Behavioral and neural mechanisms of chemosensation in skin-penetrating parasitic nematodes

PROJECT SUMMARY The goal of this project is to elucidate the behavioral and neural mechanisms that mediate host seeking and host invasion in skin-penetrating, human-parasitic nematodes. Nearly one billion individuals globally are infected with skin-penetrating nematodes, particularly in socioeconomically disadvantaged communities with

limited waste management and healthcare infrastructure. Strongyloides stercoralis, the human threadworm, is

estimated to infect over 600 million individuals globally, resulting in chronic gastrointestinal infections, respiratory distress, growth delays in children, and fatality in immunosuppressed individuals. Infections are expected to rise with climate change and resistance to available anthelmintic drugs is a growing concern; therefore, elucidating

the mechanisms that mediate parasite host seeking and host invasion is crucial for developing novel strategies to prevent and treat individuals infected with S. stercoralis and other parasitic nematodes. Skin-penetrating nematodes freely navigate the environment as developmentally arrested infective third-

stage larvae (iL3s) and rely upon sensory cues to seek out and infect new hosts. Previous studies have shown that the iL3s of S. stercoralis and other skin-penetrating nematode species are robustly attracted to host- associated odorants. However, how olfactory cues drive host-seeking and host-invasion behaviors remains

poorly understood, and the neural mechanisms that mediate odor-evoked behaviors have not been investigated. This proposal hypothesizes that skin-penetrating nematodes have evolved unique neural and behavioral responses to olfactory cues that facilitate specific host-seeking and host-invasion behaviors. To test this

hypothesis, I will investigate the odor-evoked responses of skin-penetrating nematodes at the behavioral and neural levels. I will use S. stercoralis for these experiments because it is a human parasite with direct health relevance and because several genetic manipulation tools have been successfully developed for this species.

Experiments proposed in Aim 1 will characterize and quantitatively analyze motility, host-seeking, and host- invasion responses to host-associated and non-host-associated odorants in vitro and ex vivo. Experiment outlined in Aim 2 will identify putative olfactory neurons and utilize in vivo calcium imaging and chemogenetic

silencing to functionally characterize parasite-specific olfactory neuron response properties. Collectively, my results will illuminate how skin-penetrating nematodes respond to host-associated odorants and how these responses enable the parasites to specifically target human hosts. This work will provide fundamental insights

into the poorly understood field of endoparasite chemosensation and may contribute to the development of novel preventative and treatment methods to control nematode infections.