Versatility Of Eosinophils In Immunity To The Parasitic Nematode, Trichinella Spiralis
Helminth infections continue to threaten human and animal health worldwide. Dissection of the interactions between helminths and helminth-induced Th2 immunity is necessary for the development of effective prophylactic and therapeutic approaches to disease control. Trichinella spiralis is natural pathogen of humans and rodents, providing a valuable context for study of the relationships between Th2 immunity and parasitic worms. Eosinophilia is a hallmark of Th2 immunity in helminth infections, yet the roles of eosinophils in worm infection have remained elusive. Our early studies have revealed unexpected functions of eosinophils in T. spiralis infection. Rather than promoting clearance of parasites, eosinophils supported muscle larvae survival and growth by regulating local immunity. The results presented here define the eosinophil-dependent mechanisms that protect muscle larvae against nitric oxide-mediated killing in primary infection. Our results demonstrate that early recruitment of eosinophils to sites of infection is essential for driving local immunity that promotes larval survival. Eosinophil-derived IL-10 expands IL-10+ myeloid dendritic cells and CD4+IL-10+ T cells that suppress iNOS expression and protect intracellular larvae. The results reveal a novel immunoregulatory function of eosinophils in helminth infection. In secondary infection by T. spiralis, eosinophils are dispensable for intestinal immunity that clear adult worms while having a profound effect on the migration of newborn larvae. This interference limits further colonization of skeletal muscle. The protective effect is dependent on the presence of immune serum and reinforces the dogma that eosinophils adhere to larvae in the presences of antibodies. Eosinophils regulate larval growth through a third distinct mechanism. Current results indicate that intrinsic STAT6 signaling of eosinophils and eosinophil-derived IL-4 are required for larval growth. Importantly, larval growth is supported by eosinophils independently of adaptive immunity. Gene expression array analysis of skeletal muscles of infected Rag1-/- mice revealed a signature compatible with muscle regeneration and a shift in the source of energy, indicating that eosinophils are likely promoting larval growth by regulating metabolism in local tissues, thereby creating a suitable microenvironment.
Appleton, Judith Ann
Denkers, Eric Young; Leifer, Cynthia Anne
Ph.D. of Immunology
Doctor of Philosophy
dissertation or thesis