Induction Of The Intestinal Th2 Immune Response To The Parasitic Nematode Trichinella Spiralis: Rapid Expulsion, Distinct Regional Immunity, And The Role Of Innate Mediators.
Intestinal helminths infect over 2 billion people worldwide, and the mechanisms by which immunity to these pathogens is induced are not well-understood. Trichinella spiralis exhibits a broad geographic and host range, and is a natural pathogen of humans and rodents. Infection of mice and rats with T. spiralis provides a useful model of Th2 immunity in the mucosa. Rats exhibit a dramatic protective immune response, called rapid expulsion, in which 90% of parasites are cleared from the intestine within one hour of challenge. We observed that intestinal priming and mucosal mast cell degranulation are not required for rapid expulsion to occur. Thus, mast cells may play a role during the induction of Th2 immunity in rats, rather than during the effector phase. The specific intestinal habitat of the parasite may influnce immunity. Although many parasite species are restricted in their distribution in the gastrointestinal tract, T. spiralis colonizes both the small and large intestines (SI and LI). The results demonstrate that mucosal mastocytosis and the cytokines that influence it are not prominent in the LI during worm expulsion, and that immunopathology is more tightly regulated in the LI than the SI. Thus, mechanisms of immunity and enteropathy vary in different regions of the intestine during helminth infection. The influence of innate mediators on the adaptive immune response to T. spiralis was also investigated. Evidence was collected suggesting that although MyD88 is influential in promoting Th2 responses, and there was a modest influence of the microbiota, MyD88 operates independently of TLRs. Mice deficient in ST2, the receptor for IL-33, recapitulated the results seen in MyD88-/- mice, supporting the role of IL-33 as a mediator of Th2 responses. IL-33 was observed in intestinal leukocytes and in epithelial cells, where it concentrated in the nucleus within two days of infection. Array analysis revealed that at two days after infection, targets of NF-[kappa]B were downregulated in the epithelium, while the TGF-[beta] pathway was increased. IL-33 may carry out dual functions as part of a complex mechanism of innate induction of the Th2 response.
Trichinella spiralis; mast cells; interleukin-33
Appleton, Judith Ann
Holowka, David Allan; Denkers, Eric Young
Ph.D. of Immunology
Doctor of Philosophy
dissertation or thesis