Accumulating evidence suggest that SARS-CoV-2 infection induces tissue pathology in multiple organs in addition to the lung, including, among others, intestine, heart, liver, kidney, and brain. Furthermore, SARS- CoV-2 infection can exacerbate many chronic inflammatory diseases. However, mouse models that allow to study SARS-CoV-2-induced pathology in specific organs are currently lacking. Additionally, therapeutic strategies using the commercially available K18-hACE2 transgenic mouse model are limited due to ectopic hACE2 expression in the brain driving high lethality. To overcome these problems, we have generated mice with conditional tissue-specific hACE2 expression. The goal of this proposal is to characterize these novel mouse models and define the impact of SARS-CoV-2 specifically on lung immunopathology and intestinal disease. Our central hypothesis is that mice with conditional expression of hACE2 in Rosa26 locus represent a robust platform to study tissue-specific SARS-CoV-2-induced pathology. In Aim 1, we will test the hypothesis that hACE2 expression in type II alveolar epithelial cells and club cells is necessary and sufficient for SARS-CoV-2-induced lung immunopathology. We will analyze SARS-CoV-2 infection dynamics and lung immunopathology in mice with specific expression of hACE2 in type II alveolar epithelial cells and club cells, using our recently developed dual reporter- expressing mCherry-Nluc recombinant (r)SARS-CoV-2. In Aim 2, we will test the hypothesis that SARS-CoV-2 infection exacerbates intestinal inflammation using mice with specific expression of hACE2 in intestinal epithelial cells. This proposal is innovative and significant, as it will generate and characterize novel small animal models to study SARS- CoV-2 mediated organ-specific disease and provide insights into mechanisms of SARS-CoV-2-mediated lung and gut pathology. These mouse models will provide a robust platform to study and monitor SARS-CoV-2 infection in desired cell types and long-term complications of SARS-CoV-2 infection, and to perform therapeutic interventions.