TREM2+ and interstitial macrophages orchestrate airway inflammation in SARS-CoV-2 infection in rhesus macaques
TREM2+ and interstitial macrophages orchestrate airway inflammation in SARS-CoV-2 infection in rhesus macaques
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?), 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 summaryMulti-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 baricitinib
Schinazi Raymond F.、Paiardini Mirko、Harper Justin L.、Lee Michelle Y.H.、Strongin Zachary、Cowan David A.、Beagle Elizabeth N.、Horton Tristan R.、Hamilton Sydney、Nguyen Kevin、Pellegrini Kathryn L.、Piantadosi Anne、Boddapati Arun K.、Bosinger Steven E.、Vanderford Thomas H.、Upadhyay Amit A.、Hoang Timothy N.、Amara Rama R.、Tharp Gregory K.、Viox Elise G.、Ribeiro Susan P.、Levit Rebecca D.、Sekaly Rafick P.、Barratt-Boyes Simon M.、Corry Jacqueline、Pino Maria、Aoued Hadj
Department of Pediatrics, School of Medicine, Emory University and Children?ˉs Healthcare of AtlantaDivision of Microbiology and Immunology, Yerkes National Primate Research Center, Emory University||Department of Pathology and Laboratory Medicine, School of Medicine, Emory UniversityDivision of Microbiology and Immunology, Yerkes National Primate Research Center, Emory UniversityDivision of Microbiology and Immunology, Yerkes National Primate Research Center, Emory UniversityDivision of Microbiology and Immunology, Yerkes National Primate Research Center, Emory UniversityYerkes Genomics Core Laboratory, Yerkes National Primate Research Center, Emory UniversityYerkes Genomics Core Laboratory, Yerkes National Primate Research Center, Emory UniversityYerkes Genomics Core Laboratory, Yerkes National Primate Research Center, Emory UniversityYerkes Genomics Core Laboratory, Yerkes National Primate Research Center, Emory UniversityDivision of Microbiology and Immunology, Yerkes National Primate Research Center, Emory UniversityYerkes Genomics Core Laboratory, Yerkes National Primate Research Center, Emory UniversityDepartment of Pathology and Laboratory Medicine, School of Medicine, Emory UniversityYerkes Genomics Core Laboratory, Yerkes National Primate Research Center, Emory UniversityDivision of Microbiology and Immunology, Yerkes National Primate Research Center, Emory University||Department of Pathology and Laboratory Medicine, School of Medicine, Emory UniversityDivision of Microbiology and Immunology, Yerkes National Primate Research Center, Emory UniversityDivision of Microbiology and Immunology, Yerkes National Primate Research Center, Emory UniversityDivision of Microbiology and Immunology, Yerkes National Primate Research Center, Emory UniversityDivision of Microbiology and Immunology, Yerkes National Primate Research Center, Emory University||Department of Microbiology and Immunology, Emory School of Medicine, Emory UniversityYerkes Genomics Core Laboratory, Yerkes National Primate Research Center, Emory UniversityDivision of Microbiology and Immunology, Yerkes National Primate Research Center, Emory UniversityDepartment of Pathology and Laboratory Medicine, School of Medicine, Emory UniversityDepartment of Medicine, School of Medicine, Emory UniversityDepartment of Pathology and Laboratory Medicine, School of Medicine, Emory UniversityDepartment of Infectious Diseases and Microbiology, University of Pittsburgh||Department of Immunology, University of PittsburghDepartment of Infectious Diseases and Microbiology, University of PittsburghDivision of Microbiology and Immunology, Yerkes National Primate Research Center, Emory UniversityYerkes Genomics Core Laboratory, Yerkes National Primate Research Center, Emory University
医学研究方法基础医学微生物学
Schinazi Raymond F.,Paiardini Mirko,Harper Justin L.,Lee Michelle Y.H.,Strongin Zachary,Cowan David A.,Beagle Elizabeth N.,Horton Tristan R.,Hamilton Sydney,Nguyen Kevin,Pellegrini Kathryn L.,Piantadosi Anne,Boddapati Arun K.,Bosinger Steven E.,Vanderford Thomas H.,Upadhyay Amit A.,Hoang Timothy N.,Amara Rama R.,Tharp Gregory K.,Viox Elise G.,Ribeiro Susan P.,Levit Rebecca D.,Sekaly Rafick P.,Barratt-Boyes Simon M.,Corry Jacqueline,Pino Maria,Aoued Hadj.TREM2+ and interstitial macrophages orchestrate airway inflammation in SARS-CoV-2 infection in rhesus macaques[EB/OL].(2025-03-28)[2025-07-16].https://www.biorxiv.org/content/10.1101/2021.10.05.463212.点此复制
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