Interstitial macrophages are a focus of viral takeover and inflammation in COVID-19 initiation in human lung.

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  • Additional Information
    • Source:
      Publisher: Rockefeller University Press Country of Publication: United States NLM ID: 2985109R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1540-9538 (Electronic) Linking ISSN: 00221007 NLM ISO Abbreviation: J Exp Med Subsets: MEDLINE
    • Publication Information:
      Original Publication: New York, NY : Rockefeller University Press
    • Subject Terms:
      COVID-19*; Humans ; SARS-CoV-2 ; Macrophages ; Inflammation ; RNA, Viral ; Lung
    • Abstract:
      Early stages of deadly respiratory diseases including COVID-19 are challenging to elucidate in humans. Here, we define cellular tropism and transcriptomic effects of SARS-CoV-2 virus by productively infecting healthy human lung tissue and using scRNA-seq to reconstruct the transcriptional program in "infection pseudotime" for individual lung cell types. SARS-CoV-2 predominantly infected activated interstitial macrophages (IMs), which can accumulate thousands of viral RNA molecules, taking over 60% of the cell transcriptome and forming dense viral RNA bodies while inducing host profibrotic (TGFB1, SPP1) and inflammatory (early interferon response, CCL2/7/8/13, CXCL10, and IL6/10) programs and destroying host cell architecture. Infected alveolar macrophages (AMs) showed none of these extreme responses. Spike-dependent viral entry into AMs used ACE2 and Sialoadhesin/CD169, whereas IM entry used DC-SIGN/CD209. These results identify activated IMs as a prominent site of viral takeover, the focus of inflammation and fibrosis, and suggest targeting CD209 to prevent early pathology in COVID-19 pneumonia. This approach can be generalized to any human lung infection and to evaluate therapeutics.
      (© 2024 Wu et al.)
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    • Grant Information:
      K08 AI163369 United States AI NIAID NIH HHS; T32 GM007365 United States GM NIGMS NIH HHS; T32 AI007502 United States AI NIAID NIH HHS; T32 GM145402 United States GM NIGMS NIH HHS; United States HHMI Howard Hughes Medical Institute; T32 DK007217 United States DK NIDDK NIH HHS; T32 GM007276 United States GM NIGMS NIH HHS; T32 AI007502 United States NH NIH HHS
    • Accession Number:
      0 (RNA, Viral)
    • Publication Date:
      Date Created: 20240410 Date Completed: 20240411 Latest Revision: 20240425
    • Publication Date:
      20240425
    • Accession Number:
      PMC11009983
    • Accession Number:
      10.1084/jem.20232192
    • Accession Number:
      38597954