UCSF

The ongoing coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), continues to cause significant morbidity and mortality worldwide. Although most infections are mild and a majority of patients recover, some experience severe and often fatal systemic inflammation, cytokine storm, and acute respiratory distress syndrome. The innate immune system of the human body is the first line of defense against SARS-CoV-2, sensing the virus through pattern recognition receptors and activating inflammatory cascades that promote viral clearance. Simultaneously, the virus has evolved numerous strategies to escape detection and surveillance of the immune system for successful replication. An improved understanding of innate immunity and viral evasion strategies will help identify targeted therapies to mitigate disease and improve patient outcome. Here, we report two cellular epigenetic proteins, BRD4 and SIRT5, as anti- and proviral binding partners of SARS-CoV-2 envelope (E) and non-structural protein Nsp14, respectively. We identify bromodomain and extra-terminal (BET) proteins as critical antiviral factors as genetic or chemical inactivation of BRD4 exacerbates viral infection in cells and enhanced mortality in mice. BET inactivation suppresses interferon production induced by SARS-CoV-2, a process phenocopied by the “histone mimetic” E protein, supporting a model where the E protein evolved to antagonize the innate immune system via BET protein inhibition. Conversely, genetic or chemical inactivation of SIRT5 reduces SARS-CoV-2 replication in cells. While SIRT5 interacts with Nsp14 through its catalytic domain, Nsp14 does not appear to be directly deacylated by SIRT5. Depletion of SIRT5 results in higher basal levels of innate immunity and a stronger antiviral response during infection, indicating SIRT5 is a proviral factor necessary for efficient viral replication. Lastly, we compared the humoral immune responses elicited by SARS-CoV-2 variants, WA1, Delta, and Omicron. We show that without vaccination, infection with Omicron induces a limited humoral immune response in mice and humans. In contrast to WA1 and Delta, Omicron replicates at low levels in the lungs and brains of infected mice, leading to mild disease with reduced expression of proinflammatory cytokines, diminished activation of lung-resident T cells, and limited cross-variant immunity against non-Omicron variants in unvaccinated individuals. Collectively, these findings advance our understanding on the various host-pathogen interactions that need to be considered in designing novel SARS-CoV-2 therapeutics.