Expression of the Mxra8 Receptor Promotes Alphavirus Infection and Pathogenesis in Mice and Drosophila

• Published in: Cell reports (Cambridge) 2019-09, Vol.28 (10), p.2647-2658.e5
• Main Authors: Zhang, Rong, Earnest, James T., Kim, Arthur S., Winkler, Emma S., Desai, Pritesh, Adams, Lucas J., Hu, Gaowei, Bullock, Christopher, Gold, Beth, Cherry, Sara, Diamond, Michael S.
• Format: Article
• Language: English
• Subjects: alphavirus; arthritis; mice; pathogenesis; receptor
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2019.07.105

Mxra8 is a recently described receptor for multiple alphaviruses, including Chikungunya (CHIKV), Mayaro (MAYV), Ross River (RRV), and O’nyong nyong (ONNV) viruses. To determine its role in pathogenesis, we generated mice with mutant Mxra8 alleles: an 8-nucleotide deletion that produces a truncated, soluble form (Mxra8Δ8/Δ8) and a 97-nucleotide deletion that abolishes Mxra8 expression (Mxra8Δ97/Δ97). Mxra8Δ8/Δ8 and Mxra8Δ97/Δ97 fibroblasts show reduced CHIKV infection in culture, and Mxra8Δ8/Δ8 and Mxra8Δ97/Δ97 mice have decreased infection of musculoskeletal tissues with CHIKV, MAYV, RRV, or ONNV. Less foot swelling is observed in CHIKV-infected Mxra8 mutant mice, which correlated with fewer infiltrating neutrophils and cytokines. A recombinant E2-D71A CHIKV with diminished binding to Mxra8 is attenuated in vivo in wild-type mice. Ectopic Mxra8 expression is sufficient to enhance CHIKV infection and lethality in transgenic flies. These studies establish a role for Mxra8 in the pathogenesis of multiple alphaviruses and suggest that targeting this protein may mitigate disease in humans. [Display omitted] •Reduced infection of four different alphaviruses is seen in Mxra8-deficient mice•Reduced CHIKV-induced joint swelling is observed in Mxra8-deficient mice•D71A mutant CHIKV that lacks binding to Mxra8 is attenuated in wild-type mice•Ectopic Mxra8 expression is sufficient to enhance CHIKV infection in Drosophila Zhang et al. use CRISPR-Cas9 gene editing to generate mice with out-of-frame 8- and 97-nucleotide deletions in Mxra8. These mice show markedly reduced infection of CHIKV, MAYV, RRV, and ONNV during the acute phase. These experiments establish a key role for Mxra8 in the pathogenesis of multiple alphaviruses.