MXRA8-dependent chikungunya virus infection in PDGFRα+ mesenchymal cells increases vascular permeability and facilitates hematogenous spread

Alphaviruses are mosquito-transmitted pathogens in the Togaviridae family that cause severe arthritogenic or encephalitic disease in humans. Swelling of peripheral joints and soft tissues is a hallmark of arthritogenic alphavirus infection, although the mechanism by which tissue edema occurs is not well understood. The cell surface protein, matrix remodeling-associated protein 8 (MXRA8), is a cell entry receptor for several arthritogenic alphaviruses. Global loss of MXRA8 expression in mice abrogates foot swelling and reduces virus dissemination. Here, we demonstrate that specific ablation of MXRA8 from platelet-derived growth factor receptor alpha (PDGFR) cells, including fibroblasts, phenocopies the foot swelling and dissemination deficits observed in chikungunya virus (CHIKV)-infected global MXRA8 knock-out mice. Edema in the foot requires CHIKV infection of PDGFR+ cells, which enhances both infection efficiency and permeability of endothelial cells. CHIKV-induced vascular leakage requires both MXRA8 expression and vascular endothelial growth factor signaling and contributes to dissemination by enabling virus access to the bloodstream. Collectively, our study establishes the role of MXRA8-dependent cell tropism in CHIKV dissemination and pathogenesis.