Abstract
Mumps virus (MuV) is a neurotropic non-segmented, negative-stranded, enveloped RNA virus in the Paramyxovirus family. The 15.4 kb genome encodes seven genes, including the V/P, which encodes, among other proteins, the V protein. The MuV V protein has been shown to target the cellular signal transducer and activator of transcription proteins STAT1 and STAT3 for proteasome-mediated degradation. While MuV V protein targeting of STAT1 is generally accepted as a means of limiting innate antiviral responses, the consequence of V protein targeting of STAT3 is less clear. Further, since the MuV V protein targets both STAT1 and STAT3, specifically investigating viral antagonism of STAT3 targeting is challenging. However, a previous study reported that a single amino acid substitution in the MuV V protein (E95D) inhibits targeting of STAT3, but not STAT1. This provided us with a unique opportunity to examine the specific role of STAT 3 in MuV virulence in an in vivo model. Here, using a clone of a wild type MuV strain expressing the E95D mutant V protein, we present data linking inhibition of STAT3 targeting with the accelerated clearance of the virus and reduced neurovirulence in vivo, suggesting its role in promoting antiviral responses. These data suggest a rational approach to virus attenuation that could be exploited for future vaccine development.
Highlights
Mumps virus (MuV), a rubulavirus of the Paramyxoviridae family, causes an acute infectious disease mainly in children and young adults
In 2007, Puri et al showed that a single amino acid change at position 95 in the MuV V protein, from a glutamic acid to an aspartic acid (E95D), disrupts its ability to associate with STAT3, but not STAT1 [34]
Given that only 1% of brain cells are infected by MuV, no differences were observed in STAT3 levels in vivo between rats infected with r88-1961E95D versus r88-1961WT
Summary
Mumps virus (MuV), a rubulavirus of the Paramyxoviridae family, causes an acute infectious disease mainly in children and young adults. Most mumps vaccines have been causally-linked to aseptic meningitis in vaccinees, highlighting the difficulty in successfully attenuating the virus [13,14]. The V protein-deficient MuV generated by Xu et al was found to be highly attenuated in vivo relative to its wild type parent virus (28); given that the V protein targets both STAT1 and STAT3, it is not known if this effect was mediated by one, the other, or both STATs. In 2007, Puri et al showed that a single amino acid change at position 95 in the MuV V protein, from a glutamic acid to an aspartic acid (E95D), disrupts its ability to associate with STAT3, but not STAT1 [34]. We have extended these studies and examined the role of STAT3 per se in MuV infection in vitro and in vivo
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