PROJECT SUMMARY: SARS-CoV-2 is a novel coronavirus and the cause of the current global pandemic. This outbreak started in December of 2019 and has now spread over the entire world. SARS-CoV-2 is a respiratory pathogen that causes COVID-19, which has been the cause of more than 2.6 million deaths worldwide, with over 538,000 deaths in the US alone as of March 2021. The primary pathology caused by SARS-CoV-2 infection in humans is in the lungs. In this proposal, we seek to study the early events following coronavirus infection by infecting human lung tissue ex vivo. In order to understand the mechanism by which SARS-CoV-2 causes such severe disease outcomes, we will compare two coronavirus strains, SARS-CoV-2 (which is highly pathogenic) and NL63 (which is mildly pathogenic) in humans. In Aim 1, we will identify differences in viral replication kinetics, infected cell types, and the inflammatory response. In Aim 2, we will characterize the host response to infection using mass spectrometry-based proteomics. Understanding these complex virus:host components in a human system and how these differ between coronaviruses will lead to new hypotheses for in vivo susceptibility and identify new drug targets for therapeutic development.