A molecular single-cell lung atlas of lethal COVID-19.

TitleA molecular single-cell lung atlas of lethal COVID-19.
Publication TypeJournal Article
Year of Publication2021
AuthorsMelms JC, Biermann J, Huang H, Wang Y, Nair A, Tagore S, Katsyv I, Rendeiro AF, Amin ADipak, Schapiro D, Frangieh CJ, Luoma AM, Filliol A, Fang Y, Ravichandran H, Clausi MG, Alba GA, Rogava M, Chen SW, Ho P, Montoro DT, Kornberg AE, Han AS, Bakhoum MF, Anandasabapathy N, Suárez-Fariñas M, Bakhoum SF, Bram Y, Borczuk A, Guo XV, Lefkowitch JH, Marboe C, Lagana SM, Del Portillo A, Tsai EJ, Zorn E, Markowitz GS, Schwabe RF, Schwartz RE, Elemento O, Saqi A, Hibshoosh H, Que J, Izar B
JournalNature
Volume595
Issue7865
Pagination114-119
Date Published2021 07
ISSN1476-4687
KeywordsAged, Aged, 80 and over, Alveolar Epithelial Cells, Atlases as Topic, Autopsy, Case-Control Studies, COVID-19, Female, Fibroblasts, Fibrosis, Humans, Inflammation, Lung, Macrophages, Macrophages, Alveolar, Male, Middle Aged, Plasma Cells, SARS-CoV-2, Single-Cell Analysis, T-Lymphocytes
Abstract

Respiratory failure is the leading cause of death in patients with severe SARS-CoV-2 infection1,2, but the host response at the lung tissue level is poorly understood. Here we performed single-nucleus RNA sequencing of about 116,000 nuclei from the lungs of nineteen individuals who died of COVID-19 and underwent rapid autopsy and seven control individuals. Integrated analyses identified substantial alterations in cellular composition, transcriptional cell states, and cell-to-cell interactions, thereby providing insight into the biology of lethal COVID-19. The lungs from individuals with COVID-19 were highly inflamed, with dense infiltration of aberrantly activated monocyte-derived macrophages and alveolar macrophages, but had impaired T cell responses. Monocyte/macrophage-derived interleukin-1β and epithelial cell-derived interleukin-6 were unique features of SARS-CoV-2 infection compared to other viral and bacterial causes of pneumonia. Alveolar type 2 cells adopted an inflammation-associated transient progenitor cell state and failed to undergo full transition into alveolar type 1 cells, resulting in impaired lung regeneration. Furthermore, we identified expansion of recently described CTHRC1+ pathological fibroblasts3 contributing to rapidly ensuing pulmonary fibrosis in COVID-19. Inference of protein activity and ligand-receptor interactions identified putative drug targets to disrupt deleterious circuits. This atlas enables the dissection of lethal COVID-19, may inform our understanding of long-term complications of COVID-19 survivors, and provides an important resource for therapeutic development.

DOI10.1038/s41586-021-03569-1
Alternate JournalNature
PubMed ID33915568
PubMed Central IDPMC8814825
Grant List / WT_ / Wellcome Trust / United Kingdom
T32 CA203702 / CA / NCI NIH HHS / United States
K08 CA222663 / CA / NCI NIH HHS / United States
R56 AR078686 / AR / NIAMS NIH HHS / United States
R01 CA194547 / CA / NCI NIH HHS / United States
R01 CA234614 / CA / NCI NIH HHS / United States
UL1 TR002384 / TR / NCATS NIH HHS / United States
R01 DK121072 / DK / NIDDK NIH HHS / United States
R01 AI107301 / AI / NIAID NIH HHS / United States
R37 CA258829 / CA / NCI NIH HHS / United States
U54 CA225088 / CA / NCI NIH HHS / United States
R01 HL152293 / HL / NHLBI NIH HHS / United States
S10 RR027050 / RR / NCRR NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
R01 HL132996 / HL / NHLBI NIH HHS / United States
P30 CA013696 / CA / NCI NIH HHS / United States
R03 DK117252 / DK / NIDDK NIH HHS / United States