Discussion

Skin-penetrating gastrointestinal parasitic nematodes have an infective third-larval stage (iL3) that actively searches for hosts to infect. We are interested in understanding the host-seeking behaviors of iL3s, as well as the molecular and cellular mechanisms that underlie host seeking, using the human-parasitic threadworm Strongyloides stercoralis as a model system. We found that S. stercoralis iL3s display robust attraction to a diverse array of human-emitted odorants. The strongest attractants we identified for S. stercoralis iL3s are also mosquito attractants, suggesting that mosquitoes and worms target humans using many of the same olfactory cues. S. stercoralis iL3s are also robustly attracted to temperatures approximating mammalian body temperature. Both chemosensory behaviors and thermosensory behaviors are flexible such that S. stercoralis iL3s display experience-dependent and life-stage-specific sensory behaviors. To investigate the molecular mechanisms that drive sensory-driven host seeking, we first developed a method for introducing CRISPR/Cas9-mediated gene disruptions in S. stercoralis. We then used this system to identify genes required for host seeking. In C. elegans, many sensory behaviors require the cGMP-gated cation channel subunit gene tax-4. We found that targeted mutagenesis of the S. stercoralis tax-4 homolog abolishes sensory-driven host seeking, demonstrating that parasitic host-seeking behaviors are generated through an adaptation of sensory cascades that drive environmental navigation in C. elegans. We also found that responses to carbon dioxide require the receptor guanylate cyclase gene gcy-9. Our results provide insight into the molecular mechanisms by which human-parasitic nematodes find human hosts to infect.