NRP1 is a receptor for mammalian orthoreovirus engaged by distinct capsid subunits

Pengcheng Shang; Rita Dos Santos Natividade; Gwen M Taylor; Ankita Ray; Olivia L Welsh; Kay L Fiske; Danica M Sutherland; David Alsteens; Terence S Dermody

doi:10.1016/j.chom.2024.04.014

NRP1 is a receptor for mammalian orthoreovirus engaged by distinct capsid subunits

Cell Host Microbe. 2024 May 8:S1931-3128(24)00134-3. doi: 10.1016/j.chom.2024.04.014. Online ahead of print.

Authors

Pengcheng Shang¹, Rita Dos Santos Natividade², Gwen M Taylor¹, Ankita Ray², Olivia L Welsh¹, Kay L Fiske¹, Danica M Sutherland¹, David Alsteens³, Terence S Dermody⁴

Affiliations

¹ Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Institute of Infection, Inflammation, and Immunity, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.
² Louvain Institute of Biomolecular Science and Technology, Université catholique de Louvain, Louvain-la-Neuve, Belgium.
³ Louvain Institute of Biomolecular Science and Technology, Université catholique de Louvain, Louvain-la-Neuve, Belgium; WELBIO department, WEL Research Institute, Wavre, Belgium.
⁴ Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Institute of Infection, Inflammation, and Immunity, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA; Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Electronic address: terence.dermody@chp.edu.

PMID: 38729153
DOI: 10.1016/j.chom.2024.04.014

Abstract

Mammalian orthoreovirus (reovirus) is a nonenveloped virus that establishes primary infection in the intestine and disseminates to sites of secondary infection, including the CNS. Reovirus entry involves multiple engagement factors, but how the virus disseminates systemically and targets neurons remains unclear. In this study, we identified murine neuropilin 1 (mNRP1) as a receptor for reovirus. mNRP1 binds reovirus with nanomolar affinity using a unique mechanism of virus-receptor interaction, which is coordinated by multiple interactions between distinct reovirus capsid subunits and multiple NRP1 extracellular domains. By exchanging essential capsid protein-encoding gene segments, we determined that the multivalent interaction is mediated by outer-capsid protein σ3 and capsid turret protein λ2. Using capsid mutants incapable of binding NRP1, we found that NRP1 contributes to reovirus dissemination and neurovirulence in mice. Collectively, our results demonstrate that NRP1 is an entry receptor for reovirus and uncover mechanisms by which NRPs promote viral entry and pathogenesis.

Keywords: CNS; NRP1; affinity; atomic force microscopy; binding; capsid proteins; dissemination; infection; neuropathogenesis; reovirus.