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

Arthur S Kim1, Ofer Zimmerman2, Julie M Fox2

  • 1Department of Medicine, Washington University School of Medicine, Saint Louis, MO 63110, USA; Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO 63110, USA.

Cell Host & Microbe
|February 21, 2020
PubMed

Insights

Cattle Mxra8 protein prevents alphavirus infection due to a unique insertion. This finding offers insights into developing countermeasures against alphaviruses like chikungunya virus (CHIKV).

Area of Science:

  • Virology
  • Molecular Biology
  • Immunology

Background:

  • Alphaviruses are mosquito-borne RNA viruses with significant public health implications.
  • The cellular tropism and species selectivity of alphaviruses are not fully understood.
  • Mxra8 has been identified as a key receptor for several alphaviruses, including chikungunya virus (CHIKV).

Purpose of the Study:

  • To investigate the role of Mxra8 in species selectivity of alphavirus infection.
  • To identify the molecular basis for resistance to alphavirus infection in certain species.
  • To explore potential strategies for developing countermeasures against alphaviruses.

Main Methods:

  • Comparative analysis of Mxra8 sequences across different species.
  • Cell-based assays to assess alphavirus binding and infection.
  • Genetic manipulation of Mxra8 to study the effect of specific insertions.
  • In vivo studies using mouse models to evaluate CHIKV pathogenesis.

Main Results:

  • Cattle Mxra8, unlike that of other tested species (mouse, rat, chimpanzee, dog, horse, goat, sheep, human), does not support alphavirus infection.
  • A 15-amino acid insertion in the ectodomain of cattle Mxra8 prevents binding to CHIKV.
  • This insertion is conserved in other Bovinae species and likely evolved over 5 million years ago.
  • Removing the insertion in cattle Mxra8 restores alphavirus binding and infection; introducing it into mouse Mxra8 confers resistance to multiple alphaviruses and mitigates CHIKV pathogenesis in mice.

Conclusions:

  • A specific 15-amino acid insertion in cattle Mxra8 confers resistance to alphavirus infection.
  • This insertion acts as a barrier to CHIKV binding and subsequent infection.
  • Understanding this resistance mechanism could lead to novel therapeutic strategies against alphaviruses.
  • The findings highlight the importance of Mxra8 in alphavirus-host interactions and species tropism.
Keywords:
BovinaeX-ray crystallographyalphavirusevolutioninfectionpathogenesisreceptor

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