Innate immune responses to SARS-CoV-2 in the lung and blood of patients with severe COVID-19

SUMMARYCOVID-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 immuneresponses that can lead to an uncontrolled hyper-inflammation in the lung and, ultimately, to anacute respiratory distress syndrome (ARDS) in some patients but not others. Due to the rapidemergence of this pandemic, very limited knowledge is available on the lung-specific innateimmune responses to SARS-CoV-2 that could lead to ARDS (and in some cases death) or insteadelicit 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 "cytokinestorm" and generalized hyper-inflammation has been reported, but specifically how lung-residentmacrophages vs. infiltrating monocytes differentially respond to SARS-CoV-2 and how eachmyeloid subset contribute to either protective antiviral responses or uncontrolled hyper-inflammation and ARDS remain unknown. Hence, an in-depth study of the myeloid compartmentin the lung and blood of severe COVID-19 patients in ICU is critical to better understand theinitiation and persistence of ARDS and, most importantly, to the development of more efficientand 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 infiltratingblood 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 novelinsights into the molecular programming and heterogeneity of the human innate immuneresponses to SARS-CoV-2 infection and identify potential target genes to inform effectivetreatment strategies.