Interstitial macrophages are a focus of viral takeover and inflammation in COVID-19 initiation in human lung-Reference-Cited by-同舟云学术

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

Published:2024-04-10 Issue:6 Volume:221 Page:
ISSN:0022-1007
Container-title:Journal of Experimental Medicine
language:en
Short-container-title:

Author:

Wu Timothy Ting-Hsuan¹²^ORCID,Travaglini Kyle J.¹²^ORCID,Rustagi Arjun³^ORCID,Xu Duo¹⁴^ORCID,Zhang Yue¹²⁵^ORCID,Andronov Leonid⁶^ORCID,Jang SoRi¹²^ORCID,Gillich Astrid¹²^ORCID,Dehghannasiri Roozbeh¹⁷^ORCID,Martínez-Colón Giovanny J.³⁸^ORCID,Beck Aimee³^ORCID,Liu Daniel Dan⁹^ORCID,Wilk Aaron J.³⁸^ORCID,Morri Maurizio¹⁰^ORCID,Trope Winston L.¹¹^ORCID,Bierman Rob¹^ORCID,Weissman Irving L.⁹¹²^ORCID,Shrager Joseph B.¹¹¹³^ORCID,Quake Stephen R.¹⁰¹⁴,Kuo Christin S.¹⁵^ORCID,Salzman Julia¹⁷^ORCID,Moerner W.E.⁶^ORCID,Kim Peter S.¹¹⁰⁴^ORCID,Blish Catherine A.³⁸¹⁰^ORCID,Krasnow Mark A.¹¹⁶²^ORCID

Affiliation:

1. Stanford University School of Medicine 1 Department of Biochemistry, , Stanford, CA, USA

2. Howard Hughes Medical Institute 11 , San Francisco, CA, USA

3. Stanford University School of Medicine 2 Division of Infectious Diseases and Geographic Medicine, Department of Medicine, , Stanford, CA, USA

4. Sarafan ChEM-H, Stanford University 16 , Stanford, CA, USA

5. Stanford University 13 Department of Biology, , Stanford, CA, USA

6. Stanford University 14 Department of Chemistry, , Stanford, CA, USA

7. Stanford University School of Medicine 6 Department of Biomedical Data Science, , Stanford, CA, USA

8. Stanford University School of Medicine 7 Program in Immunology, , Stanford, CA, USA

9. Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine 8 , Stanford, CA, USA

10. Chan Zuckerberg Biohub 12 , San Francisco, CA, USA

11. Stanford University School of Medicine 3 Department of Cardiothoracic Surgery, , Stanford, CA, USA

12. Stanford University School of Medicine 9 Department of Pathology, , Stanford, CA, USA

13. Veterans Affairs Palo Alto Healthcare System 10 , Palo Alto, CA, USA

14. Stanford University 15 Department of Bioengineering, , Stanford, CA, USA

15. Stanford University School of Medicine 5 Department of Pediatrics, Pulmonary Medicine, , Stanford, CA, USA

16. Vera Moulton Wall Center for Pulmonary Vascular Disease, Stanford University School of Medicine 4 , Stanford, CA, USA

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.

Funder

Bill and Melinda Gates Foundation

Chan Zuckerberg Biohub

Burroughs Wellcome Fund

Howard Hughes Medical Institute

National Institutes of Health

American Cancer Society

Stanford Maternal and Child Health Research Institute

Stanford Graduate Fellowship

Stanford Cell and Molecular Biology Training

Stanford Bio-X

Stanford University