Why the study?
Viral encephalomyelitis causes long-term disability and fatal disease, and identifying viral determinants of outcome helps in assessing severity and developing treatments.
The macrodomain function of alphavirus nonstructural protein 3 is a key determinant of viral neurovirulence and encephalomyelitis outcome in mice.
Answers are grounded in this paper and cite their sources.
Both nsP3 macrodomain activities may drive alphavirus neurovirulence in mice; leaves open antiviral targeting for encephalomyelitis.
Viral encephalomyelitis is an important cause of long-term disability, as well as acute fatal disease. Identifying viral determinants of outcome helps in assessing disease severity and developing new treatments. Mosquito-borne alphaviruses infect neurons and cause fatal disease in mice. The highly conserved macrodomain of nonstructural protein 3 binds and can remove ADP-ribose (ADPr) from ADP-ribosylated proteins. To determine the importance of these functions for virulence, recombinant mutant viruses were produced. If macrodomain mutations eliminated ADPr-binding or hydrolase activity, viruses did not grow. If the binding and hydrolase activities were impaired, the viruses grew less well than the wild-type virus, induced similar innate responses, and caused less severe disease, and most of the infected mice recovered. If binding was improved, but hydrolase activity was decreased, the virus replicated well and induced greater innate responses than did the WT, but clearance from the nervous system was impaired, and mice remained paralyzed. Therefore, macrodomain function determined the outcome of alphavirus encephalomyelitis.
No takes yet. Share an insight, caveat, or question.
Abraham et al. (2020) studied this question.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: