ADP-ribosylhydrolase activity of Chikungunya virus macrodomain is critical for virus replication and virulence

Abstract

Significance Viral outbreaks can be sudden and result in devastating social and economic consequences. Chikungunya virus (CHIKV) outbreaks of rash, arthritis, and neurologic disease have occurred in Africa, Asia, Europe, and the Americas. There are no licensed vaccines to prevent or drugs to treat CHIKV infection, and the mechanisms of disease generation are poorly understood. Here, we identify a macrodomain-containing CHIKV protein with enzymatic ADP-ribosylhydrolase activity that is critical for virulence in mammals and define the substrate specificity of this enzyme. Given the conservation of viral macrodomains in all alphaviruses and coronaviruses, our study may guide the design of small molecule chemical compounds that block hydrolase activity for treatment of a range of virus infections.