Characterization of the endogenous DAF-12 ligand and its use as an anthelmintic agent in <i>Strongyloides stercoralis</i>.

Abstract

A prevalent feature of <i>Strongyloides stercoralis</i> is a life-long and potentially lethal infection that is due to the nematode parasite's ability to autoinfect and, thereby, self-replicate within its host. Here, we investigated the role of the parasite's nuclear receptor, <i>Ss-</i>DAF-12, in governing infection. We identified Δ7-DA as the endogenous <i>Ss-</i>DAF-12 ligand and elucidated the hormone's biosynthetic pathway. Genetic loss of function of the ligand's rate-limiting enzyme demonstrated that Δ7-DA synthesis is necessary for parasite reproduction, whereas its absence is required for the development of infectious larvae. Availability of the ligand permits <i>Ss-</i>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 Δ7-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.