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We find that disease severity in lung tissue is driven by myeloid cell phenotypes and cell-cell interactions with lung epithelial cells and T cells. Based on these results, we propose a model of immune and epithelial cell interactions that drive cell-type specific and tissue-specific damage in severe COVID-19.Although the global response to COVID-19 has not been entirely unified, the opportunity arises to assess the impact of regional public health interventions and to classify strategies according to their outcome. Analysis of genetic s