Mxra8 is a receptor for multiple arthritogenic alphaviruses

Abstract

Arthritogenic alphaviruses comprise a group of enveloped RNA viruses that are transmitted to humans by mosquitoes and cause debilitating acute and chronic musculoskeletal disease1. The host factors required for alphavirus entry remain poorly characterized2. Using a genome-wide CRISPR/Cas9-based screen, we identified the cell adhesion molecule Mxra8 as an entry mediator for multiple emerging arthritogenic alphaviruses including chikungunya (CHIKV), Ross River, Mayaro, and O’nyong nyong (ONNV) viruses. Gene editing of mouse Mxra8 or human MXRA8 resulted in reduced viral infection of cells, and reciprocally, ectopic expression resulted in increased infection. Mxra8 bound directly to CHIKV particles and enhanced virus attachment and internalization into cells. Consistent with these findings, Mxra8-Fc protein or anti-Mxra8 monoclonal antibodies blocked CHIKV 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 CHIKV E2, a speculated site of attachment. Finally, administration of Mxr8a-Fc protein or anti-Mxra8 blocking antibodies reduced CHIKV or ONNV infection and associated foot swelling in mice. Pharmacological targeting of Mxra8 could form a strategy for mitigating infection and disease by multiple arthritogenic alphaviruses.

Human Neonatal Fc Receptor Is the Cellular Uncoating Receptor for Enterovirus B

“…The assays were performed in suspension as described previously (Zhang et al, 2018) with modifications. Briefly, FCGRT KO , B2M KO , CD55 KO , and WT HEK293T cells were collected in suspension.…”

Suramin Inhibits Chikungunya Virus Replication by Interacting with Virions and Blocking the Early Steps of Infection

“…The viral replication cycle begins with attachment of the virion to the cell surface through interactions with glycosaminoglycans, such as heparan sulfate [17]. Subsequent binding to a receptor, like the recently identified Mxra8 protein [18] will lead to uptake of the virion via receptor-mediated endocytosis [19]. Endosomal acidification causes structural rearrangements in the virion that induce E1 protein-mediated fusion of the viral envelope with the endosomal membrane [20].…”

Genome-wide CRISPR screening identifies new regulators of glycoprotein secretion

“…As such, it provides an opportunity to uncover new information about the regulation of protein secretion. Pooled CRISPR screening has been used for a wide range of applications, including the investigation of drug-resistance mechanisms in cancer cells 9 , the genetics of pluripotency 10 , autophagy regulators 11,12 and host factors required for viral infection 13 . We previously demonstrated that unbiased pooled genome-wide CRISPR screening could effectively reveal key players required for glycoprotein secretion, using galectin-3 retention at the cell surface to assess glycoprotein secretion 14 .…”