Thursday, December 26, 2024
12/26/2024
PROJECT SUMMARY Skin-penetrating nematodes, including the human-parasitic threadworm Strongyloides stercoralis, infect over one billion people worldwide and are a major source of morbidity in low-resource settings. Infections can cause gastrointestinal distress, stunted growth and cognitive impairment in children, and even death in the case of S. stercoralis infection. S. stercoralis infective larvae are developmentally arrested third-stage larvae that navigate through the soil searching for hosts to infect. When they find a host, they infect by skin penetration, resume growth and development inside the host in a process called activation, and navigate through the host body to the small intestine. These parasites encounter widely varying levels of ambient oxygen (O2) and carbon dioxide (CO2) throughout their life cycle, ranging from the near-atmospheric levels of O2 and CO2 they encounter as infective larvae host seeking at the soil surface to the low O2/high CO2 levels they encounter as parasitic adults residing in the human intestine. However, remarkably little is known about gas sensing in S. stercoralis or any other mammalian-parasitic nematode. We propose to investigate the behavioral, neural, and molecular mechanisms of gas sensing in S. stercoralis. We will conduct an in-depth, quantitative analysis of the behavioral responses of S. stercoralis to acute changes in ambient O2 and CO2 levels as well as O2, CO2, and combined O2/CO2 gradients using automated worm motility tracking. We will compare the responses of infective larvae, activated infective larvae, free-living adults, and parasitic adults to changes in ambient O2 and CO2 to determine how O2/CO2-evoked behaviors vary across life stages. We will then map and functionally characterize the neural microcircuits that mediate behavioral responses to changes in ambient O2 and CO2. We will test the hypothesis that the S. stercoralis homologs of sensory neurons and interneurons that mediate gas sensing in C. elegans also mediate gas sensing in S. stercoralis but contain functional adaptations that enable parasite-specific behavioral responses. Finally, we will identify and characterize the O2 and CO2 receptors that are required for gas sensing in S. stercoralis. Together, our results will provide insight into how skin-penetrating nematodes use gas sensing to find and infect human hosts. In the long-term, our results may identify new molecular targets that could inform the design of novel anthelmintic drugs.
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