Mediators and modulators of immunity to helminths

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.