Global absence and targeting of protective immune states in severe COVID-19

Alexis J. Combes (), Tristan Courau, Nicholas F. Kuhn, Kenneth H. Hu, Arja Ray, William S. Chen, Nayvin W. Chew, Simon J. Cleary, Divyashree Kushnoor, Gabriella C. Reeder, Alan Shen, Jessica Tsui, Kamir J. Hiam-Galvez, Priscila Muñoz-Sandoval, Wandi S. Zhu, David S. Lee, Yang Sun, Ran You, Mélia Magnen, Lauren Rodriguez, K. W. Im, Nina K. Serwas, Aleksandra Leligdowicz, Colin R. Zamecnik, Rita P. Loudermilk, Michael R. Wilson, Chun J. Ye, Gabriela K. Fragiadakis, Mark R. Looney, Vincent Chan, Alyssa Ward, Sidney Carrillo, Michael Matthay, David J. Erle, Prescott G. Woodruff, Charles Langelier, Kirsten Kangelaris, Carolyn M. Hendrickson, Carolyn Calfee, Arjun Arkal Rao () and Matthew F. Krummel ()
Additional contact information
Alexis J. Combes: University of California San Francisco
Tristan Courau: University of California San Francisco
Nicholas F. Kuhn: University of California San Francisco
Kenneth H. Hu: University of California San Francisco
Arja Ray: University of California San Francisco
William S. Chen: University of California San Francisco
Nayvin W. Chew: University of California San Francisco
Simon J. Cleary: University of California San Francisco
Divyashree Kushnoor: University of California San Francisco
Gabriella C. Reeder: University of California San Francisco
Alan Shen: University of California San Francisco
Jessica Tsui: University of California San Francisco
Kamir J. Hiam-Galvez: University of California San Francisco
Priscila Muñoz-Sandoval: University of California San Francisco
Wandi S. Zhu: University of California San Francisco
David S. Lee: University of California San Francisco
Yang Sun: University of California San Francisco
Ran You: University of California San Francisco
Mélia Magnen: University of California San Francisco
Lauren Rodriguez: University of California San Francisco
K. W. Im: University of California San Francisco
Nina K. Serwas: University of California San Francisco
Aleksandra Leligdowicz: University of California San Francisco
Colin R. Zamecnik: University of California San Francisco
Rita P. Loudermilk: University of California San Francisco
Michael R. Wilson: University of California San Francisco
Chun J. Ye: University of California San Francisco
Gabriela K. Fragiadakis: University of California San Francisco
Mark R. Looney: University of California San Francisco
Vincent Chan: University of California San Francisco
Alyssa Ward: University of California San Francisco
Sidney Carrillo: University of California San Francisco
Michael Matthay: University of California San Francisco
David J. Erle: University of California San Francisco
Prescott G. Woodruff: University of California San Francisco
Charles Langelier: University of California San Francisco
Kirsten Kangelaris: University of California San Francisco
Carolyn M. Hendrickson: University of California San Francisco
Carolyn Calfee: University of California San Francisco
Arjun Arkal Rao: University of California San Francisco
Matthew F. Krummel: University of California San Francisco

Nature, 2021, vol. 591, issue 7848, 124-130

Abstract: Abstract Although infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has pleiotropic and systemic effects in some individuals1–3, many others experience milder symptoms. Here, to gain a more comprehensive understanding of the distinction between severe and mild phenotypes in the pathology of coronavirus disease 2019 (COVID-19) and its origins, we performed a whole-blood-preserving single-cell analysis protocol to integrate contributions from all major immune cell types of the blood—including neutrophils, monocytes, platelets, lymphocytes and the contents of the serum. Patients with mild COVID-19 exhibit a coordinated pattern of expression of interferon-stimulated genes (ISGs)3 across every cell population, whereas these ISG-expressing cells are systemically absent in patients with severe disease. Paradoxically, individuals with severe COVID-19 produce very high titres of anti-SARS-CoV-2 antibodies and have a lower viral load compared to individuals with mild disease. Examination of the serum from patients with severe COVID-19 shows that these patients uniquely produce antibodies that functionally block the production of the ISG-expressing cells associated with mild disease, by activating conserved signalling circuits that dampen cellular responses to interferons. Overzealous antibody responses pit the immune system against itself in many patients with COVID-19, and perhaps also in individuals with other viral infections. Our findings reveal potential targets for immunotherapies in patients with severe COVID-19 to re-engage viral defence.

Date: 2021
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DOI: 10.1038/s41586-021-03234-7

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