Arthritogenic alphaviruses are enveloped RNA viruses transmitted by mosquitoes, however the host factors required for alphavirus entry are not fully understood. The authors used a genome-wide CRISPR-Cas9-based screen to identify the cell adhesion molecule Mxra8 as an entry mediator for a number of emerging arthritogenic alphaviruses, including chikungunya, Ross River, Mayaro and O’nyong nyong viruses. When they gene edited mouse Mxra8 or human MXRA8 it led to reduced levels of viral infection of cells, whilst the ectopic expression of these genes led to increased infection. Mxra8 was found to bind directly to chikungunya virus particles and enhanced virus attachment and internalisation into cells. Mxra8-Fc fusion protein or anti-Mxra8 monoclonal antibodies were also found to block chikungunya virus infection in multiple cell types, including primary human synovial fibroblasts, osteoblasts, chondrocytes and skeletal muscle cells. The authors found that Mxra8 binds to a surface-exposed region across the A and B domains of the chikungunya virus E2 protein, which are speculated sites of attachment. The administration of Mxra8-Fc protein or anti-Mxra8 blocking antibodies to mice reduced chikungunya and O’nyong nyong virus infection, together with associated foot swelling. Therefore Mxra8 represents a potential therapeutic target for treating infection and disease by multiple arthritogenic alphaviruses.
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