Fig. 1.

Administered small molecules can manipulate Ss-DAF-12 signaling to suppress infection and autoinfection by S. stercoralis. a Under natural conditions in nematode development, insulin-like signaling, along with TGFβ-like signaling, upregulates biosynthesis of dafachronic acids from dietary cholesterol. In C. elegans, the DAF-9 cytochrome P450 (CYP) catalyzes the final oxidative step in this biosynthetic pathway [80, 83]. DAF-12 signaling is conserved in parasitic nematodes, including S. stercoralis [77], and previous findings indicate that the cytochrome P450 inhibitor ketoconazole can block developmental activation of infective third-stage larvae (iL3) of S. stercoralis under host-like culture conditions and that this effect is partially reversed by the DAF-12 ligand Δ7-dafachronic acid [78]. This finding underscores the potential of CYP function in DAF-12 signaling as a chemotherapeutic target in blocking the infectious process by S. stercoralis. b Shutdown of insulin- and TGFβ-like signaling in C. elegans downregulates dafachronic acid biosynthesis, and in its unliganded state, DAF-12 downregulates dauer formation and upregulates continuous development [80, 83]. Likewise, in Strongyloides spp., administration of Δ7-dafachronic acid suppresses iL3 morphogenesis and promotes formation of second-generation free-living larvae and adults [77, 81]. Significantly, administering Δ7-dafachronic acid orally to NSG mice undergoing autoinfection with S. stercoralis also suppresses morphogenesis of autoinfective L3 [66••], underscoring the potential of Ss-DAF-12 signaling as a chemotherapeutic target in potentially fatal disseminated hyperinfection in human strongyloidiasis [84]