Single-cell multi-omics reveals dyssynchrony of the innate and adaptive immune system in progressive COVID-19

Avraham Unterman; Tomokazu S Sumida; Nima Nouri; Xiting Yan; Amy Y Zhao; Victor Gasque; Jonas C Schupp; Hiromitsu Asashima; Yunqing Liu; Carlos Cosme Jr; Wenxuan Deng; Ming Chen; Micha Sam Brickman Raredon; Kenneth B Hoehn; Guilin Wang; Zuoheng Wang; Giuseppe DeIuliis; Neal G Ravindra; Ningshan Li; Christopher Castaldi; Patrick Wong; John Fournier; Santos Bermejo; Lokesh Sharma; Arnau Casanovas-Massana; Chantal B F Vogels; Anne L Wyllie; Nathan D Grubaugh; Anthony Melillo; Hailong Meng; Yan Stein; Maksym Minasyan; Subhasis Mohanty; William E Ruff; Inessa Cohen; Khadir Raddassi; Yale IMPACT Research Team; Laura E Niklason; Albert I Ko; Ruth R Montgomery; Shelli F Farhadian; Akiko Iwasaki; Albert C Shaw; David van Dijk; Hongyu Zhao; Steven H Kleinstein; David A Hafler; Naftali Kaminski; Charles S Dela Cruz

doi:10.1038/s41467-021-27716-4

Single-cell multi-omics reveals dyssynchrony of the innate and adaptive immune system in progressive COVID-19

Nat Commun. 2022 Jan 21;13(1):440. doi: 10.1038/s41467-021-27716-4.

Authors

Avraham Unterman^{1

2}, Tomokazu S Sumida^{3

4}, Nima Nouri^{5

6

7}, Xiting Yan^{8

9}, Amy Y Zhao^{8

10

11}, Victor Gasque^{12

13}, Jonas C Schupp^{8

14}, Hiromitsu Asashima^{15

16}, Yunqing Liu⁹, Carlos Cosme Jr⁸, Wenxuan Deng⁹, Ming Chen⁹, Micha Sam Brickman Raredon^{8

17

18}, Kenneth B Hoehn⁵, Guilin Wang¹⁹, Zuoheng Wang⁹, Giuseppe DeIuliis⁸, Neal G Ravindra^{12

13}, Ningshan Li^{9

20}, Christopher Castaldi²¹, Patrick Wong¹⁶, John Fournier²², Santos Bermejo⁸, Lokesh Sharma⁸, Arnau Casanovas-Massana²³, Chantal B F Vogels²³, Anne L Wyllie²³, Nathan D Grubaugh²³, Anthony Melillo⁵, Hailong Meng⁵, Yan Stein²⁴, Maksym Minasyan⁸, Subhasis Mohanty²⁵, William E Ruff^{15

16}, Inessa Cohen^{15

16}, Khadir Raddassi^{15

16}; Yale IMPACT Research Team; Laura E Niklason²⁶, Albert I Ko²³, Ruth R Montgomery¹¹, Shelli F Farhadian^{15

25}, Akiko Iwasaki^{16

27}, Albert C Shaw²⁵, David van Dijk^{12

13}, Hongyu Zhao^{9

10

20

28}, Steven H Kleinstein^{16

5

28}, David A Hafler^{15

16}, Naftali Kaminski⁸, Charles S Dela Cruz^{8

29}

Collaborators

Yale IMPACT Research Team:
Allison Nelson, Denise Shepard, Michael Rainone, Xiaohua Peng

Affiliations

¹ Section of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, School of Medicine, Yale University, New Haven, CT, USA. [email protected].
² Pulmonary Institute, Tel Aviv Sourasky Medical Center, Tel Aviv University, Tel Aviv, Israel. [email protected].
³ Department of Neurology, School of Medicine, Yale University, New Haven, CT, USA. [email protected].
⁴ Department of Immunobiology, School of Medicine, Yale University, New Haven, CT, USA. [email protected].
⁵ Department of Pathology, Yale School of Medicine, New Haven, CT, USA.
⁶ Center for Medical Informatics, Yale School of Medicine, New Haven, CT, USA.
⁷ The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.
⁸ Section of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, School of Medicine, Yale University, New Haven, CT, USA.
⁹ Department of Biostatistics, Yale School of Public Health, Yale University, New Haven, CT, USA.
¹⁰ Department of Genetics, Yale School of Medicine, New Haven, CT, USA.
¹¹ Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.
¹² Department of Computer Science, Yale University, New Haven, CT, USA.
¹³ Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.
¹⁴ Department of Respiratory Medicine, Hannover Medical School and Biomedical Research in End-stage and Obstructive Lung Disease Hannover, German Lung Research Center (DZL), Hannover, Germany.
¹⁵ Department of Neurology, School of Medicine, Yale University, New Haven, CT, USA.
¹⁶ Department of Immunobiology, School of Medicine, Yale University, New Haven, CT, USA.
¹⁷ Department of Biomedical Engineering, Yale University, New Haven, CT, USA.
¹⁸ Medical Scientist Training Program, Yale School of Medicine, New Haven, CT, USA.
¹⁹ Yale Center for Genome Analysis/Keck Biotechnology Resource Laboratory, Department of Molecular Biophysics and Biochemistry, Yale School of Medicine, New Haven, CT, USA.
²⁰ SJTU-Yale Joint Center for Biostatistics and Data Science, Department of Bioinformatics and Biostatistics, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.
²¹ Yale Center for Genome Analysis, Yale School of Medicine, New Haven, CT, USA.
²² School of Medicine, Yale University, New Haven, CT, USA.
²³ Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, USA.
²⁴ Pulmonary Institute, Tel Aviv Sourasky Medical Center, Tel Aviv University, Tel Aviv, Israel.
²⁵ Section of Infectious Diseases, Department of Internal Medicine, Yale School of Medicine, Yale University, New Haven, CT, USA.
²⁶ Departments of Anesthesiology & Biomedical Engineering, Yale University, New Haven, CT, USA.
²⁷ Howard Hughes Medical Institute, Chevy Chase, MD, USA.
²⁸ Inter-Departmental Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA.
²⁹ West Haven Veterans Affair Medical Center, West Haven, CT, USA.

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 S100A^hi/HLA-DR^lo classical monocytes and activated LAG-3^hi 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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

MeSH terms

Adaptive Immunity / drug effects
Adaptive Immunity / genetics
Adaptive Immunity / immunology*
Aged
Antibodies, Monoclonal, Humanized / therapeutic use
CD4-Positive T-Lymphocytes / drug effects
CD4-Positive T-Lymphocytes / immunology
CD4-Positive T-Lymphocytes / metabolism
CD8-Positive T-Lymphocytes / drug effects
CD8-Positive T-Lymphocytes / immunology
CD8-Positive T-Lymphocytes / metabolism
COVID-19 / genetics
COVID-19 / immunology*
COVID-19 Drug Treatment
Cells, Cultured
Female
Gene Expression Profiling / methods*
Gene Expression Regulation / drug effects
Gene Expression Regulation / immunology
Humans
Immunity, Innate / drug effects
Immunity, Innate / genetics
Immunity, Innate / immunology*
Male
RNA-Seq / methods
Receptors, Antigen, B-Cell / genetics
Receptors, Antigen, B-Cell / immunology
Receptors, Antigen, T-Cell / genetics
Receptors, Antigen, T-Cell / immunology
SARS-CoV-2 / drug effects
SARS-CoV-2 / immunology*
SARS-CoV-2 / physiology
Single-Cell Analysis / methods*

Substances

Antibodies, Monoclonal, Humanized
Receptors, Antigen, B-Cell
Receptors, Antigen, T-Cell
tocilizumab

Abstract

Publication types

MeSH terms

Substances

Grants and funding