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Mechanisms of skin penetration in skin-penetrating parasitic nematodes

Award Number: R01AI175183
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 11/14/2023
PERIOD OF PERFORMANCE END DATE: 10/31/2028

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Mechanisms of skin penetration in skin-penetrating parasitic nematodes - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $637,257 )
2026	2026	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	3	12/4/2025	NON-COMPETING CONTINUATION	$637,257
														Subtotal = $637,257

Issue Date FY: 2025 ( Subtotal = $613,556 )
2025	2025	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	2	11/1/2024	NON-COMPETING CONTINUATION	$613,556
														Subtotal = $613,556

Issue Date FY: 2024 ( Subtotal = $679,174 )
2024	2024	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Allergy and Infectious Diseases Research	001	1	9/4/2024	NEW	$67,917
2024	2024	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	1	11/14/2023	NEW	$611,257
														Subtotal = $679,174

Grand Total All Awards = $1,929,987

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Mechanisms of skin penetration in skin-penetrating parasitic nematodes

Award Number: R01AI175183

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 11/14/2023

PERIOD OF PERFORMANCE END DATE: 10/31/2028

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