Hess, Jessica A.

Significance The intestinal parasite Strongyloides stercoralis infects an estimated 100 million people. This nematode’s unique ability to autoinfect its host enables it to persist for decades undetected and to progress to a potentially fatal hyperinfection that often is induced by glucocorticoid treatment. We report a mouse model, involving the NSG strain, that recapitulates all forms of human strongyloidiasis. Even in severely immunocompromised NSG mice, glucocorticoid treatment was required for autoinfection, raising intriguing questions about the mechanism of glucocorticoid action. Notably, administering a nematode-derived steroid, Δ7-dafachronic acid, which acts through a receptor within S. stercoralis to regulate parasite development, significantly diminished autoinfection in glucocorticoid-treated NSG mice. This opens the possibility of new chemotherapy for hyperinfective strongyloidiasis, targeting the parasite’s own steroid hormone mechanisms.

ABSTRACTEosinophils and neutrophils contribute to larval killing during the primary immune response, and neutrophils are effector cells in the secondary response toStrongyloides stercoralisin mice. The objective of this study was to determine the molecular mechanisms used by eosinophils and neutrophils to control infections withS. stercoralis. Using mice deficient in the eosinophil granule products major basic protein (MBP) and eosinophil peroxidase (EPO), it was determined that eosinophils kill the larvae through an MBP-dependent mechanism in the primary immune response if other effector cells are absent. InfectingPHILmice, which are eosinophil deficient, withS. stercoralisresulted in development of primary and secondary immune responses that were similar to those of wild-type mice, suggesting that eosinophils are not an absolute requirement for larval killing or development of secondary immunity. TreatingPHILmice with a neutrophil-depleting antibody resulted in a significant impairment in larval killing. Naïve and immunized mice with neutrophils deficient in myeloperoxidase (MPO) infected withS. stercoralishad significantly decreased larval killing. It was concluded that there is redundancy in the primary immune response, with eosinophils killing the larvae through an MBP-dependent mechanism and neutrophils killing the worms through an MPO-dependent mechanism. Eosinophils are not required for the development or function of secondary immunity, but MPO from neutrophils is required for protective secondary immunity.

ABSTRACTThe goal of this study was to determine the roles of eosinophils and neutrophils in innate and adaptive protective immunity to larvalStrongyloides stercoralisin mice. The experimental approach used was to treat mice with an anti-CCR3 monoclonal antibody to eliminate eosinophils or to use CXCR2−/−mice, which have a severe neutrophil recruitment defect, and then determine the effect of the reduction or elimination of the particular cell type on larval killing. It was determined that eosinophils killed theS. stercoralislarvae in naïve mice, whereas these cells were not required for the accelerated killing of larvae in immunized mice. Experiments using CXCR2−/−mice demonstrated that the reduction in recruitment of neutrophils resulted in significantly reduced innate and adaptive protective immunity. Protective antibody developed in the immunized CXCR2−/−mice, thereby demonstrating that neutrophils were not required for the induction of the adaptive protective immune response. Moreover, transfer of neutrophil-enriched cell populations recovered from either wild-type or CXCR2−/−mice into diffusion chambers containing larvae demonstrated that larval killing occurred with both cell populations when the diffusion chambers were implanted in immunized wild-type mice. Thus, the defect in the CXCR2−/−mice was a defect in the recruitment of the neutrophils and not a defect in the ability of these cells to kill larvae. This study therefore demonstrated that both eosinophils and neutrophils are required in the protective innate immune response, whereas only neutrophils are necessary for the protective adaptive immune response to larvalS. stercoralisin mice.