Eosinophilia is a hallmark of immune responses mounted against helminth infections. Our objective is to challenge the paradigm that eosinophils function exclusively as effector cells that attack parasitic worms. Trichinella spiralis initiates he chronic phase of infection when newborn, first-stage larvae infect skeletal muscle cells. We have discovered that eosinophils contribute to the ensuing myositis while simultaneously protecting larvae against immune-mediated destruction. Specifically, we find that larvae fail to grow normally, and then are killed in large numbers, in two strains of mice in which the eosinophil lineage has been ablated. Parasite survival improves when eosinophils are restored to such mice. Our goal is to elucidate the properties and actions of eosinophils that enable them to support growth and prevent killing of the nematode. We hypothesize that eosinophils support larval growth by influencing metabolism in the host cell by a STAT6- dependent mechanism, and that they prevent larval killing by activating IL-10+CD4+CD25- T cells. Supported by strong preliminary data and published work, our specific aims are to: 1. Determine the role of eosinophils in local innate responses that promote larval growth. 2. Define how eosinophils promote T cell activation and recruitment that prevents parasite killing. 3. Elucidate how eosinophils direct protective immunity against reinfection. Our experimental approaches are highly mechanistic, are conducted almost exclusively in vivo, and are designed to reveal the interplay among the host immune response, the cellular habitat of the T. spiralis larva, and the larva itself. In studies of resistance to re-infection, we will be testing a new mouse strain that an be induced to deplete eosinophils. Our studies are particularly valuable because T. spiralis is a natural pathogen of rodents that occupies an extra-intestinal site; there are very few natural animal models of tissue-dwelling nematode infection. Findings from the proposed investigations will provide new insights that can be applied to the design of vaccines and therapies for diseases caused by parasitic worms that continue to plague people worldwide. Finally, our studies have relevance to other chronic diseases in which eosinophils also populate the microenvironment, including obesity, cancer, and allergy.
Nematodes are important causes of morbidity in human populations around the world. Our findings have changed the way we view the eosinophil, a cell type that is prominent in the immune response to nematode infection. The proposed experiments will determine how the eosinophil directs the development of immunity in a way that supports the survival of a parasitic worm, Trichinella spiralis.
|Huang, Lu; Appleton, Judith A (2016) Eosinophils in Helminth Infection: Defenders and Dupes. Trends Parasitol 32:798-807|
|Huang, Lu; Gebreselassie, Nebiat G; Gagliardo, Lucille F et al. (2015) Eosinophils mediate protective immunity against secondary nematode infection. J Immunol 194:283-90|
|Huang, Lu; Beiting, Daniel P; Gebreselassie, Nebiat G et al. (2015) Eosinophils and IL-4 Support Nematode Growth Coincident with an Innate Response to Tissue Injury. PLoS Pathog 11:e1005347|
|Huang, Lu; Gebreselassie, Nebiat G; Gagliardo, Lucille F et al. (2014) Eosinophil-derived IL-10 supports chronic nematode infection. J Immunol 193:4178-87|