Role of Nsp1-mediated general host shutoff in SARS-CoV-2 replication

To successfully infect and replicate inside host cells, viruses evolved many mechanisms that block antiviral responses. One of the common mechanisms that viruses use to suppress cellular responses triggered by virus infection is called host shutoff. Host shutoff refers to the general inhibition of the infected cell's ability to produce new proteins, undermining realization of host's genetic programs for combating the virus infection. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that has recently emerged in humans and caused a global pandemic of coronavirus disease 2019 (COVID19) is known to cause host shutoff. Viral protein called non-structural protein 1 (Nsp1) is the first protein produced by SARS-CoV-2 in newly-infected cells and it is responsible for implementing host shutoff by destroying cellular messenger RNAs. Previous research, including from our team, have discovered many activities and properties of Nsp1 and revealed importance of this protein for virus replication and its ability to block antiviral responses. However, which functions of Nsp1 are important for SARS-CoV-2 replication and pathogenesis and how viruses' own messenger RNAs avoid destruction by Nsp1 remains poorly understood. In the proposed research, we will study how Nsp1 contributes to virus fitness. This research will identify key processes and molecules affected by Nsp1 shutoff in infected cells and reveal new targets for developing therapies for COVID19.