Nematode parasitism is a worldwide health problem resulting in malnutrition and morbidity in over 1 billion people. The molecular mechanisms governing infection are poorly understood. Here, we report that an evolutionarily conserved nuclear hormone receptor signaling pathway governs development of the stage 3 infective larvae (iL3) in several nematode parasites, including Strongyloides stercoralis, Ancylostoma spp., and Necator americanus. As in the free-living Caenorhabditis elegans, steroid hormone-like dafachronic acids induced recovery of the dauer-like iL3 in parasitic nematodes by activating orthologs of the nuclear receptor DAF-12. Moreover, administration of dafachronic acid markedly reduced the pathogenic iL3 population in S. stercoralis, indicating the potential use of DAF-12 ligands to treat disseminated strongyloidiasis. To understand the pharmacology of targeting DAF-12, we solved the 3-dimensional structure of the S. stercoralis DAF-12 ligand-binding domain cocrystallized with dafachronic acids. These results reveal the molecular basis for DAF-12 ligand binding and identify nuclear receptors as unique therapeutic targets in parasitic nematodes.dafachronic acid ͉ parasitology ͉ pharmacology ͉ X-ray crystal structure P arasitic nematodes constitute a large family of pathogens that infect hosts ranging from plants and animals to people, causing great economic loss and worldwide health threats (1, 2). One of the most problematic parasites, Strongyloides stercoralis, is estimated to infect 100-200 million people. Primary infections are often asymptomatic and clinically silent in immunocompetent individuals. However, once the immune system is compromised (e.g., by corticosteroid therapy), the parasite establishes autoinfection cycles that result in a frequently fatal disseminated strongyloidiasis (3, 4). Hookworms (Ancylostoma and Necator spp.) are other parasitic nematodes that affect Ͼ1 billion people and are the dominant cause for iron-deficient anemia worldwide (2). Oral administration of anthelmintics such as benzimidazoles (microtuble toxins) and ivermectin (a neurotoxin) is currently the preferred treatment for nematode infections (5). However, no reliable options exist for treating the more severe form of disseminated strongyloidiasis (6). Moreover, resistance to the anthelmintics has become widespread in animals and is beginning to occur in humans (2, 7). Therefore, studying the mechanisms that govern nematode life cycles is an attractive approach to identifying new therapeutic targets.Infection of hosts by parasitic nematodes is mediated by infective larvae, which in S. stercoralis and hookworm are the third stage or L3 larvae (iL3) (4, 5). Interestingly, iL3 larvae resemble the dauer larvae of the free-living nematode Caenorhabditis elegans in that they are all nonfeeding, developmentally arrested, dormant filariform larvae with a sealed buccal capsule and thickened body wall cuticle, enabling them to survive environmental challenges (8). Like C. elegans dauer larvae, iL3 recover from their ar...
