Neuronally sensed oxygen drives behavior and development in human-infective, skin-penetrating nematodes

Parasitic nematodes infect over a billion people worldwide and cause some of the most prevalent neglected tropical diseases^1-5. Many of these parasites are skin penetrating and have both extra-host life stages that inhabit host feces and surrounding soil, and intra-host life stages that inhabit host niches such as skin, vasculature, and intestine^2,6-8. Across life stages, these parasites encounter oxygen (O₂) levels that range from ~21% at the soilair interface to near-anaerobic levels in the host intestine^9-12. However, whether parasitic nematodes detect and respond to changes in O₂ levels was unknown. Here, we examine O₂ sensation in skin-penetrating parasitic nematodes and find that they show robust responses to changes in O₂ levels. Moreover, their O₂-evoked behaviors differ from those of the free-living nematode Caenorhabditis elegans. We then investigate the molecular and neural mechanisms of O₂ sensing in Strongyloides stercoralis, a genetically tractable human-infective nematode, and find that parasite-specific behavioral responses to O₂ arise in part from evolutionary changes in their soluble guanylate cyclase repertoire. Finally, we find that neuronal O₂ sensing regulates intrahost development in S. stercoralis. Our results demonstrate that skin-penetrating nematodes exhibit neuronally mediated O₂ responses that are critical for multiple steps of their parasitic life cycle.