Sunday, December 8, 2024
12/8/2024
PROJECT SUMMARY Skin-penetrating nematodes, including the human-parasitic threadworm Strongyloides stercoralis, infect nearly one billion people worldwide and are a major source of morbidity in low-resource settings. Infections can cause chronic gastrointestinal distress, stunted growth and cognitive impairment in children, and even death in the case of S. stercoralis infection. Skin-penetrating nematodes have a soil-dwelling infective third-larval stage that actively searches for a host to infect using host-emitted sensory cues, and then invades the host by penetrating directly through the host’s skin. Host invasion via skin penetration is an essential step of the parasitic life cycle, yet remarkably little is known about this process. We propose to investigate the behavioral, neural, and molecular mechanisms that mediate skin penetration in S. stercoralis and the closely related rat parasite Strongyloides ratti. We will leverage new methods we recently adapted for mechanistic studies of these species, including methods for CRISPR/Cas9-mediated targeted mutagenesis, reversible chemogenetic neuronal silencing, and in vivo calcium imaging. In Aim 1, we will elucidate the behavioral program that leads to skin penetration using in vitro and ex vivo skin-penetration assays. We will compare the behaviors of S. stercoralis and S. ratti infective larvae on host vs. non-host skin to identify behavioral sequences specific to host skin. We will also compare the responses of infective larvae vs. non-infective life stages to identify behaviors that are specific to infective larvae. Finally, we will compare the behaviors of S. stercoralis and S. ratti infective larvae to those of distantly related skin-penetrating infective larvae, passively ingested infective larvae, and free-living larvae to gain insight into the evolution of skin-penetration behavior. In Aim 2, we will investigate the role of dopamine signaling in regulating skin-penetration behavior. We will test the hypothesis that the Strongyloides dopaminergic neurons are mechanosensory neurons that detect the texture of the skin surface and initiate skin-penetration behavior upon contact with host skin. We will also functionally characterize the response properties of the dopaminergic neurons upon contact with host skin. In Aim 3, we will identify and functionally characterize the mechanosensory neurons and mechanotransduction pathways that recognize specific mechanical features of host skin and enable the infective larvae to burrow through the skin. We will also compare mechanosensory function in Strongyloides spp. and the free-living nematode C. elegans to pinpoint the specific mechanosensory adaptations of the parasites that support skin penetration. Together, our results will provide key insights into the molecular and neural mechanisms by which skin-penetrating nematodes invade hosts, which may inform the development of novel topical anthelmintics.
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