2. Academic Validation
  3. Mxra8 is a receptor for multiple arthritogenic alphaviruses

Mxra8 is a receptor for multiple arthritogenic alphaviruses

  • Nature. 2018 May;557(7706):570-574. doi: 10.1038/s41586-018-0121-3.
Rong Zhang 1,  Arthur S Kim 1 2,  Julie M Fox 1,  Sharmila Nair 1,  Katherine Basore 3,  William B Klimstra 4,  Rebecca Rimkunas 5,  Rachel H Fong 5,  Hueylie Lin 1,  Subhajit Poddar 1,  James E Crowe Jr 6,  Benjamin J Doranz 5,  Daved H Fremont 3,  Michael S Diamond 7 8 9 10
Affiliations

Affiliations

  • 1 Department of Medicine, Washington University School of Medicine, Saint Louis, MO, USA.
  • 2 Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, MO, USA.
  • 3 Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO, USA.
  • 4 Center for Vaccine Research, University of Pittsburgh, Pittsburgh, PA, USA.
  • 5 Integral Molecular Inc., Philadelphia, PA, USA.
  • 6 Vanderbilt Vaccine Center, Department of Pediatrics and Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.
  • 7 Department of Medicine, Washington University School of Medicine, Saint Louis, MO, USA. [email protected].
  • 8 Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, MO, USA. [email protected].
  • 9 Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO, USA. [email protected].
  • 10 Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, Saint Louis, MO, USA. [email protected].
PMID: 29769725 DOI: 10.1038/s41586-018-0121-3
Abstract

Arthritogenic alphaviruses comprise a group of enveloped RNA viruses that are transmitted to humans by mosquitoes and cause debilitating acute and chronic musculoskeletal disease 1 . The host factors required for alphavirus entry remain poorly characterized 2 . Here we use a genome-wide CRISPR-Cas9-based screen to identify the cell adhesion molecule Mxra8 as an entry mediator for multiple emerging arthritogenic alphaviruses, including chikungunya, Ross River, Mayaro and O'nyong nyong viruses. Gene editing of mouse Mxra8 or human MXRA8 resulted in reduced levels of viral Infection of cells and, reciprocally, ectopic expression of these genes resulted in increased Infection. Mxra8 bound directly to chikungunya virus particles and enhanced virus attachment and internalization into cells. Consistent with these findings, Mxra8-Fc fusion protein or anti-Mxra8 monoclonal Antibodies blocked chikungunya virus Infection in multiple cell types, including primary human synovial fibroblasts, osteoblasts, chondrocytes and skeletal muscle cells. Mutagenesis experiments suggest that Mxra8 binds to a surface-exposed region across the A and B domains of chikungunya virus E2 protein, which are a speculated site of attachment. Finally, administration of the Mxra8-Fc protein or anti-Mxra8 blocking Antibodies to mice reduced chikungunya and O'nyong nyong virus Infection as well as associated foot swelling. Pharmacological targeting of Mxra8 could form a strategy for mitigating Infection and disease by multiple arthritogenic alphaviruses.

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