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

Cell Host Microbe. 2020 Mar 11;27(3):428-440.e9. doi: 10.1016/j.chom.2020.01.008. Epub 2020 Feb 18.


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.

Keywords: Bovinae; X-ray crystallography; alphavirus; evolution; infection; pathogenesis; receptor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Cattle / genetics
  • Chikungunya Fever / genetics*
  • Chikungunya virus*
  • Chlorocebus aethiops
  • Disease Resistance
  • Evolution, Molecular
  • Female
  • Gene Knock-In Techniques
  • HEK293 Cells
  • Humans
  • Immunoglobulins / genetics
  • Membrane Proteins / chemistry
  • Membrane Proteins / genetics*
  • Mice
  • Mice, Inbred C57BL
  • Molecular Docking Simulation
  • NIH 3T3 Cells
  • Protein Domains
  • Receptors, Virus / chemistry
  • Receptors, Virus / genetics*
  • Vero Cells


  • Immunoglobulins
  • Membrane Proteins
  • Mxra8 protein, mouse
  • Receptors, Virus