Molecular mechanisms of host shutoff by respiratory viruses and their contribution to viral pathogenesis

Viral respiratory disease burden remains high despite continuous efforts to limit virus infection and spread through vaccination, surveillance, and quarantine measures. Now the world is in the middle of a pandemic caused by a novel respiratory virus - severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Despite unprecedented efforts by researchers worldwide to develop vaccines against SARS-CoV-2, there is still uncertainty as to whether and when they will become available. Even if vaccines are deployed, people with underlying health conditions will remain under threat. This is true in the case of another respiratory virus, influenza, to which vaccines were developed decades ago, and which continues to cause seasonal epidemics. In Canada, influenza infections peak each year in the late fall and winter months resulting in over 12,000 hospitalizations and over 3,000 deaths annually. This underscores the need for better treatment options for those who develop severe respiratory disease. The long-term goal of our research program is the development of new antiviral treatments based on detailed understanding of virus-host interactions. Specifically, we are interested in the mechanisms used by respiratory viruses like influenza and SARS-CoV-2 to overcome antiviral immune responses. One such mechanism is host shutoff - the blockade of new protein synthesis in infected cells. Both influenza A viruses and coronaviruses produce dedicated host shutoff factors: polymerase acidic X (PA-X) and non-structural protein 1 (Nsp1), respectively. These viral genes interfere with cells ability to synthesise new proteins, including those that are involved in immune responses. In the proposed research, we will determine how PA-X and Nsp1 work at the molecular level and how their function disrupt immune responses to these respiratory viruses.