Oxygen sensation in human-parasitic skin-penetrating nematodes

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PROJECT SUMMARY / ABSTRACT The goal of this proposal is to leverage molecular neuroscience techniques to define the role of oxygen (O2) as a biologically relevant chemosensory cue in the human-infective threadworm Strongyloides stercoralis. Globally, S. stercoralis infects ~610 million people, with a high disease burden in resource-poor settings. Strongyloidiasis, considered an emerging and/or re-emerging disease, can manifest as an indolent multi-decade gastrointestinal infection; immunocompromised individuals are at high risk of hyperinfection syndrome and disseminated disease – of which most cases are fatal. Given the threat of anthelmintic resistance, novel chemotherapeutic strategies are needed to treat and cure individuals with strongyloidiasis. Parasitic nematodes rely upon neuronally detected sensory cues to actively seek hosts, navigate intra- and extra-host environments, and coordinate their development with their local context. S. stercoralis, as a soil- transmitted helminth, thrives in O2 concentrations that range from atmospheric levels (~21%) at the soil surface to near-anaerobic conditions in the host intestinal tract. However, O2 sensation remains completely unstudied in S. stercoralis or any other parasitic nematode. This proposal hypothesizes that the neural and molecular machinery mediating O2 sensation in S. stercoralis may yield promising targets vulnerable to intervention. This proposal will explore O2 sensation in S. stercoralis at the behavioral, neuronal, and molecular levels. The first aim of this proposal seeks to characterize how O2 serves as a chemosensory cue to sculpt the motile behaviors of S. stercoralis throughout its parasitic life cycle. Quantitative analysis of parasite behaviors in different O2 contexts will be performed. Additionally, work proposed in the first aim will interrogate the role of shifting O2 levels as a developmental cue that enables parasitism. In the second aim of this proposal, chemogenetic neuronal silencing and calcium imaging techniques will be employed to both identify O2-sensing neurons and describe parasite-specific encoding properties in these neurons. In the proposal’s third aim, CRISPR/Cas9-mediated mutagenesis and ectopic expression systems will be used to determine the molecular sensors of O2 in S. stercoralis and explore their mechanism of action. This proposal will generate new insights into parasite chemosensory neurobiology and may reveal novel strategies for preventing nematode infections. This proposal will support the applicant’s goal of becoming a physician-scientist dedicated to the study and clinical management of parasitic infectious diseases. In completing the proposed aims, the applicant will augment prior training in parasitology and molecular biology with the development of new skills in neuroscience research. This work will be performed in one of the only laboratories studying neurobiology in parasitic nematodes; the applicant will also seek mentorship from the rich community of parasitologists and neuroscientists at UCLA.