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Series GSE198882 Query DataSets for GSE198882
Status Public on Feb 09, 2023
Title TREM2+ and interstitial macrophages orchestrate airway inflammation in SARS-CoV-2 infection in rhesus macaques
Organism Macaca mulatta
Experiment type Expression profiling by high throughput sequencing
Summary 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.
 
Overall design Eight rhesus macaques (Macaca mulatta) were infected with SARS-CoV-2. Four RMs were administered 4 mg Baricitinib starting at day 2 post-infection (DPI) for 8-9 consecutive days. RNA-Seq profiling of cells isolated from PBMC and BAL (bronchoalveolar lavages) prior to SARS-CoV-2 inoculation (-5 DPI; Baseline); after virus inoculation, PBMCs were isolated 1,2,4,6,7,8 DPI, and BALs were sampled 2,4,7 DPI; PBMC and BAL were samples at Necropsy 10-11 DPI.
Web link https://doi.org/10.1038/s41467-023-37425-9
 
Contributor(s) Upadhyay AA, Hoang TN, Pino M, Boddapati AK, Viox EG, Lee MY, Corry J, Strongin Z, Cowan DA, Beagle EN, Horton TR, Hamilton S, Aoued H, Harper JL, Nguyen K, Pellegrini KL, Tharp GK, Piantadosi A, Levit RD, Amara RR, Barratt-Boyes SM, Ribeiro SP, Sekaly RP, Vanderford TH, Schinazi RF, Paiardini M, Bosinger SE
Citation(s) 37024448
Submission date Mar 17, 2022
Last update date May 16, 2023
Contact name Gregory K Tharp
E-mail(s) gktharp@emory.edu
Phone 404-727-7797
Organization name Yerkes National Primate Research Center
Department Developmental and Cognitive Neuroscience
Lab Genomics Core
Street address 954 Gatewood Dr
City Atlanta
State/province GA
ZIP/Postal code 30329-4208
Country USA
 
Platforms (1)
GPL27943 Illumina NovaSeq 6000 (Macaca mulatta)
Samples (101)
GSM5958810 PBMCs, p20097-s001
GSM5958811 PBMCs, p20097-s002
GSM5958812 PBMCs, p20097-s003
Relations
BioProject PRJNA817233

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MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE198882_BAL_raw_counts.txt.gz 1.3 Mb (ftp)(http) TXT
GSE198882_PBMC_raw_counts.txt.gz 1.8 Mb (ftp)(http) TXT
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