Norovirus protein NS4 may play a role in immunomodulation during infection 9278

Description Human noroviruses (Caliciviridae family) are the leading cause of gastroenteritis worldwide. Murine norovirus (MNV) has been used as a model system to study human noroviruses due to its robust replication in vitro and in a mouse model. Calicivirus replication involves translation of a single non-structural polyprotein complex from its ssRNA genome, which is then cleaved into individual non-structural proteins (NS1-7) by its protease NS6. Previously, we found that a mutation (MNV NS6F182C) which decreased the efficiency of NS6-NS7 cleavage was able to overcome restriction imposed by Trim7 but resulted in attenuation of the virus. We used Trim7 as a tool to uncover suppressor mutations in this attenuated MNV system (MNV NS6F182C) via viral passaging. We identified NS4V11I as the only mutation that arose in this screen. Norovirus NS4 is a part of the viral replication complex and forms double membrane vesicles in host cells. Previous reports have shown that overexpression of NS4 activates the cGAS-Sting pathway by promoting the release of mitochondrial DNA. While NS4 is considered to have immunomodulatory functions, little is known of the function of NS4 during norovirus infection. Therefore, we leverage viral genetics tools to study differences in replication kinetics of WT MNV and MNV NS4V11I and an unbiased proteomics screen to determine protein interactors of NS4 that will provide critical insight into new mechanisms of viral antagonists to the immune system. Topic Categories Viral Immunology (VIR)