Single-cell epitope and RNA-sequencing reveals the systemic immune associations with type I interferon autoantibodies in COVID-19
Creators
- van der Wijst, Monique G.P.1
- Vazquez, Sara E.2
- Hartoularos, George C.3
- Bastard, Paul4
- Grant, Tianna3
- Bueno, Raymund3
- Lee, David S.5
- Greenland, John R.6
- Sun, Yang5
- Perez, Richard7
- Ogorodnikov, Anton3
- Ward, Alyssa3
- Mann, Sabrina A.8
- Lynch, Kara L.9
- Yun, Cassandra9
- Havlir, Diane V.10
- Chamie, Gabriel10
- Marquez, Carina10
- Greenhouse, Bryan10
- Lionakis, Michail S.11
- Norris, Philip J.12
- Dumont, Larry J.13
- Kelly, Kathleen14
- Zhang, Peng15
- Zhang, Qian15
- Gervais, Adrian16
- Le Voyer, Tom16
- Whatley, Alexander17
- Si, Yichen18
- Byrne, Ashley19
- Combes, Alexis J.20
- Rao, Arjun Arkal20
- Song, Yun S.21
- Fragiadakis, Gabriela K.22
- Kangelaris, Kirsten23
- Calfee, Carolyn S.24
- Erle, David J.5
- Hendrickson, Carolyn24
- Krummel, Matthew F.25
- Woodruff, Prescott G.26
- Langelier, Charles R.23
- Casanova, Jean-Laurent27
- Derisi, Joseph L.8
- Anderson, Mark S.28
- Ye, Chun Jimmie29
- 1. Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherland; Institute of Human Genetics, University of California, San Francisco, CA, USA; Division of Rheumatology, Department of Medicine, University of California, San Francisco, California, USA.
- 2. Medical Scientist Training Program, University of California. San Francisco, CA, USA; Tetrad Graduate Program, University of California, San Francisco, CA, USA; Diabetes Center, University of California, San Francisco, CA, USA; Department of Biochemistry and Biophysics, University of California, San Francisco, CA, USA.
- 3. Institute of Human Genetics, University of California, San Francisco, CA, USA; Division of Rheumatology, Department of Medicine, University of California, San Francisco, California, USA.
- 4. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France; University of Paris, Imagine Institute, Paris, France; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA.
- 5. Institute of Human Genetics, University of California, San Francisco, CA, USA; Division of Rheumatology, Department of Medicine, University of California, San Francisco, California, USA; ImmunoX Initiative, University of California, San Francisco, CA, USA.
- 6. Department of Medicine, San Francisco VA Health Care System, University of California, San Francisco, CA, USA.
- 7. Institute of Human Genetics, University of California, San Francisco, CA, USA; School of Medicine, University of California, San Francisco, San Francisco, California, USA.
- 8. Department of Biochemistry and Biophysics, University of California, San Francisco, CA, USA; Chan Zuckerberg Biohub, San Francisco, CA, USA.
- 9. Zuckerberg San Francisco General, San Francisco, CA, USA.
- 10. Division of HIV, Infectious Disease and Global Medicine, Department of Medicine, University of California, San Francisco, CA, USA.
- 11. 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.
- 12. Zuckerberg San Francisco General, San Francisco, CA, USA; Department of Laboratory Medicine, University of California, San Francisco, CA, USA; Vitalant Research Institute, San Francisco, CA, USA.
- 13. Vitalant Research Institute, Denver, CO, USA; University of Colorado School of Medicine, Aurora, CO, USA; Geisel School of Medicine at Dartmouth, Lebanon, NH, USA.
- 14. Vitalant Research Institute, Denver, CO, USA.
- 15. St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA.
- 16. University of Paris, Imagine Institute, Paris, France; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA.
- 17. Department of Electrical Engineering and Computer Sciences, University of California, Berkeley, CA, USA.
- 18. Department of Biostaticstics, University of Michigan.
- 19. Chan Zuckerberg Biohub, San Francisco, CA, USA.
- 20. ImmunoX Initiative, University of California, San Francisco, CA, USA; Department of Pathology, University of California, San Francisco, CA, USA; UCSF CoLabs, University of California, San Francisco, CA, USA.
- 21. Chan Zuckerberg Biohub, San Francisco, CA, USA; Department of Electrical Engineering and Computer Sciences, University of California, Berkeley, CA, USA; Department of Statistics, University of California, Berkeley, CA, USA.
- 22. Division of Rheumatology, Department of Medicine, University of California, San Francisco, California, USA; ImmunoX Initiative, University of California, San Francisco, CA, USA; UCSF CoLabs, University of California, San Francisco, CA, USA.
- 23. Division of Infectious Disease, Department of Medicine, University of California, San Francisco, CA, USA.
- 24. Division of Pulmonary and Critical Care Medicine, Department of Medicine and the Cardiovascular Research Institute, University of California, San Francisco, CA, USA.
- 25. ImmunoX Initiative, University of California, San Francisco, CA, USA; Department of Pathology, University of California, San Francisco, CA, USA.
- 26. ImmunoX Initiative, University of California, San Francisco, CA, USA; Division of Pulmonary and Critical Care Medicine, Department of Medicine and the Cardiovascular Research Institute, University of California, San Francisco, CA, USA.
- 27. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France; University of Paris, Imagine Institute, Paris, France; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA; Howard Hughes Medical Institute, New York, NY, USA.
- 28. Diabetes Center, University of California, San Francisco, CA, USA; Endocrine Division, Department of Medicine, University of California, San Francisco, CA, USA.
- 29. Institute of Human Genetics, University of California, San Francisco, CA, USA; Division of Rheumatology, Department of Medicine, University of California, San Francisco, California, USA; ImmunoX Initiative, University of California, San Francisco, CA, USA; Chan Zuckerberg Biohub, San Francisco, CA, USA; Departments of Epidemiology and Biostatistics, Bioengineering and Therapeutic Sciences; Bakar Computational Health Sciences Institute, University of California, San Francisco, CA, USA; Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA.
Description
Neutralizing autoantibodies against type I interferons (IFNs) have been found in some patients with critical coronavirus disease 2019 (COVID-19), the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, the prevalence of these antibodies, their longitudinal dynamics across the disease severity scale, and their functional effects on circulating leukocytes remain unknown. Here, in 284 patients with COVID-19, we found type I IFN-specific autoantibodies in peripheral blood samples from 19% of patients with critical cases and 6% of patients with severe cases. We found no type I IFN autoantibodies in individuals with moderate cases. Longitudinal profiling of over 600,000 peripheral blood mononuclear cells using multiplexed single-cell epitope and transcriptome sequencing from 54 patients with COVID-19 and 26 non-COVID-19 controls revealed a lack of type I IFN-stimulated gene (ISG-I) responses in myeloid cells from patients with critical cases. This was especially evident in dendritic cell populations isolated from critical cases producing type I IFN-specific autoantibodies. Moreover, we found elevated expression of the inhibitory receptor leukocyte-associated immunoglobulin-like receptor 1 (LAIR-1) on the surface of monocytes isolated from patients with critical cases early in the disease course. LAIR-1 expression is inversely correlated with ISG-I expression response in patients with COVID-19 but is not expressed in healthy controls. The deficient ISG-I response observed in patients with critical COVID-19 with and without type I IFN-specific autoantibodies supports a unifying model for disease pathogenesis involving ISG-I suppression through convergent mechanisms.
Notes
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