PROJECT SUMMARY SARS-CoV-2, the causative agent of the COVID-19 pandemic, modifies the cells that it infects in profound ways. One such modification is the activation of host cellular mitogen-activated protein kinase (MAPK) pathways, which contribute to severe inflammation that is a hallmark of severe COVID-19 disease. Inhibition of one MAPK pathway, the p38/MAPK pathway, reduces SARS-CoV-2 replication by an undefined mechanism. This proposal aims to measure the impact of human MAPK pathways on SARS-CoV-2 infection using a multidisciplinary approach that combines state-of-the-art proteomics technologies, medium-throughput genetic screening, and in vivo and ex vivo models of SARS-CoV-2 infection. These findings will inform the potential application of MAPK inhibitors for COVID-19 treatment and may identify alternative targets within the MAPK families. MAPK pathways play critical roles in many disease states, and this work will inform research in these areas by providing molecular mechanisms for MAPK regulation and providing tools for the unbiased discovery of MAPK substrates and regulators.

PROJECT NARRATIVE SARS-CoV-2 infection of human cells requires a number of activated human cellular pathways for successful replication. Inhibition of the human mitogen-activated protein kinase (MAPK) pathway blocks SARS-CoV-2 replication, suggesting that MAPK pathway activation is required for viral replication. This project aims to understand how additional MAPK pathways benefit SARS-CoV-2 replication to identify novel drug targets that may be developed for COVID-19 treatment.