Friday, April 26, 2024
4/26/2024
PROJECT SUMMARY/ABSTRACT The overall goal of this research proposal is to characterize the mechanosensory behaviors of skin-penetrating parasitic nematodes that enable the location and invasion of a host organism. Skin-penetrating parasitic nematodes, including the threadworm Strongyloides stercoralis, infect nearly one billion people worldwide and are major sources of neglected tropical disease. S. stercoralis is normally found in the soil as infective third- stage larvae (iL3s); soil-dwelling iL3s engage in a variety of behaviors that are thought to increase the likelihood of host contact. The hypothesis that the sensation of mechanical stimuli by S. stercoralis iL3s and the ensuing behavioral response are together integral to host seeking and skin penetration has long been postulated but has not been tested. Furthermore, the underlying mechanotransduction pathways and mechanosensory neuronal circuits are not known. The experiments in this proposal will address this gap in knowledge. The first set of experiments will characterize the behavioral response of S. stercoralis iL3s to vibrations resembling those generated by humans walking on soil. Specifically, the extent to which vibration attracts iL3s and promotes behaviors that facilitate host attachment, including nictation, will be examined in detail. In parallel, an in-depth analysis of the behavioral paradigm of skin penetration will be conducted using human skin. The proposed experiments will also determine whether the stiffness or texture that is particular to human skin promotes skin penetration. Behaviors induced by exposure to vibration and host skin will also be studied in other species of parasitic nematodes – the skin-penetrating human-parasitic hookworm Ancylostoma ceylanicum and the passively ingested murine parasite Heligmosomoides polygyrus – and the free-living nematode Caenorhabditis elegans to identify species-specific behavioral adaptations of skin-penetrating nematodes. Additionally, this work will identify the mechanosensory genes and circuits that underlie host seeking and skin penetration by using a combination of approaches: transcriptional reporters for genes that encode predicted mechanoreceptors to identify putative mechanosensory neurons; targeted mutagenesis of the same genes with CRISPR/Cas9 followed by tracking of behavior; chemogenetic silencing of potential mechanosensory neurons using the histamine-gated chloride channel HisCl1 followed by behavioral studies; and imaging of calcium transients in the same neurons upon stimulation. Together, the work in this proposal will identify the mechanosensory behaviors that are specific to skin-penetrating parasitic nematodes that enable host contact and host invasion. Existing therapeutics for strongyloidiasis do not prevent re-infection; this work may alleviate the problem by uncovering novel molecular targets for the development of preventive anthelmintic drugs and topical creams.
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