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FSHR-1 as a key receptor mediating Orsay virus entry in C. elegans

Award Number: R21AI196827
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: 07/16/2026
PERIOD OF PERFORMANCE END DATE: 06/30/2028

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FSHR-1 as a key receptor mediating Orsay virus entry in C. elegans - The primary objective of this grant is to investigate the role of FSHR-1, a G protein-coupled receptor (GPCR) highly expressed in the intestinal cells of Caenorhabditis elegans (C. elegans), as a potential host receptor mediating the endosomal uptake of Orsay virus (OrV) during viral entry. OrV is the only known virus that naturally infects C. elegans, a widely used small animal model in biological research. The chronic, non-lethal nature of OrV infection, together with the genetic tractability, optical transparency, and ease of handling of C. elegans, provides a powerful in vivo system to study viral infection dynamics and host–pathogen interactions within polarized intestinal cells. OrV, a positive-sense single-stranded RNA (+ssRNA) virus, encodes a nonstructural protein called δ, which can also be expressed as a CP-δ fusion protein through ribosomal frameshifting. Previous work from our lab revealed that CP-δ is incorporated into infectious virions as a pentameric head fiber critical for host receptor binding and viral entry. New preliminary data from our lab indicate that the distal knob domain of the CP-δ head fiber interacts with FSHR-1, and C. elegans lacking FSHR-1 exhibit resistance to OrV infection. Structural studies of a δ protein C-terminal fragment δ(220-346) showed a pentameric assembly with a fibrous shaft followed by a β-stranded knob domain. Additionally, fluorescence co-localization and co-immunoprecipitation experiments confirm the direct interaction between δ and FSHR-1. A preliminary cryo-electron microscopy (cryo-EM) reconstruction of the FSHR-1(ED):δ(220-346) complex revealed that the FSHR-1 hinge region extensively wraps around the δ knob domain. Based on these findings, we hypothesize that OrV binding to FSHR-1 triggers receptor internalization, facilitating viral entry via clathrin-mediated endocytosis. To test this hypothesis, we propose two complementary research aims. Aim 1: Elucidate the molecular interaction between FSHR-1 and the CP-δ head fiber. We will determine a high-resolution structure of the FSHR-1:OrV δ fiber complex and use site-directed mutagenesis to map critical binding motifs in both proteins. Aim 2: Confirm that FSHR-1 facilitates OrV entry via clathrin-mediated endocytosis. We will use super-resolution microscopy and cryo-electron tomography to track OrV uptake and determine whether disruption of the FSHR-1:δ interaction blocks viral internalization and infection. To assess the contribution of receptor specificity to host range, we will also evaluate whether expression of C. briggsae FSHR-1 supports infection by OrV or other nematode viruses in C. elegans. The insights gained from this study will define a previously uncharacterized GPCR-dependent mechanism of viral entry and deepen our understanding of virus–host interactions using the Orsay–C. elegans model. Moreover, elucidating viral receptor interactions may enable the rational engineering of nematode viruses with altered host range and tissue tropism, offering potential applications in antiviral therapeutics and parasitic worm control.


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 = $234,750 )
2026	2026	WILLIAM MARSH RICE UNIVERSITY	6100 MAIN ST	HOUSTON	TX	77005	HARRIS	USA	Allergy and Infectious Diseases Research	000	1	7/16/2026	NEW	$234,750
														Subtotal = $234,750

Grand Total All Awards = $234,750

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FSHR-1 as a key receptor mediating Orsay virus entry in C. elegans

Award Number: R21AI196827

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: 07/16/2026

PERIOD OF PERFORMANCE END DATE: 06/30/2028

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