Project Summary Programmed cell death is an ancient and effective defense mechanism against intracellular infection: activation of cellular suicide in response to intracellular pathogens eliminates pathogens’ replicative niches and exposes them to immune-mediated killing. However, when these responses occur incorrectly or overexuberantly, they can cause tissue destruction and exacerbate inflammation. Work from many groups including our own has shown that infection of the lung with RNA viruses can trigger cell death via the inflammatory process termed “necroptosis.” Our preliminary data confirm that infection of cells of the lung epithelium with SARS-CoV-2 leads to their death by necroptosis. These findings, along with additional preliminary data contained within the proposal, lead us to hypothesize that cell death by necroptosis is a key early response to infection of the lung with SARS-CoV-2. We further hypothesize that while a measured necroptotic response helps to eliminate SARS-CoV-2 virus, excessive necroptosis in the lung can lead to detrimental inflammatory pathology. We will test these hypotheses by focusing on three Aims: First, we will carry out detailed immunological and pathological profiling of SARS-2 infected mice lacking key components of necroptotic signaling. Next, we will use a mouse model developed in our lab to experimentally induce necroptosis in the alveolar epithelium in conjunction with SARS-2 infection. Finally, we will use human lung slices to assess cell death responses to SARS-2 infection in intact human tissue.