TREM2+ and interstitial macrophages orchestrate airway inflammation in SARS-CoV-2 infection in rhesus macaques
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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 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 baricitinib
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SciScore for 10.1101/2021.10.05.463212: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IACUC: Emory University’s Institutional Animal Care and Use Committee (IACUC) reviewed and approved all animal experiments under permit PROTO202000035.
Field Sample Permit: Emory University’s Institutional Animal Care and Use Committee (IACUC) reviewed and approved all animal experiments under permit PROTO202000035.Sex as a biological variable Eight (4 female, 4 males, aged >11 yrs Randomization not detected. Blinding not detected. Power Analysis not detected. Table 2: Resources
Software and Algorithms Sentences Resources For purification of CD163+CD206+ (AM), CD163+CD206− (IM) cells, cryopreserved single-cell lung suspensions from RMs were stained with BD CD163(GHI/61), CD206(19.2)(BD Biosciences), and … SciScore for 10.1101/2021.10.05.463212: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IACUC: Emory University’s Institutional Animal Care and Use Committee (IACUC) reviewed and approved all animal experiments under permit PROTO202000035.
Field Sample Permit: Emory University’s Institutional Animal Care and Use Committee (IACUC) reviewed and approved all animal experiments under permit PROTO202000035.Sex as a biological variable Eight (4 female, 4 males, aged >11 yrs Randomization not detected. Blinding not detected. Power Analysis not detected. Table 2: Resources
Software and Algorithms Sentences Resources For purification of CD163+CD206+ (AM), CD163+CD206− (IM) cells, cryopreserved single-cell lung suspensions from RMs were stained with BD CD163(GHI/61), CD206(19.2)(BD Biosciences), and purified using BD FACSAria in the Regional Biocontainment Laboratory at the University of Pittsburgh. BD FACSAriasuggested: (BD FACSAria II Cell Sorter, RRID:SCR_018934)The Seurat library v4.0.433 was used to perform the analysis (see SI for details). Seuratsuggested: (SEURAT, RRID:SCR_007322)Regularized log counts obtained from DESeq2 for bulk sorted IM and AM were used as reference to annotate the cells from BAL samples using SingleR with default parameters. DESeq2suggested: (DESeq, RRID:SCR_000154)Results from OddPub: Thank you for sharing your code and data.
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:Our study had some limitations; first, while the RM/SARS-CoV-2 model has rapidly been adopted by several groups for pre-clinical testing of anti-COVID drugs and vaccines, no group has demonstrated overt, reproducible symptomatic disease11. Thus, linking early immunological events to the development of severe COVID-19 requires validation in human studies, such as the observations of reduced MARCO expression in the airway myeloid populations of severe COVID-19 patients noted above40. Another drawback was the relatively low power of our study. While our observations at 0, 1, and 2dpi were n = 8, we were limited to n = 4 for day 4-10 observations. However, it should be noted that there was no lack of statistical power for our key observations. While the global vaccine rollout has made great strides to reduce the transmission and severity of SARS-CoV-2 infection, millions of people remain vulnerable. Understanding the early events of SARS-CoV-2 infection, and the mechanisms by which clinically approved drugs afford protection, remains a global priority. In this study, we have identified a novel population of inflammatory myeloid cells that are responsible for the preponderance of airway inflammation in acute SARS-CoV-2 infection. We also demonstrated that treatment with the emergency authorized JAK1/2 inhibitor baricitinib in combination with remdesivir, blocked infiltration of these inflammatory cells into the alveolar space. These data identify both a key druggable target (airwa...
Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
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- No protocol registration statement was detected.
Results from scite Reference Check: We found no unreliable references.
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