Mediators and modulators of immunity to helminths
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Date
28/11/2013Author
Filbey, Kara Jayne
Metadata
Abstract
Parasitic helminths infect millions of people and animals worldwide. A key feature
of their lifecycle is the longevity of survival within a single host, which is often
attributed to the ability of the parasite to divert or modulate the immune response
against it. The excretory-secretory (ES) products released by helminths are of
interest as the mediators of such immunomodulation. Heligmosomoides polygyrus is
an excellent model of gastrointestinal (GI) helminth infection in rodents, and has
been used here to investigate several aspects of the immune response, and the
manipulation of these, in mice.
Firstly, the roles of B cells and antibodies in infection with H. polygyrus and towards
the adult ES (HES) were investigated. Using several B cell-deficient mouse strains,
a minimal effect on immunity to primary infection with H. polygyrus was
demonstrated. However, primary infection serum binds to a select set of highly
immunodominant components of the complex protein mixture of HES, which were
identified as venom allergen-like proteins (VALs).
Utilising four strains of mice that vary in their resistance phenotype to H. polygyrus,
several aspects of immunity towards the worm were investigated. Increased levels of
markers of alternatively activated macrophages, which are a key component of the
granulomatous inflammatory response around invading H. polygyrus larvae, were
found in the most resistant strains, SJL and BALB/c. Depletion of macrophages, by
administration of clodronate, severely disrupted the granuloma and parasite clearance.
Numbers of innate lymphoid cells and the subsequent Th2 response, specificity range
and titre of antibody, and activation of regulatory T cells all correlate with a resistant
phenotype.
A deficiency in the cytokine macrophage migration inhibitory factor (MIF) renders a
resistant BALB/c mouse completely susceptible to infections with H. polygyrus, and
Nippostronygylus brasiliensis, an acute model of GI helminth infection. This is
accompanied by a failure to induce both ILCs and an early myeloid-derived cell
population upon infection. The influx of alternatively activated macrophages around
larvae in the mucosa of the small intestine is delayed in MIF-/- mice, although all
immunological parameters are comparable to wild-type by day 14 post-infection.
The susceptible phenotype of MIF-/- mice can be replicated using a chemical
inhibitor of MIF in BALB/c mice.
Finally, the previously documented transforming growth factor-β (TGF-β) activity of
HES was dissected out further using two methods of fractionation. Distinct fractions
with TGF-β activity were subjected to mass spectrometry to identify protein
components that could be potential candidates for this activity.