Characterization of the Endogenous DAF-12 Ligand and Its Use as an Anthelmintic Agent in Strongyloides stercoralis

A prevalent feature of Strongyloides stercoralis is a life-long and potentially lethal infection that is due to the nematode parasites ability to autoinfect and, thereby, self-replicate within its host. Here, we investigated the role of the parasites nuclear receptor, Ss-DAF-12, in governing infection. We identified {Delta}7-DA as the endogenous Ss-DAF-12 ligand and elucidated the hormones biosynthetic pathway. Genetic loss of function of the ligands rate-limiting enzyme demonstrated that {Delta}7-DA synthesis is necessary for parasite reproduction, whereas its absence is required for development of infectious larvae. Availability of the ligand permits Ss-DAF-12 to function as an on/off switch governing autoinfection, making it vulnerable to therapeutic intervention. In a preclinical model of hyperinfection, pharmacologic activation of DAF-12 suppressed autoinfection and markedly reduced lethality. Moreover, when {Delta}7-DA was administered with ivermectin, the current but limited drug of choice for treating strongyloidiasis, the combinatorial effects of the two drugs resulted in a near cure of the disease.