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

Author

Listed:
  • Avraham Unterman

    (School of Medicine, Yale University
    Tel Aviv Sourasky Medical Center, Tel Aviv University)

  • Tomokazu S. Sumida

    (School of Medicine, Yale University
    School of Medicine, Yale University)

  • Nima Nouri

    (Yale School of Medicine
    Yale School of Medicine
    The Jackson Laboratory for Genomic Medicine)

  • Xiting Yan

    (School of Medicine, Yale University
    Yale School of Public Health, Yale University)

  • Amy Y. Zhao

    (School of Medicine, Yale University
    Yale School of Medicine
    Yale School of Medicine)

  • Victor Gasque

    (Yale University
    Department of Internal Medicine, Yale School of Medicine)

  • Jonas C. Schupp

    (School of Medicine, Yale University
    German Lung Research Center (DZL))

  • Hiromitsu Asashima

    (School of Medicine, Yale University
    School of Medicine, Yale University)

  • Yunqing Liu

    (Yale School of Public Health, Yale University)

  • Carlos Cosme

    (School of Medicine, Yale University)

  • Wenxuan Deng

    (Yale School of Public Health, Yale University)

  • Ming Chen

    (Yale School of Public Health, Yale University)

  • Micha Sam Brickman Raredon

    (School of Medicine, Yale University
    Yale University
    Yale School of Medicine)

  • Kenneth B. Hoehn

    (Yale School of Medicine)

  • Guilin Wang

    (Yale School of Medicine)

  • Zuoheng Wang

    (Yale School of Public Health, Yale University)

  • Giuseppe DeIuliis

    (School of Medicine, Yale University)

  • Neal G. Ravindra

    (Yale University
    Department of Internal Medicine, Yale School of Medicine)

  • Ningshan Li

    (Yale School of Public Health, Yale University
    School of Life Sciences and Biotechnology, Shanghai Jiao Tong University)

  • Christopher Castaldi

    (Yale School of Medicine)

  • Patrick Wong

    (School of Medicine, Yale University)

  • John Fournier

    (Yale University)

  • Santos Bermejo

    (School of Medicine, Yale University)

  • Lokesh Sharma

    (School of Medicine, Yale University)

  • Arnau Casanovas-Massana

    (Yale School of Public Health)

  • Chantal B. F. Vogels

    (Yale School of Public Health)

  • Anne L. Wyllie

    (Yale School of Public Health)

  • Nathan D. Grubaugh

    (Yale School of Public Health)

  • Anthony Melillo

    (Yale School of Medicine)

  • Hailong Meng

    (Yale School of Medicine)

  • Yan Stein

    (Tel Aviv Sourasky Medical Center, Tel Aviv University)

  • Maksym Minasyan

    (School of Medicine, Yale University)

  • Subhasis Mohanty

    (Yale School of Medicine, Yale University)

  • William E. Ruff

    (School of Medicine, Yale University
    School of Medicine, Yale University)

  • Inessa Cohen

    (School of Medicine, Yale University
    School of Medicine, Yale University)

  • Khadir Raddassi

    (School of Medicine, Yale University
    School of Medicine, Yale University)

  • Laura E. Niklason

    (Yale University)

  • Albert I. Ko

    (Yale School of Public Health)

  • Ruth R. Montgomery

    (Yale School of Medicine)

  • Shelli F. Farhadian

    (School of Medicine, Yale University
    Yale School of Medicine, Yale University)

  • Akiko Iwasaki

    (School of Medicine, Yale University
    Howard Hughes Medical Institute)

  • Albert C. Shaw

    (Yale School of Medicine, Yale University)

  • David Dijk

    (Yale University
    Department of Internal Medicine, Yale School of Medicine)

  • Hongyu Zhao

    (Yale School of Public Health, Yale University
    Yale School of Medicine
    School of Life Sciences and Biotechnology, Shanghai Jiao Tong University
    Yale University)

  • Steven H. Kleinstein

    (School of Medicine, Yale University
    Yale School of Medicine
    Yale University)

  • David A. Hafler

    (School of Medicine, Yale University
    School of Medicine, Yale University)

  • Naftali Kaminski

    (School of Medicine, Yale University)

  • Charles S. Cruz

    (School of Medicine, Yale University
    West Haven Veterans Affair Medical Center)

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.

Suggested Citation

  • Avraham Unterman & Tomokazu S. Sumida & Nima Nouri & Xiting Yan & Amy Y. Zhao & Victor Gasque & Jonas C. Schupp & Hiromitsu Asashima & Yunqing Liu & Carlos Cosme & Wenxuan Deng & Ming Chen & Micha Sam, 2022. "Single-cell multi-omics reveals dyssynchrony of the innate and adaptive immune system in progressive COVID-19," Nature Communications, Nature, vol. 13(1), pages 1-23, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-021-27716-4
    DOI: 10.1038/s41467-021-27716-4
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    Cited by:

    1. Praveen Weeratunga & Laura Denney & Joshua A. Bull & Emmanouela Repapi & Martin Sergeant & Rachel Etherington & Chaitanya Vuppussetty & Gareth D. H. Turner & Colin Clelland & Jeongmin Woo & Amy Cross , 2023. "Single cell spatial analysis reveals inflammatory foci of immature neutrophil and CD8 T cells in COVID-19 lungs," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    2. Junedh M. Amrute & Alexandra M. Perry & Gautam Anand & Carlos Cruchaga & Karl G. Hock & Christopher W. Farnsworth & Gwendalyn J. Randolph & Kory J. Lavine & Ashley L. Steed, 2022. "Cell specific peripheral immune responses predict survival in critical COVID-19 patients," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    3. Hideki Ogura & Jin Gohda & Xiuyuan Lu & Mizuki Yamamoto & Yoshio Takesue & Aoi Son & Sadayuki Doi & Kazuyuki Matsushita & Fumitaka Isobe & Yoshihiro Fukuda & Tai-Ping Huang & Takamasa Ueno & Naomi Mam, 2022. "Dysfunctional Sars-CoV-2-M protein-specific cytotoxic T lymphocytes in patients recovering from severe COVID-19," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    4. Sandra Curras-Alonso & Juliette Soulier & Thomas Defard & Christian Weber & Sophie Heinrich & Hugo Laporte & Sophie Leboucher & Sonia Lameiras & Marie Dutreix & Vincent Favaudon & Florian Massip & Tho, 2023. "An interactive murine single-cell atlas of the lung responses to radiation injury," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    5. Chang Su & Zichun Xu & Xinning Shan & Biao Cai & Hongyu Zhao & Jingfei Zhang, 2023. "Cell-type-specific co-expression inference from single cell RNA-sequencing data," Nature Communications, Nature, vol. 14(1), pages 1-12, December.

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