Lung immunopathology is a major cause of the morbidity and mortality associated with the SARS-CoV-2 infection. Accumulating evidence suggests that SARS-CoV-2-associated lung damage is caused not only by the virus, but also by excessive production of proinflammatory cytokines, known as cytokine storm. Although available vaccines and antiviral drugs protect against infection, these strategies do not specifically target immune-mediated pathology. Therefore, uncoupling anti-viral host defense mechanisms from the immunopathology induced by these mechanisms, represents a novel therapeutic strategy for COVID-19 treatment. However, to develop such strategies, a better understanding of the fundamental mechanisms that regulate SARS-CoV-2-induced immunopathology using animal models of COVID-19 disease is critical. The critical gap is limited therapeutic approaches that specifically target immune-mediated pathology and availability of animal models that recapitulate human lung disease. Experiments with mouse models expressing SARS-CoV-2 receptor, human ACE2 (hACE2) demonstrated virus invasion to the brain and multiple organ pathology with limited lung pathology, which does not fully recapitulate acute respiratory distress syndrome in patients with severe COVID-19 disease. Our ongoing results demonstrate that lymphotoxin beta receptor (LTR)-deficient mice are protected from SARS-CoV-2-induced immunopathology. We also found that LTβR promotes cytokine storm and lung damage in another model of respiratory disease, influenza infection. The objective of this proposal is to develop novel mouse models that mimic lung disease of COVID-19 patients and to test the efficacy of LTR inhibitor to block SARS-CoV- 2-induced lung damage. Our central hypothesis is that expression of hACE2 in type II alveolar epithelial cells is required for SARS-CoV-2 induced lung disease and that LTR antagonist inhibits SARS- CoV-2 induced lung immunopathology. To test this hypothesis, we propose two specific aims. In Aim 1, we will generate mice with regulated hACE2 expression in type II alveolar epithelial cells using CRISPR- Cas9 system. We will infect these mice intranasally with SARS-CoV-2 and evaluate lung immunopathology and cytokine expression. In Aim 2, we will test the effectiveness of LTR antagonist to block SARS-CoV- 2-induced immunopathology. We will optimize dose and timing of LTR inhibitors and evaluate lung immunopathology, viral replication, cytokine production, and protective immunity. This proposal is innovative and significant, as it will generate novel animal models to study SARS-CoV-2 pathogenesis, provide deeper understanding of the mechanisms regulating virus-induced immunopathology and test the feasibility of targeting novel immune regulator, LTR, to inhibit SARS-CoV-2 induced immunopathology without limiting protective immunity.