Carbon dioxide shapes parasite-host interactions in a human-infective nematode.

Skin-penetrating nematodes infect nearly one billion people worldwide. The developmentally arrested infective larvae (iL3s) seek out hosts, invade hosts via skin penetration, and resume development inside the host in a process called activation. Activated infective larvae (iL3as) traverse the host body, ending up as parasitic adults in the small intestine. Skin-penetrating nematodes respond to many chemosensory cues, but how chemosensation contributes to host seeking, intra-host development, and intra-host navigation - three crucial steps of the parasite-host interaction - remains poorly understood. Here, we investigate the role of carbon dioxide (CO 2 ) in promoting parasite-host interactions in the human-infective threadworm Strongyloides stercoralis . We show that S. stercoralis exhibits life-stage-specific preferences for CO 2 : iL3s are repelled, non-infective larvae and adults are neutral, and iL3as are attracted. CO 2 repulsion in iL3s may prime them for host seeking by stimulating dispersal from host feces, while CO 2 attraction in iL3as may direct worms toward high-CO 2 areas of the body such as the lungs and intestine. We also identify sensory neurons that detect CO 2 ; these neurons are depolarized by CO 2 in iL3s and iL3as. In addition, we demonstrate that the receptor guanylate cyclase Ss -GCY-9 is expressed specifically in CO 2 -sensing neurons and is required for CO 2 -evoked behavior . Ss -GCY-9 also promotes activation, indicating that a single receptor can mediate both behavioral and physiological responses to CO 2 . Our results illuminate chemosensory mechanisms that shape the interaction between parasitic nematodes and their human hosts and may aid in the design of novel anthelmintics that target the CO 2 -sensing pathway.