Methylprednisolone acetate induces, and Δ7-dafachronic acid suppresses,Strongyloides stercoralishyperinfection in NSG mice

Abstract

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 , 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-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 -DAF-12, significantly reduced the worm burden in MPA-treated mice undergoing hyperinfection with Overall, this study provides a useful mouse model for autoinfection and suggests a therapeutic strategy for treating lethal hyperinfection.

Nuclear option prevents hyperinfection in theStrongyloidesworm war

“…The well-defined effects of glucocorticoids on the intestine and intestinal barrier (13) and the L3a translocation through the intestine occur during hyperinfection, suggesting that this could be a mechanism that is involved. Glucocorticoids do not suppress the DAF-12 receptor of either C. elegans or S. stercoralis, but as reported here by Patton et al (4), Δ7-dafachronic acid will inhibit hyperinfection in a dose-dependent manner. In C. elegans activation of the nuclear receptor, DAF-12, by Δ7-dafachronic acid converts the development from the dauer stage to the continuous growth stages.…”

“…In S. stercoralis Δ7-dafachronic acid inhibits the formation of L3i that are passed out into the feces. Patton et al (4) show here that L1 recovered from the infected gerbils, when exposed to Δ7-dafachronic acid and incubated at 37°C, develop into free living female worms rather than L3i (Fig. 1D).…”

“…There is a real and urgent need for novel therapeutic approaches to be developed to control these parasites. An innovative model and original therapeutic approach is described in PNAS by Patton et al (4), who show that the nematode parasite, Strongyloides stercoralis (5), which causes a deadly hyperinfection in immunocompromised humans, can be accurately modeled in NOD.Cg-Prkdc scid Il2rg tm1Wjl /SzJ (NSG) mice, and wonderfully, can be controlled by a DAF-12 nuclear receptor agonist, Δ7-dafachronic acid. This approach provides a novel strategy for treating these lethal hyperinfections and perhaps other parasitic nematodes.…”

“…Patton et al (4), show that this human hyperinfection condition can be closely modeled in NSG immunocompromised mice when triggered by treatment with the glucocorticoid, methylprednisolone, and that Δ7-dafachronic acid, an agonist of the DAF-12 nuclear receptor, limits the development of hyperinfection. Their observations are both remarkable and important because they illustrate the significance of a nuclear receptor in nematode parasite disease, and they describe the first mouse model that recapitulates the full range of the human Strongyloides hyperinfection disease characteristics.…”

Dafachronic acid and temperature regulate canonical dauer pathways during Nippostrongylus brasiliensis infectious larvae activation

“…Since iL3 can undergo arrest inside the human host [70], an understanding of the genetic pathways controlling their activation may provide insight into development of future therapeutic strategies. As dafachronic acid can reduce worm burden in other species of parasitic nematodes [71], similar examination of dafachronic acid as a therapeutic agent in hookworm infections may be a fruitful area of future study.…”