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Longitudinal analyses reveal immunological misfiring in severe COVID-19

Author

Listed:
  • Carolina Lucas

    (Yale University School of Medicine)

  • Patrick Wong

    (Yale University School of Medicine)

  • Jon Klein

    (Yale University School of Medicine)

  • Tiago B. R. Castro

    (The Rockefeller University)

  • Julio Silva

    (Yale University School of Medicine)

  • Maria Sundaram

    (Yale School of Public Health)

  • Mallory K. Ellingson

    (Yale School of Public Health)

  • Tianyang Mao

    (Yale University School of Medicine)

  • Ji Eun Oh

    (Yale University School of Medicine)

  • Benjamin Israelow

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

  • Takehiro Takahashi

    (Yale University School of Medicine)

  • Maria Tokuyama

    (Yale University School of Medicine)

  • Peiwen Lu

    (Yale University School of Medicine)

  • Arvind Venkataraman

    (Yale University School of Medicine)

  • Annsea Park

    (Yale University School of Medicine)

  • Subhasis Mohanty

    (Yale University School of Medicine)

  • Haowei Wang

    (Yale University School of Medicine)

  • Anne L. Wyllie

    (Yale School of Public Health)

  • Chantal B. F. Vogels

    (Yale School of Public Health)

  • Rebecca Earnest

    (Yale School of Public Health)

  • Sarah Lapidus

    (Yale School of Public Health)

  • Isabel M. Ott

    (Yale School of Public Health)

  • Adam J. Moore

    (Yale School of Public Health)

  • M. Catherine Muenker

    (Yale School of Public Health)

  • John B. Fournier

    (Yale University School of Medicine)

  • Melissa Campbell

    (Yale University School of Medicine)

  • Camila D. Odio

    (Yale University School of Medicine)

  • Arnau Casanovas-Massana

    (Yale School of Public Health)

  • Roy Herbst

    (Yale Cancer Center, and Smilow Cancer Hospital)

  • Albert C. Shaw

    (Yale University School of Medicine)

  • Ruslan Medzhitov

    (Yale University School of Medicine
    Howard Hughes Medical Institute)

  • Wade L. Schulz

    (Yale University School of Medicine
    Yale-New Haven Hospital)

  • Nathan D. Grubaugh

    (Yale School of Public Health)

  • Charles Cruz

    (Yale University School of Medicine)

  • Shelli Farhadian

    (Yale University School of Medicine)

  • Albert I. Ko

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

  • Saad B. Omer

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

  • Akiko Iwasaki

    (Yale University School of Medicine
    Howard Hughes Medical Institute)

Abstract

Recent studies have provided insights into the pathogenesis of coronavirus disease 2019 (COVID-19)1–4. However, the longitudinal immunological correlates of disease outcome remain unclear. Here we serially analysed immune responses in 113 patients with moderate or severe COVID-19. Immune profiling revealed an overall increase in innate cell lineages, with a concomitant reduction in T cell number. An early elevation in cytokine levels was associated with worse disease outcomes. Following an early increase in cytokines, patients with moderate COVID-19 displayed a progressive reduction in type 1 (antiviral) and type 3 (antifungal) responses. By contrast, patients with severe COVID-19 maintained these elevated responses throughout the course of the disease. Moreover, severe COVID-19 was accompanied by an increase in multiple type 2 (anti-helminths) effectors, including interleukin-5 (IL-5), IL-13, immunoglobulin E and eosinophils. Unsupervised clustering analysis identified four immune signatures, representing growth factors (A), type-2/3 cytokines (B), mixed type-1/2/3 cytokines (C), and chemokines (D) that correlated with three distinct disease trajectories. The immune profiles of patients who recovered from moderate COVID-19 were enriched in tissue reparative growth factor signature A, whereas the profiles of those with who developed severe disease had elevated levels of all four signatures. Thus, we have identified a maladapted immune response profile associated with severe COVID-19 and poor clinical outcome, as well as early immune signatures that correlate with divergent disease trajectories.

Suggested Citation

  • Carolina Lucas & Patrick Wong & Jon Klein & Tiago B. R. Castro & Julio Silva & Maria Sundaram & Mallory K. Ellingson & Tianyang Mao & Ji Eun Oh & Benjamin Israelow & Takehiro Takahashi & Maria Tokuyam, 2020. "Longitudinal analyses reveal immunological misfiring in severe COVID-19," Nature, Nature, vol. 584(7821), pages 463-469, August.
  • Handle: RePEc:nat:nature:v:584:y:2020:i:7821:d:10.1038_s41586-020-2588-y
    DOI: 10.1038/s41586-020-2588-y
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    Cited by:

    1. Shelly J. Robertson & Olivia Bedard & Kristin L. McNally & Carl Shaia & Chad S. Clancy & Matthew Lewis & Rebecca M. Broeckel & Abhilash I. Chiramel & Jeffrey G. Shannon & Gail L. Sturdevant & Rebecca , 2023. "Genetically diverse mouse models of SARS-CoV-2 infection reproduce clinical variation in type I interferon and cytokine responses in COVID-19," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    2. Quy Xiao Xuan Lin & Deepa Rajagopalan & Akshamal M. Gamage & Le Min Tan & Prasanna Nori Venkatesh & Wharton O. Y. Chan & Dilip Kumar & Ragini Agrawal & Yao Chen & Siew-Wai Fong & Amit Singh & Louisa J, 2024. "Longitudinal single cell atlas identifies complex temporal relationship between type I interferon response and COVID-19 severity," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    3. Tiago Fazolo & Karina Lima & Julia C. Fontoura & Priscila Oliveira Souza & Gabriel Hilario & Renata Zorzetto & Luiz Rodrigues Júnior & Veridiane Maria Pscheidt & Jayme Castilhos Ferreira Neto & Alisso, 2021. "Pediatric COVID-19 patients in South Brazil show abundant viral mRNA and strong specific anti-viral responses," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    4. Kim McFann & Bridget A. Baxter & Stephanie M. LaVergne & Sophia Stromberg & Kailey Berry & Madison Tipton & Jared Haberman & Jeremy Ladd & Tracy L. Webb & Julie A. Dunn & Elizabeth P. Ryan, 2021. "Quality of Life (QoL) Is Reduced in Those with Severe COVID-19 Disease, Post-Acute Sequelae of COVID-19, and Hospitalization in United States Adults from Northern Colorado," IJERPH, MDPI, vol. 18(21), pages 1-9, October.
    5. Fábio Santos Lira & Telmo Pereira & Luciele Guerra Minuzzi & Caique Figueiredo & Tiago Olean-Oliveira & Ana Paula Coelho Figueira Freire & Manuel João Coelho-e-Silva & Armando Caseiro & Ronaldo Vagner, 2021. "Modulatory Effects of Physical Activity Levels on Immune Responses and General Clinical Functions in Adult Patients with Mild to Moderate SARS-CoV-2 Infections—A Protocol for an Observational Prospect," IJERPH, MDPI, vol. 18(24), pages 1-13, December.
    6. Yvonne M. Mueller & Thijs J. Schrama & Rik Ruijten & Marco W. J. Schreurs & Dwin G. B. Grashof & Harmen J. G. van de Werken & Giovanna Jona Lasinio & Daniel Álvarez-Sierra & Caoimhe H. Kiernan & Melis, 2022. "Stratification of hospitalized COVID-19 patients into clinical severity progression groups by immuno-phenotyping and machine learning," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    7. Changli Wei & Prasun K. Datta & Florian Siegerist & Jing Li & Sudhini Yashwanth & Kwi Hye Koh & Nicholas W. Kriho & Anis Ismail & Shengyuan Luo & Tracy Fischer & Kyle T. Amber & David Cimbaluk & Alan , 2023. "SuPAR mediates viral response proteinuria by rapidly changing podocyte function," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    8. Nikaïa Smith & Céline Possémé & Vincent Bondet & Jamie Sugrue & Liam Townsend & Bruno Charbit & Vincent Rouilly & Violaine Saint-André & Tom Dott & Andre Rodriguez Pozo & Nader Yatim & Olivier Schwart, 2022. "Defective activation and regulation of type I interferon immunity is associated with increasing COVID-19 severity," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    9. Lucie Bernard-Raichon & Mericien Venzon & Jon Klein & Jordan E. Axelrad & Chenzhen Zhang & Alexis P. Sullivan & Grant A. Hussey & Arnau Casanovas-Massana & Maria G. Noval & Ana M. Valero-Jimenez & Jua, 2022. "Gut microbiome dysbiosis in antibiotic-treated COVID-19 patients is associated with microbial translocation and bacteremia," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    10. Wei Feng & Joanne C. Beer & Qinyu Hao & Ishara S. Ariyapala & Aparna Sahajan & Andrei Komarov & Katie Cha & Mason Moua & Xiaolei Qiu & Xiaomei Xu & Shweta Iyengar & Thu Yoshimura & Rajini Nagaraj & Li, 2023. "NULISA: a proteomic liquid biopsy platform with attomolar sensitivity and high multiplexing," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    11. Clovis S. Palmer & Chrysostomos Perdios & Mohamed Abdel-Mohsen & Joseph Mudd & Prasun K. Datta & Nicholas J. Maness & Gabrielle Lehmicke & Nadia Golden & Linh Hellmers & Carol Coyne & Kristyn Moore Gr, 2024. "Non-human primate model of long-COVID identifies immune associates of hyperglycemia," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    12. Olga Scudiero & Barbara Lombardo & Mariarita Brancaccio & Cristina Mennitti & Arturo Cesaro & Fabio Fimiani & Luca Gentile & Elisabetta Moscarella & Federica Amodio & Annaluisa Ranieri & Felice Gragna, 2021. "Exercise, Immune System, Nutrition, Respiratory and Cardiovascular Diseases during COVID-19: A Complex Combination," IJERPH, MDPI, vol. 18(3), pages 1-20, January.
    13. Minami Nagai & Miyu Moriyama & Chiharu Ishii & Hirotake Mori & Hikaru Watanabe & Taku Nakahara & Takuji Yamada & Dai Ishikawa & Takamasa Ishikawa & Akiyoshi Hirayama & Ikuo Kimura & Akihito Nagahara &, 2023. "High body temperature increases gut microbiota-dependent host resistance to influenza A virus and SARS-CoV-2 infection," Nature Communications, Nature, vol. 14(1), pages 1-13, December.

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