A cross-reactive antibody protects against Ross River virus musculoskeletal disease despite rapid neutralization escape in mice

PLoS Pathog. 2020 Aug 6;16(8):e1008743. doi: 10.1371/journal.ppat.1008743. eCollection 2020 Aug.

Abstract

Arthritogenic alphaviruses cause debilitating musculoskeletal disease and historically have circulated in distinct regions. With the global spread of chikungunya virus (CHIKV), there now is more geographic overlap, which could result in heterologous immunity affecting natural infection or vaccination. Here, we evaluated the capacity of a cross-reactive anti-CHIKV monoclonal antibody (CHK-265) to protect against disease caused by the distantly related alphavirus, Ross River virus (RRV). Although CHK-265 only moderately neutralizes RRV infection in cell culture, it limited clinical disease in mice independently of Fc effector function activity. Despite this protective phenotype, RRV escaped from CHK-265 neutralization in vivo, with resistant variants retaining pathogenic potential. Near the inoculation site, CHK-265 reduced viral burden in a type I interferon signaling-dependent manner and limited immune cell infiltration into musculoskeletal tissue. In a parallel set of experiments, purified human CHIKV immune IgG also weakly neutralized RRV, yet when transferred to mice, resulted in improved clinical outcome during RRV infection despite the emergence of resistant viruses. Overall, this study suggests that weakly cross-neutralizing antibodies can protect against heterologous alphavirus disease, even if neutralization escape occurs, through an early viral control program that tempers inflammation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alphavirus Infections / complications*
  • Alphavirus Infections / virology
  • Animals
  • Antibodies, Neutralizing / immunology*
  • Antibodies, Viral / immunology*
  • Cross Reactions / immunology*
  • Female
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Musculoskeletal Diseases / immunology
  • Musculoskeletal Diseases / prevention & control*
  • Musculoskeletal Diseases / virology
  • Receptors, Fc / physiology
  • Ross River virus / immunology
  • Ross River virus / isolation & purification*
  • Viral Load / immunology*
  • Virulence

Substances

  • Antibodies, Neutralizing
  • Antibodies, Viral
  • Receptors, Fc