Strongyloides stercoralis - Immunological basis for susceptibility and resistance in mice and humans

Strongyloides stercoralis is a parasitic nematode of humans that causes chronic disease resulting in significant morbidity and mortality. Several studies in mice have defined the protective innate and adaptive immune response to the parasite. The objective of this thesis was to determine: 1) the capacity of macrophages to kill larvae, 2) the ability of neutrophils to release extracellular traps and 3) to examine hyperinfection in mice. The use of the diffusion chamber system in mice and the development of an in vitro killing assay have enabled the examination of both mouse and human immune components. We demonstrate that macrophages, like neutrophils and eosinophils have the ability to kill the larvae of S. stercoralis. Interestingly, the larval killing process in vitro required cooperation of human or mouse macrophages, neutrophils and complement. In mice, infection with the parasite results in the induction of alternatively activated macrophages which demonstrated an enhanced capacity to kill the parasite over naïve macrophages. Together these studies validate the concept that immunity to S. stercoralis is comprised of redundant killing mechanisms. In order for larval killing to occur the host immune response must first seize the large and highly motile parasite. Here we show that human and mouse neutrophils release neutrophil extracellular traps (NETs) that serve as a mechanism for ensnaring the parasite. Furthermore, NET formation was required but not sufficient for larval killing. Therefore, functional immune components are integral to trapping and parasite elimination, which ultimately lead to resistance. These findings were further substantiated by the observation that infected immunodeficient and humanized mice developed high parasite burdens. Although these mice were highly susceptible to infection they failed to generate hyperinfection. The occurrence of hyperinfection in severely immunodeficient mice following corticosteroid administration reveals a direct role for steroids in the development of autoinfective larvae. This thesis validates the utility of mice as a model of S. stercoralis infection and hyperinfection. Furthermore, we propose that these findings will help address current drawbacks in the diagnosis and treatment of strongyloidiasis in humans