Heligmosomoides polygyrus: a model intestinal parasite

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Heligmosomoides polygyrus a model intestinal
parasite
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Gut parasite infections

• Significant problem worldwide, with billions
  infected, mostly in developing countries.
• No vaccine for any gut parasite.
• Effectively combated by drug treatment and
  improvements in hygiene.

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Intestinal parasites

• H. polygyrus related to hookworm and (to a lesser
  extent) pinworm
• Human hookworms Ancylostoma duodenale and Necator
  americanus.
• Mainly affect developing countries now, but in
  the past were worldwide.
• Human pinworm Enterobius vermicularis
• Worldwide distribution.

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Hookworms

• Usually asymptomatic, but can cause anemia,
  growth retardation, malnutrition etc. in heavy
  infections.
• Bite walls of intestine to blood-feed, causing
  blood loss.
• Require drug treatment to eradicate, otherwise
  tolerated indefinitely.
• Infection route through skin, migrate through
  heart and lungs, then coughed up and swallowed
  into gut.

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Pinworm

• Causes peri-anal itching, otherwise asymptomatic.
• Direct fecal-oral infection
• Develop in gut to adults, release eggs in faeces.
• Also require drug treatment to cure, otherwise
  tolerated.

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• pinworm video

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Hygiene hypothesis

• Better hygiene and treatment in the first world
  has resulted in vastly decreased prevalence of
  intestinal parasites.
• Coincides with increases in allergy and
  autoimmunity.
• Worms tolerated in the host - suppressing the
  immune system?

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Experimental Human Infection

• Irritable Bowel Disease and Chrones disease
• Both immune-mediated inflammation of the gut
• Studies infecting affected individuals with
  intestinal parasites showed significant
  improvement of symptoms.
• Suppression of immune system.

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Heligmosomoides polygyrus

• Mouse model of intestinal parasite
• Tolerated in mouse for many months
• Only chronic intestinal nematode in a mouse model
• Why use mouse model?
• Ethical issues of infecting humans
• Immune system of mice much better understood than
  human.
• Reagents for working with mice much more readily
  available than for any other mammal.

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H. polygyrus infection

• Immune response to H. polygyrus decreases as
  infection continues
• Suppresses experimentally induced allergy and
  autoimmunity.
• So H. polygyrus must interact with and suppress
  the immune response against itself and other
  antigens.

Immune response
Day post-infection
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H. polygyrus lifecycle

• L3 larvae infect orally, penetrate stomach wall
  and develop to L4 larvae
• L4 larvae in gut wall
• Cause damage
• Exposed to full force of immune system
• Develop to adults, which reside in mucous of gut
  lumen
• Only sexual stage - male and females
• Females produce eggs, deposited in feces
• Eggs hatch into L1 larvae, which develop to
  infective L3 larvae in soil.

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Why sequence parasite genomes?

• Phylogenetic analysis
• Identification of genes necessary for parasitism
• Compare to C. elegans.
• Identify and test drug/vaccine targets

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Gene Identification

• Homology to
• C. elegans - non-parasitic nematode.
• Related nematode parasites
• Model parasites - Nippostrongylus braziliensis,
  Brugia malayi, Haemonchus contortus, Ancylostoma
  caninum.
• Human parasites - Necator americanus, Ancylostoma
  duodenale
• Host
• Mouse/human genes - molecular mimicry.
• Immunologically relevant genes - suppress host
  immunity

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Gene Functions

• Housekeeping genes
• Metabolic, structural, DNA-binding
• Developmental genes
• Moulting, sex determination.
• Invasive genes
• Proteases, collagenases.
• Immune genes
• Host mimicry, cytokine homologues (interleukins).

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TGF-Beta Homologues

• TGF-beta is an immunosuppressive cytokine in
  mammals
• Homologues in many nematodes.
• Identified new homologues in Nippostrongylus
  brasiliensis.
• Use expression profile to assign function
• If expressed where the parasite is exposed to
  immune system, evidence of immunoregulatory
  function.

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H. polygyrus products

• Culture H. polygyrus adults and collect whatever
  they produce.
• In immune assays, H. polygyrus products suppress
  immune cells, through a TGF-beta pathway
• Need to identify what is doing this.