SUMMARY COVID-19 disease is an ongoing global pandemic caused by a new beta-coronavirus SARS-CoV- 2. A major obstacle to battling SARS-CoV-2 is a better understanding of the human innate immune responses that can lead to an uncontrolled hyper-inflammation in the lung and, ultimately, to an acute respiratory distress syndrome (ARDS) in some patients but not others. Due to the rapid emergence of this pandemic, very limited knowledge is available on the lung-specific innate immune responses to SARS-CoV-2 that could lead to ARDS (and in some cases death) or instead elicit a protective antiviral response (e.g., type-I interferons, interferon-stimulated genes). The role of the human innate immune system, particularly the myeloid cells, in initiating a “cytokine storm” and generalized hyper-inflammation has been reported, but specifically how lung-resident macrophages vs. infiltrating monocytes differentially respond to SARS-CoV-2 and how each myeloid subset contribute to either protective antiviral responses or uncontrolled hyper- inflammation and ARDS remain unknown. Hence, an in-depth study of the myeloid compartment in the lung and blood of severe COVID-19 patients in ICU is critical to better understand the initiation and persistence of ARDS and, most importantly, to the development of more efficient and targeted therapy. Our project’s primary objective is to resolve, at a single-cell level, the specific myeloid subsets, including lung-resident alveolar and interstitial macrophages, dendritic cells, as well as infiltrating blood monocytes, that are responsible for protective antiviral responses (e.g., type-I interferons, interferon-stimulated genes) and/or aberrant hyper-inflammatory responses that lead to ARDS (e.g., “cytokine storm”, neutrophil recruitment, etc.). Through these studies, we will develop novel insights into the molecular programming and heterogeneity of the human innate immune responses to SARS-CoV-2 infection and identify potential target genes to inform effective treatment strategies.