1. Interstitial macrophages are a focus of viral takeover and inflammation in COVID-19 initiation in human lung
- Author
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Wu, Timothy Ting-Hsuan, Travaglini, Kyle J, Rustagi, Arjun, Xu, Duo, Zhang, Yue, Andronov, Leonid, Jang, SoRi, Gillich, Astrid, Dehghannasiri, Roozbeh, Martínez-Colón, Giovanny J, Beck, Aimee, Liu, Daniel Dan, Wilk, Aaron J, Morri, Maurizio, Trope, Winston L, Bierman, Rob, Weissman, Irving L, Shrager, Joseph B, Quake, Stephen R, Kuo, Christin S, Salzman, Julia, Moerner, WE, Kim, Peter S, Blish, Catherine A, and Krasnow, Mark A
- Subjects
Medical Microbiology ,Biomedical and Clinical Sciences ,Lung ,Vaccine Related ,Emerging Infectious Diseases ,Infectious Diseases ,Pneumonia ,Prevention ,Pneumonia & Influenza ,2.2 Factors relating to the physical environment ,2.1 Biological and endogenous factors ,Aetiology ,Infection ,Respiratory ,Good Health and Well Being ,Humans ,COVID-19 ,SARS-CoV-2 ,Macrophages ,Inflammation ,RNA ,Viral ,Medical and Health Sciences ,Immunology ,Biomedical and clinical sciences ,Health sciences - 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.
- Published
- 2024