Methylprednisolone acetate induces, and Δ7-dafachronic acid suppresses,<i>Strongyloides stercoralis</i>hyperinfection in NSG mice

Abstract

<i>Strongyloides stercoralis</i> hyperinfection causes high mortality rates in humans, and, while hyperinfection can be induced by immunosuppressive glucocorticoids, the pathogenesis remains unknown. Since immunocompetent mice are resistant to infection with <i>S. stercoralis</i>, we hypothesized that NSG mice, which have a reduced innate immune response and lack adaptive immunity, would be susceptible to the infection and develop hyperinfection. Interestingly, despite the presence of large numbers of adult and first-stage larvae in <i>S. stercoralis</i>-infected NSG mice, no hyperinfection was observed even when the mice were treated with a monoclonal antibody to eliminate residual granulocyte activity. NSG mice were then infected with third-stage larvae and treated for 6 wk with methylprednisolone acetate (MPA), a synthetic glucocorticoid. MPA treatment of infected mice resulted in 50% mortality and caused a significant >10-fold increase in the number of parasitic female worms compared with infected untreated mice. In addition, autoinfective third-stage larvae, which initiate hyperinfection, were found in high numbers in MPA-treated, but not untreated, mice. Remarkably, treatment with Δ7-dafachronic acid, an agonist of the parasite nuclear receptor <i>Ss</i>-DAF-12, significantly reduced the worm burden in MPA-treated mice undergoing hyperinfection with <i>S. stercoralis</i> Overall, this study provides a useful mouse model for <i>S. stercoralis</i> autoinfection and suggests a therapeutic strategy for treating lethal hyperinfection.