An Evolutionary Insertion in the Mxra8 Receptor-Binding Site Confers Resistance to Alphavirus Infection and Pathogenesis

• Published in: Cell host & microbe 2020-03, Vol.27 (3), p.428-440.e9
• Main Authors: Kim, Arthur S., Zimmerman, Ofer, Fox, Julie M., Nelson, Christopher A., Basore, Katherine, Zhang, Rong, Durnell, Lorellin, Desai, Chandni, Bullock, Christopher, Deem, Sharon L., Oppenheimer, Jonas, Shapiro, Beth, Wang, Ting, Cherry, Sara, Coyne, Carolyn B., Handley, Scott A., Landis, Michael J., Fremont, Daved H., Diamond, Michael S.
• Format: Article
• Language: English
• Subjects: alphavirus; Amino Acid Sequence; Animals; Binding Sites; Bovinae; Cattle - genetics; Chikungunya Fever - genetics; Chikungunya virus; Chlorocebus aethiops; Disease Resistance; evolution; Evolution, Molecular; Female; Gene Knock-In Techniques; HEK293 Cells; Humans; Immunoglobulins - genetics; infection; Membrane Proteins - chemistry; Membrane Proteins - genetics; Mice; Mice, Inbred C57BL; Molecular Docking Simulation; NIH 3T3 Cells; pathogenesis; Protein Domains; receptor; Receptors, Virus - chemistry; Receptors, Virus - genetics; Vero Cells; X-ray crystallography
• ISSN: 1931-3128; 1934-6069
• DOI: 10.1016/j.chom.2020.01.008

Alphaviruses are emerging, mosquito-transmitted RNA viruses with poorly understood cellular tropism and species selectivity. Mxra8 is a receptor for multiple alphaviruses including chikungunya virus (CHIKV). We discovered that while expression of mouse, rat, chimpanzee, dog, horse, goat, sheep, and human Mxra8 enables alphavirus infection in cell culture, cattle Mxra8 does not. Cattle Mxra8 encodes a 15-amino acid insertion in its ectodomain that prevents Mxra8 binding to CHIKV. Identical insertions are present in zebu, yak, and the extinct auroch. As other Bovinae lineages contain related Mxra8 sequences, this insertion likely occurred at least 5 million years ago. Removing the Mxra8 insertion in Bovinae enhances alphavirus binding and infection, while introducing the insertion into mouse Mxra8 blocks CHIKV binding, prevents infection by multiple alphaviruses in cells, and mitigates CHIKV-induced pathogenesis in mice. Our studies on how this insertion provides resistance to CHIKV infection could facilitate countermeasures that disrupt Mxra8 interactions with alphaviruses. [Display omitted] •An insertion in Bovinae Mxra8 sterically blocks alphavirus binding and infection•The sequence insertion evolved in the Miocene epoch at least 5 million years ago•Loss of the insertion in Mxra8 in several Bovinae restores alphavirus infection•Introduction of the insertion into Mxra8 of mice prevents alphavirus pathogenesis Kim et al. identify a sequence insertion in the Mxra8 receptor of Bovinae species that prevents alphavirus binding. Deletion of the Bovinae Mxra8 insertion restores alphavirus infection, while mice engineered with the Mxra8 insertion exhibit reduced CHIKV infection. Identification of this insertion could facilitate countermeasures preventing Mxra8 engagement of alphaviruses.