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, UCSF COMET Consortium, Michael Matthay, David J Erle, Prescott G Woodruff, Charles Langelier, Kirsten Kangelaris, Carolyn M Hendrickson, Carolyn Calfee, Arjun Arkal Rao, Matthew F Krummel
Author Information
Alexis J Combes: Department of Pathology, University of California San Francisco, San Francisco, CA, USA. Alexis.Combes@ucsf.edu. ORCID
Tristan Courau: Department of Pathology, University of California San Francisco, San Francisco, CA, USA. ORCID
Nicholas F Kuhn: Department of Pathology, University of California San Francisco, San Francisco, CA, USA.
Kenneth H Hu: Department of Pathology, University of California San Francisco, San Francisco, CA, USA. ORCID
Arja Ray: Department of Pathology, University of California San Francisco, San Francisco, CA, USA.
William S Chen: ImmunoX Initiative, University of California San Francisco, San Francisco, CA, USA.
Nayvin W Chew: Department of Pathology, University of California San Francisco, San Francisco, CA, USA.
Simon J Cleary: ImmunoX Initiative, University of California San Francisco, San Francisco, CA, USA. ORCID
Divyashree Kushnoor: Department of Pathology, University of California San Francisco, San Francisco, CA, USA.
Gabriella C Reeder: Department of Pathology, University of California San Francisco, San Francisco, CA, USA.
Alan Shen: Department of Pathology, University of California San Francisco, San Francisco, CA, USA.
Jessica Tsui: Department of Pathology, University of California San Francisco, San Francisco, CA, USA.
Kamir J Hiam-Galvez: ImmunoX Initiative, University of California San Francisco, San Francisco, CA, USA. ORCID
Priscila Muñoz-Sandoval: ImmunoX Initiative, University of California San Francisco, San Francisco, CA, USA.
Wandi S Zhu: ImmunoX Initiative, University of California San Francisco, San Francisco, CA, USA.
David S Lee: ImmunoX Initiative, University of California San Francisco, San Francisco, CA, USA. ORCID
Yang Sun: ImmunoX Initiative, University of California San Francisco, San Francisco, CA, USA.
Ran You: Department of Pathology, University of California San Francisco, San Francisco, CA, USA.
Mélia Magnen: ImmunoX Initiative, University of California San Francisco, San Francisco, CA, USA.
Lauren Rodriguez: ImmunoX Initiative, University of California San Francisco, San Francisco, CA, USA.
K W Im: Department of Pathology, University of California San Francisco, San Francisco, CA, USA.
Nina K Serwas: Department of Pathology, University of California San Francisco, San Francisco, CA, USA. ORCID
Aleksandra Leligdowicz: Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
Colin R Zamecnik: ImmunoX Initiative, University of California San Francisco, San Francisco, CA, USA. ORCID
Rita P Loudermilk: ImmunoX Initiative, University of California San Francisco, San Francisco, CA, USA. ORCID
Michael R Wilson: ImmunoX Initiative, University of California San Francisco, San Francisco, CA, USA. ORCID
Chun J Ye: ImmunoX Initiative, University of California San Francisco, San Francisco, CA, USA. ORCID
Gabriela K Fragiadakis: ImmunoX Initiative, University of California San Francisco, San Francisco, CA, USA.
Mark R Looney: ImmunoX Initiative, University of California San Francisco, San Francisco, CA, USA. ORCID
Vincent Chan: Department of Pathology, University of California San Francisco, San Francisco, CA, USA. ORCID
Alyssa Ward: Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA.
Sidney Carrillo: Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
Michael Matthay: Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California San Francisco, San Francisco, CA, USA. ORCID
David J Erle: ImmunoX Initiative, University of California San Francisco, San Francisco, CA, USA. ORCID
Prescott G Woodruff: ImmunoX Initiative, University of California San Francisco, San Francisco, CA, USA.
Charles Langelier: Division of Infectious Disease, Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
Kirsten Kangelaris: Division of Hospital Medicine, Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
Carolyn M Hendrickson: Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
Carolyn Calfee: Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
Arjun Arkal Rao: Department of Pathology, University of California San Francisco, San Francisco, CA, USA. ArjunArkal.Rao@ucsf.edu. ORCID
Matthew F Krummel: Department of Pathology, University of California San Francisco, San Francisco, CA, USA. Matthew.Krummel@ucsf.edu. ORCID
Although infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has pleiotropic and systemic effects in some individuals, 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) 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.
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