Abstract

Dysregulated immune responses against the SARS-CoV-2 virus are instrumental in severe COVID-19. However, the immune signatures associated with immunopathology are poorly understood. Here we use multi-omics single-cell analysis to probe the dynamic immune responses in hospitalized patients with stable or progressive course of COVID-19, explore V(D)J repertoires, and assess the cellular effects of tocilizumab. Coordinated profiling of gene expression and cell lineage protein markers shows that S100Ahi/HLA-DRlo classical monocytes and activated LAG-3hi T cells are hallmarks of progressive disease and highlights the abnormal MHC-II/LAG-3 interaction on myeloid and T cells, respectively. We also find skewed T cell receptor repertories in expanded effector CD8+ clones, unmutated IGHG+ B cell clones, and mutated B cell clones with stable somatic hypermutation frequency over time. In conclusion, our in-depth immune profiling reveals dyssynchrony of the innate and adaptive immune interaction in progressive COVID-19.

SARS-CoV-2 infection can lead to progressive pathology in patients with COVID-19, but information for this disease progression is sparse. Here the authors use multi-omics approach to profile the immune responses of patients, assessing immune repertoire and effects of tocilizumab treatments, to find a dyssynchrony between innate and adaptive immunity in progressive COVID-19.

Details

Title
Single-cell multi-omics reveals dyssynchrony of the innate and adaptive immune system in progressive COVID-19
Author
Unterman Avraham 1   VIAFID ORCID Logo  ; Sumida, Tomokazu S 2   VIAFID ORCID Logo  ; Nouri Nima 3   VIAFID ORCID Logo  ; Xiting, Yan 4 ; Zhao, Amy Y 5 ; Gasque, Victor 6   VIAFID ORCID Logo  ; Schupp, Jonas C 7   VIAFID ORCID Logo  ; Asashima Hiromitsu 2 ; Liu Yunqing 8 ; Carlos, Cosme, Jr 9 ; Deng Wenxuan 8 ; Chen, Ming 8 ; Raredon Micha Sam Brickman 10   VIAFID ORCID Logo  ; Hoehn, Kenneth B 11   VIAFID ORCID Logo  ; Wang, Guilin 12 ; Wang, Zuoheng 8   VIAFID ORCID Logo  ; DeIuliis Giuseppe 9   VIAFID ORCID Logo  ; Ravindra, Neal G 6   VIAFID ORCID Logo  ; Li Ningshan 13 ; Castaldi, Christopher 14 ; Wong, Patrick 15 ; Fournier, John 16 ; Santos, Bermejo 9 ; Sharma, Lokesh 9   VIAFID ORCID Logo  ; Casanovas-Massana Arnau 17   VIAFID ORCID Logo  ; Vogels Chantal B F 17   VIAFID ORCID Logo  ; Wyllie, Anne L 17   VIAFID ORCID Logo  ; Grubaugh, Nathan D 17 ; Melillo, Anthony 11 ; Meng Hailong 11 ; Stein, Yan 18   VIAFID ORCID Logo  ; Minasyan Maksym 9 ; Mohanty Subhasis 19 ; Ruff, William E 2   VIAFID ORCID Logo  ; Cohen, Inessa 2 ; Khadir, Raddassi 2 ; Nelson, Allison 20 ; Shepard, Denise 19 ; Rainone, Michael 9 ; Peng Xiaohua 9 ; Niklason, Laura E 21 ; Ko, Albert I 17   VIAFID ORCID Logo  ; Montgomery, Ruth R 20   VIAFID ORCID Logo  ; Farhadian, Shelli F 22   VIAFID ORCID Logo  ; Iwasaki Akiko 23   VIAFID ORCID Logo  ; Shaw, Albert C 19 ; van Dijk David 6   VIAFID ORCID Logo  ; Zhao, Hongyu 24   VIAFID ORCID Logo  ; Kleinstein, Steven H 25   VIAFID ORCID Logo  ; Hafler, David A 2   VIAFID ORCID Logo  ; Kaminski Naftali 9   VIAFID ORCID Logo  ; Dela Cruz Charles S 26   VIAFID ORCID Logo 

1  School of Medicine, Yale University, Section of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, New Haven, USA (GRID:grid.47100.32) (ISNI:0000000419368710); Tel Aviv Sourasky Medical Center, Tel Aviv University, Pulmonary Institute, Tel Aviv, Israel (GRID:grid.12136.37) (ISNI:0000 0004 1937 0546) 
2  School of Medicine, Yale University, Department of Neurology, New Haven, USA (GRID:grid.47100.32) (ISNI:0000000419368710); School of Medicine, Yale University, Department of Immunobiology, New Haven, USA (GRID:grid.47100.32) (ISNI:0000000419368710) 
3  Yale School of Medicine, Department of Pathology, New Haven, USA (GRID:grid.47100.32) (ISNI:0000000419368710); Yale School of Medicine, Center for Medical Informatics, New Haven, USA (GRID:grid.47100.32) (ISNI:0000000419368710); The Jackson Laboratory for Genomic Medicine, Farmington, USA (GRID:grid.249880.f) (ISNI:0000 0004 0374 0039) 
4  School of Medicine, Yale University, Section of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, New Haven, USA (GRID:grid.47100.32) (ISNI:0000000419368710); Yale School of Public Health, Yale University, Department of Biostatistics, New Haven, USA (GRID:grid.47100.32) (ISNI:0000000419368710) 
5  School of Medicine, Yale University, Section of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, New Haven, USA (GRID:grid.47100.32) (ISNI:0000000419368710); Yale School of Medicine, Department of Genetics, New Haven, USA (GRID:grid.47100.32) (ISNI:0000000419368710); Yale School of Medicine, Department of Internal Medicine, New Haven, USA (GRID:grid.47100.32) (ISNI:0000000419368710) 
6  Yale University, Department of Computer Science, New Haven, USA (GRID:grid.47100.32) (ISNI:0000000419368710); Department of Internal Medicine, Yale School of Medicine, Cardiovascular Research Center, Section of Cardiovascular Medicine, New Haven, USA (GRID:grid.47100.32) (ISNI:0000000419368710) 
7  School of Medicine, Yale University, Section of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, New Haven, USA (GRID:grid.47100.32) (ISNI:0000000419368710); German Lung Research Center (DZL), Department of Respiratory Medicine, Hannover Medical School and Biomedical Research in End-stage and Obstructive Lung Disease Hannover, Hannover, Germany (GRID:grid.47100.32) 
8  Yale School of Public Health, Yale University, Department of Biostatistics, New Haven, USA (GRID:grid.47100.32) (ISNI:0000000419368710) 
9  School of Medicine, Yale University, Section of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, New Haven, USA (GRID:grid.47100.32) (ISNI:0000000419368710) 
10  School of Medicine, Yale University, Section of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, New Haven, USA (GRID:grid.47100.32) (ISNI:0000000419368710); Yale University, Department of Biomedical Engineering, New Haven, USA (GRID:grid.47100.32) (ISNI:0000000419368710); Yale School of Medicine, Medical Scientist Training Program, New Haven, USA (GRID:grid.47100.32) (ISNI:0000000419368710) 
11  Yale School of Medicine, Department of Pathology, New Haven, USA (GRID:grid.47100.32) (ISNI:0000000419368710) 
12  Yale School of Medicine, Yale Center for Genome Analysis/Keck Biotechnology Resource Laboratory, Department of Molecular Biophysics and Biochemistry, New Haven, USA (GRID:grid.47100.32) (ISNI:0000000419368710) 
13  Yale School of Public Health, Yale University, Department of Biostatistics, New Haven, USA (GRID:grid.47100.32) (ISNI:0000000419368710); School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, SJTU-Yale Joint Center for Biostatistics and Data Science, Department of Bioinformatics and Biostatistics, Shanghai, China (GRID:grid.16821.3c) (ISNI:0000 0004 0368 8293) 
14  Yale School of Medicine, Yale Center for Genome Analysis, New Haven, USA (GRID:grid.47100.32) (ISNI:0000000419368710) 
15  School of Medicine, Yale University, Department of Immunobiology, New Haven, USA (GRID:grid.47100.32) (ISNI:0000000419368710) 
16  Yale University, School of Medicine, New Haven, USA (GRID:grid.47100.32) (ISNI:0000000419368710) 
17  Yale School of Public Health, Department of Epidemiology of Microbial Diseases, New Haven, USA (GRID:grid.47100.32) (ISNI:0000000419368710) 
18  Tel Aviv Sourasky Medical Center, Tel Aviv University, Pulmonary Institute, Tel Aviv, Israel (GRID:grid.12136.37) (ISNI:0000 0004 1937 0546) 
19  Yale School of Medicine, Yale University, Section of Infectious Diseases, Department of Internal Medicine, New Haven, USA (GRID:grid.47100.32) (ISNI:0000000419368710) 
20  Yale School of Medicine, Department of Internal Medicine, New Haven, USA (GRID:grid.47100.32) (ISNI:0000000419368710) 
21  Yale University, Departments of Anesthesiology & Biomedical Engineering, New Haven, USA (GRID:grid.47100.32) (ISNI:0000000419368710) 
22  School of Medicine, Yale University, Department of Neurology, New Haven, USA (GRID:grid.47100.32) (ISNI:0000000419368710); Yale School of Medicine, Yale University, Section of Infectious Diseases, Department of Internal Medicine, New Haven, USA (GRID:grid.47100.32) (ISNI:0000000419368710) 
23  School of Medicine, Yale University, Department of Immunobiology, New Haven, USA (GRID:grid.47100.32) (ISNI:0000000419368710); Howard Hughes Medical Institute, Chevy Chase, USA (GRID:grid.413575.1) (ISNI:0000 0001 2167 1581) 
24  Yale School of Public Health, Yale University, Department of Biostatistics, New Haven, USA (GRID:grid.47100.32) (ISNI:0000000419368710); Yale School of Medicine, Department of Genetics, New Haven, USA (GRID:grid.47100.32) (ISNI:0000000419368710); School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, SJTU-Yale Joint Center for Biostatistics and Data Science, Department of Bioinformatics and Biostatistics, Shanghai, China (GRID:grid.16821.3c) (ISNI:0000 0004 0368 8293); Yale University, Inter-Departmental Program in Computational Biology and Bioinformatics, New Haven, USA (GRID:grid.47100.32) (ISNI:0000000419368710) 
25  School of Medicine, Yale University, Department of Immunobiology, New Haven, USA (GRID:grid.47100.32) (ISNI:0000000419368710); Yale School of Medicine, Department of Pathology, New Haven, USA (GRID:grid.47100.32) (ISNI:0000000419368710); Yale University, Inter-Departmental Program in Computational Biology and Bioinformatics, New Haven, USA (GRID:grid.47100.32) (ISNI:0000000419368710) 
26  School of Medicine, Yale University, Section of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, New Haven, USA (GRID:grid.47100.32) (ISNI:0000000419368710); West Haven Veterans Affair Medical Center, West Haven, USA (GRID:grid.47100.32) 
Publication year
2022
Publication date
2022
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-021-27716-4
ProQuest document ID
2621820454
Copyright
© The Author(s) 2022. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.