@article {Upadhyay2021.10.05.463212, author = {Amit A. Upadhyay and Timothy N. Hoang and Maria Pino and Arun K. Boddapati and Elise G. Viox and Michelle Y.H. Lee and Jacqueline Corry and Zachary Strongin and David A. Cowan and Elizabeth N. Beagle and Tristan R. Horton and Sydney Hamilton and Hadj Aoued and Justin L. Harper and Kevin Nguyen and Kathryn L. Pellegrini and Gregory K. Tharp and Anne Piantadosi and Rebecca D. Levit and Rama R. Amara and Simon M. Barratt-Boyes and Susan P. Ribeiro and Rafick P. Sekaly and Thomas H. Vanderford and Raymond F. Schinazi and Mirko Paiardini and Steven E. Bosinger}, title = {TREM2+ and interstitial macrophages orchestrate airway inflammation in SARS-CoV-2 infection in rhesus macaques}, elocation-id = {2021.10.05.463212}, year = {2021}, doi = {10.1101/2021.10.05.463212}, publisher = {Cold Spring Harbor Laboratory}, abstract = {The COVID-19 pandemic remains a global health crisis, yet, the immunopathological mechanisms driving the development of severe disease remain poorly defined. Here, we utilize a rhesus macaque (RM) model of SARS-CoV-2 infection to delineate perturbations in the innate immune system during acute infection using an integrated systems analysis. We found that SARS-CoV-2 initiated a rapid infiltration (two days post infection) of plasmacytoid dendritic cells into the lower airway, commensurate with IFNA production, natural killer cell activation, and induction of interferon-stimulated genes. At this early interval, we also observed a significant increase of blood CD14-CD16+ monocytes. To dissect the contribution of lung myeloid subsets to airway inflammation, we generated a novel compendium of RM-specific lung macrophage gene expression using a combination of sc-RNA-Seq data and bulk RNA-Seq of purified populations under steady state conditions. Using these tools, we generated a longitudinal sc-RNA-seq dataset of airway cells in SARS-CoV-2-infected RMs. We identified that SARS-CoV-2 infection elicited a rapid recruitment of two subsets of macrophages into the airway: a C206+MRC1-population resembling murine interstitial macrophages, and a TREM2+ population consistent with CCR2+ infiltrating monocytes, into the alveolar space. These subsets were the predominant source of inflammatory cytokines, accounting for ~75\% of IL6 and TNF production, and \>90\% of IL10 production, whereas the contribution of CD206+MRC+ alveolar macrophages was significantly lower. Treatment of SARS-CoV-2 infected RMs with baricitinib (Olumiant{\textregistered}), a novel JAK1/2 inhibitor that recently received Emergency Use Authorization for the treatment of hospitalized COVID-19 patients, was remarkably effective in eliminating the influx of infiltrating, non-alveolar macrophages in the alveolar space, with a concomitant reduction of inflammatory cytokines. This study has delineated the major subsets of lung macrophages driving inflammatory and anti-inflammatory cytokine production within the alveolar space during SARS-CoV-2 infection.One sentence summary Multi-omic analyses of hyperacute SARS-CoV-2 infection in rhesus macaques identified two population of infiltrating macrophages, as the primary orchestrators of inflammation in the lower airway that can be successfully treated with baricitinibCompeting Interest StatementCompeting interests: R.F.S. has served as an unpaid consultant for Eli Lilly whose drugs are being evaluated in the research described in this paper, and owns shares in Eli Lilly. The terms of this arrangement have been reviewed and approved by Emory University in accordance with its conflict of interest policies. All other authors do not have any conflicts to declare.}, URL = {https://www.biorxiv.org/content/early/2021/10/05/2021.10.05.463212}, eprint = {https://www.biorxiv.org/content/early/2021/10/05/2021.10.05.463212.full.pdf}, journal = {bioRxiv} }