# NIH grant: FSHR-1 as a key receptor mediating Orsay virus entry in C. elegans (1R21AI196827-01A1) — retained record

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[original source ↗](https://reporter.nih.gov/project-details/1R21AI196827-01A1)

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NIH grant 1R21AI196827-01A1: FSHR-1 as a key receptor mediating Orsay virus entry in C. elegans
Institute: {'code': 'AI', 'abbreviation': 'NIAID', 'name': 'National Institute of Allergy and Infectious Diseases', 'admin_org_id': '12500003', 'admin_funding_url': ''}. PI: Yizhi Jane Tao. Award: $234750.
Start: 2026-07-16T00:00:00.
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.
```



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