Mxra8 is a receptor for multiple arthritogenic alphaviruses.

Nature
Rong ZhangMichael S Diamond

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, administrat...Continue Reading

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Citations

Jun 29, 2018·Nature Reviews. Drug Discovery·Sarah Crunkhorn
May 17, 2019·Microorganisms·Laura I Levi, Marco Vignuzzi
Sep 5, 2019·PLoS Neglected Tropical Diseases·Marietta MüllerAndrew Tuplin
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Methods Mentioned

BETA
flow cytometry
enzyme-linked immunosorbent assay
transfection
competition binding
chip
Assay
ELISA

Software Mentioned

MAGeCK
Prism
PyMOL Molecular Graphics System
BIAevaluation
PyMOL
GraphPad
FlowJo

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