Longitudinal single-cell epitope and RNA-sequencing reveals the immunological impact of type 1 interferon autoantibodies in critical COVID-19: Anti-IFN antibodies in critical COVID-19 correlate with poor ISG response and upregulation of LAIR1 surface protein in PBMCs.
Monique G P van der Wijst, Sara E Vazquez, George C Hartoularos, Paul Bastard, Tianna Grant, Raymund Bueno, David S Lee, John R Greenland, Yang Sun, Richard Perez, Anton Ogorodnikov, Alyssa Ward, Sabrina A Mann, Kara L Lynch, Cassandra Yun, Diane V Havlir, Gabriel Chamie, Carina Marquez, Bryan Greenhouse, Michail S Lionakis, Philip J Norris, Larry J Dumont, Kathleen Kelly, Peng Zhang, Qian Zhang, Adrian Gervais, Tom Le Voyer, Alexander Whatley, Yichen Si, Ashley Byrne, Alexis J Combes, Arjun Arkal Rao, Yun S Song, UCSF COMET consortium, Gabriela K Fragiadakis, Kirsten Kangelaris, Carolyn S Calfee, David J Erle, Carolyn Hendrickson, Matthew F Krummel, Prescott G Woodruff, Charles R Langelier, Jean-Laurent Casanova, Joseph L Derisi, Mark S Anderson, Chun Jimmie Ye
Author Information
Monique G P van der Wijst: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Sara E Vazquez: Medical Scientist Training Program, University of California. San Francisco, CA, USA.
George C Hartoularos: Institute of Human Genetics, University of California, San Francisco, CA, USA.
Paul Bastard: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France.
Tianna Grant: Institute of Human Genetics, University of California, San Francisco, CA, USA.
Raymund Bueno: Institute of Human Genetics, University of California, San Francisco, CA, USA.
David S Lee: Institute of Human Genetics, University of California, San Francisco, CA, USA.
John R Greenland: Department of Medicine, San Francisco VA Health Care System, University of California, San Francisco, CA, USA.
Yang Sun: Institute of Human Genetics, University of California, San Francisco, CA, USA.
Richard Perez: Institute of Human Genetics, University of California, San Francisco, CA, USA.
Anton Ogorodnikov: Institute of Human Genetics, University of California, San Francisco, CA, USA.
Alyssa Ward: Institute of Human Genetics, University of California, San Francisco, CA, USA.
Sabrina A Mann: Department of Biochemistry and Biophysics, University of California, San Francisco, CA, USA.
Kara L Lynch: Zuckerberg San Francisco General, San Francisco, CA, USA.
Cassandra Yun: Zuckerberg San Francisco General, San Francisco, CA, USA.
Diane V Havlir: Division of HIV, Infectious Disease and Global Medicine, Department of Medicine, University of California, San Francisco, CA, USA.
Gabriel Chamie: Division of HIV, Infectious Disease and Global Medicine, Department of Medicine, University of California, San Francisco, CA, USA.
Carina Marquez: Division of HIV, Infectious Disease and Global Medicine, Department of Medicine, University of California, San Francisco, CA, USA.
Bryan Greenhouse: Division of HIV, Infectious Disease and Global Medicine, Department of Medicine, University of California, San Francisco, CA, USA.
Michail S Lionakis: Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA.
Philip J Norris: Zuckerberg San Francisco General, San Francisco, CA, USA.
Larry J Dumont: Vitalant Research Institute, Denver, CO, USA.
Kathleen Kelly: Vitalant Research Institute, Denver, CO, USA.
Peng Zhang: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA.
Qian Zhang: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA.
Adrian Gervais: University of Paris, Imagine Institute, Paris, France.
Tom Le Voyer: University of Paris, Imagine Institute, Paris, France.
Alexander Whatley: Department of Electrical Engineering and Computer Sciences, University of California, Berkeley, CA, USA.
Yichen Si: Department of Biostaticstics, University of Michigan.
Ashley Byrne: Chan Zuckerberg Biohub, San Francisco, CA, USA.
Alexis J Combes: ImmunoX Initiative, University of California, San Francisco, CA, USA.
Arjun Arkal Rao: ImmunoX Initiative, University of California, San Francisco, CA, USA.
Yun S Song: Chan Zuckerberg Biohub, San Francisco, CA, USA.
Gabriela K Fragiadakis: Division of Rheumatology, Department of Medicine, University of California, San Francisco, California, USA.
Kirsten Kangelaris: Division of Infectious Disease, Department of Medicine, University of California, San Francisco, CA, USA.
Carolyn S Calfee: Division of Pulmonary and Critical Care Medicine, Department of Medicine and the Cardiovascular Research Institute, University of California, San Francisco, CA, USA.
David J Erle: Institute of Human Genetics, University of California, San Francisco, CA, USA.
Carolyn Hendrickson: Division of Pulmonary and Critical Care Medicine, Department of Medicine and the Cardiovascular Research Institute, University of California, San Francisco, CA, USA.
Matthew F Krummel: ImmunoX Initiative, University of California, San Francisco, CA, USA.
Prescott G Woodruff: ImmunoX Initiative, University of California, San Francisco, CA, USA.
Charles R Langelier: Division of Infectious Disease, Department of Medicine, University of California, San Francisco, CA, USA.
Jean-Laurent Casanova: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France.
Joseph L Derisi: Department of Biochemistry and Biophysics, University of California, San Francisco, CA, USA.
Mark S Anderson: Diabetes Center, University of California, San Francisco, CA, USA.
Chun Jimmie Ye: Institute of Human Genetics, University of California, San Francisco, CA, USA.
Type I interferon (IFN-I) neutralizing autoantibodies have been found in some critical COVID-19 patients; however, their prevalence and longitudinal dynamics across the disease severity scale, and functional effects on circulating leukocytes remain unknown. Here, in 284 COVID-19 patients, we found IFN-I autoantibodies in 19% of critical, 6% of severe and none of the moderate cases. Longitudinal profiling of over 600,000 peripheral blood mononuclear cells using multiplexed single-cell epitope and transcriptome sequencing from 54 COVID-19 patients, 15 non-COVID-19 patients and 11 non-hospitalized healthy controls, revealed a lack of IFN-I stimulated gene (ISG-I) response in myeloid cells from critical cases, including those producing anti-IFN-I autoantibodies. Moreover, surface protein analysis showed an inverse correlation of the inhibitory receptor LAIR-1 with ISG-I expression response early in the disease course. This aberrant ISG-I response in critical patients with and without IFN-I autoantibodies, supports a unifying model for disease pathogenesis involving ISG-I suppression via convergent mechanisms.
