TREM2+ and interstitial-like macrophages orchestrate airway inflammation in SARS-CoV-2 infection in rhesus macaques
Amit A. Upadhyay, Elise G. Viox, Timothy N. Hoang, Arun K. Boddapati, María Pino, Michelle Y. Lee, Jacqueline Corry, Zachary Strongin, David Cowan, Elizabeth Beagle, Tristan R. Horton, Sydney Hamilton, Hadj Aoued, Justin Harper, Christopher T Edwards, Kevin Nguyen, Kathryn L. Pellegrini, Gregory K. Tharp, Anne Piantadosi, Rebecca D. Levit, Rama Rao Amara, Simon M. Barratt‐Boyes, Susan Pereira Ribeiro, Rafick‐Pierre Sékaly, Thomas H. Vanderford, Raymond F. Schinazi, Mirko Paiardini, Steven E. Bosinger
Abstract
Abstract The immunopathological mechanisms driving the development of severe COVID-19 remain poorly defined. Here, we utilize a rhesus macaque model of acute SARS-CoV-2 infection to delineate perturbations in the innate immune system. SARS-CoV-2 initiates a rapid infiltration of plasmacytoid dendritic cells into the lower airway, commensurate with IFNA production, natural killer cell activation, and a significant increase of blood CD14 - CD16 + monocytes. To dissect the contribution of lung myeloid subsets to airway inflammation, we generate a longitudinal scRNA-Seq dataset of airway cells, and map these subsets to corresponding populations in the human lung. SARS-CoV-2 infection elicits a rapid recruitment of two macrophage subsets: CD163 + MRC1 - , and TREM2 + populations that are the predominant source of inflammatory cytokines. Treatment with baricitinib (Olumiant®), a JAK1/2 inhibitor is effective in eliminating the influx of non-alveolar macrophages, with a reduction of inflammatory cytokines. This study delineates the major lung macrophage subsets driving airway inflammation during SARS-CoV-2 infection.