
• Passive acquisition ags from blood (A, B, H)
  MHC molecules.
• Gene cloning revealed identity between parasite
  mammalian gene sequences.

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Schisto immune evasion mechanisms - vert host.

• Exploitation host signals.
• Schistosomes actively use host immune molecules
  to grow reproduce.
• Parasites might express receptors for these.
• E.g. epidermal growth factor (EGF) receptor a
  transforming growth factor (TGF- ) receptor
  identified on S. mansoni.

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Schistosome immune evasion mechanisms - invert
host.

• Anti-oxidant enzymes.
• Schistosome resistant / susceptible snails.
• Thought killing oxygen-dependent mechanism.
• Antioxidant enzymes essential for parasite
  defend against reactive oxygen metabolites.

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Schisto immune evasion mechanisms - invert host.

• E.g. in miracidia, mother daughter sporocysts
  cercaria
• Superoxide dismutase (SOD).
• Glutathione-peroxidase (GPX).
• Glutathione-S-transferase (GST).
• GST most abundant detoxification.

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Immune evasion African Trypanosomes.

• African trypanosome protozoan - causes fatal
  neurologic disease trypanosomiasis.
• Trypanosoma brucei rhodesiense Trypanosoma
  brucei gambiense Human sleeping sickness.
• Trypanosoma brucei nagana (Ngana) in cattle.
• Geographic distribution limited to sub-Saharan
  Africa by tsetse fly vector.

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Antigenic variation contd.

• Trypanosomes success antigenic variation.
• Host makes specific IgM IgG abs against
  protozoan variant surface glycoprotein coat
  (VSG).
• Antigenic variation switching major VSG
  -protective coat around protozoan.

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Antigenic variation contd.

• Recognised by Paul Ehrlich.
• T. brucei VSG coat successively changing - 1 step
  ahead immune system.
• Successive waves of parasitaemia.
• Hosts abs neutralize kill 99 original
  protozoan population.
• But a few tryps switched VSGs - gained new
  antigenically distinct VSG coat.

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Antigenic variationcontd.

• New population expressing new VSG coats.
• Immune system responds again new abs kill 99
  of trypanosome population.
• But VSG switches undetectable - evade host
  immune response.
• Cycle continues death of host.

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Antigenic variation contd.

• Many genes encode VSGs.
• Genes either in chromosome interior / near
  telomeres.
• Expressed VSG gene always near telomere.
• Although multiple telomere-proximal VSGs,
  expression mono-allelic.
• Each individual cell expresses single VSG .

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Antigenic variationcontd.

• 2 mechanisms VSG switching
• Exchange / alter active gene
• Transcription within single chromosome.
• Interior VSG copy duplicated onto cassette.
• Translocated to expression site at telomere.
• Becomes activated.

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Antigenic variationcontd.

• Change transcriptionally active telomere
• Some VSG genes expressed without being duplicated
  translocated.
• Active telomeric site on 1 chromosome silenced.
• Telomeric site on another chromosome activated.

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Antigenic variation contd.

• Silencing expression sites developmentally
  regulated.
• 20 different expression sites.

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Antigenic variation contd.

• T. brucei - no ag change in 1st 7 days infection.
• New antigenic forms every 4 / 5 days.
• Antigenic types occur in similar sequence in
  different hosts infected with same strain of
  parasite.
• True even if host 1 host 2 different species.

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Antigenic variation contd.

• Tryp ingested by tsetse - loses coat
• reverts basic type coat.
• In mammal process starts again - always same type
  A VSG.
• Few basic strain types 20.
• Each cyclically transmitted T. brucei strain
  follows semi-predictable sequential pattern
  antigenic variation.
• Starts with basic strain ag.
• Reverts back each time pass through tsetse.

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Antigenic variation contd.

• Not random mutation.
• Not clonal expansion of single trypanosome.
• Multiple activation same gene in large number
  individuals.
• Trypanosomes have set series coat types.
• Up to 100 different antigenic types.
• Trypanosome 2000 different VSG genes.
• 10 of total DNA.

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Antigenic variationcontd.

• VSG - dimeric protein.
• Completely coats surface (except flagellar
  pocket).
• Limiting VSG expression to 1 type at time
  prevents exhaustion of VSG repertoire.
• Trigger for switching unknown.
• Thought ab necessary - switching occurs in
  immunologically incompetent hosts in culture.

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Summary.

• Immune evasion mechanisms
• Schistosomes - range strategies in vertebrate
  host
• E.g. ab blocking, molecular mimicry
  immunosuppression.
• Schistosomes use antioxidant enzymes in
  invertebrate host.
• African trypanosomes use antigenic variation.