PROJECT SUMMARY/ABSTRACT A key feature of the COVID-19 infection is the vast inter-individual heterogeneity in the severity of the infection. The complex biological mechanisms that underlie this variability remain mostly obscure. We propose to provide a mechanistic understanding of this susceptibility by leveraging 3 key innovations: First, we have developed a 3-dimensional lung culture system that allows for detailed interrogation of the early events in SARS-CoV-2 infection. Second, we have established an animal model of COVID-19 in mice transgenic for the human ACE2 receptor in our facility. Third, we have built a multi-scale mathematical model of lung infection in COVID-19, that we now seek to expand and personalize to individual hosts. We have two Aims in this project: In Aim 1, we will validate, expand, and personalize our existing multi-scale model, using an unbiased approach to identify and test hypotheses relating to susceptibility to severe COVID-19, and in Aim 2 we will test a specific hypothesis regarding the mechanism of the observed inter-individual heterogeneity in COVID-19 severity, namely that it is, in part, mediated by divergent activation of the mTOR pathway in type I alveolar epithelial cells. If successful, this project will identify the biological basis of the immune pathways that result in heterogeneous outcome of COVID-19, paving the way for personalized, host-specific interventions to improve the outcome of the infection.