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

doi:10.1101/2021.03.09.434529

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

bioRxiv [Preprint]. 2021 Mar 10:2021.03.09.434529. doi: 10.1101/2021.03.09.434529.

Authors

Monique G P van der Wijst^{1

2

3}, Sara E Vazquez^{4

5

6

7}, George C Hartoularos^{2

3}, Paul Bastard^{8

9

10}, Tianna Grant^{2

3}, Raymund Bueno^{2

3}, David S Lee^{2

3

11}, John R Greenland¹², Yang Sun^{2

3

11}, Richard Perez^{2

13}, Anton Ogorodnikov^{2

3}, Alyssa Ward^{2

3}, Sabrina A Mann^{7

14}, Kara L Lynch¹⁵, Cassandra Yun¹⁵, Diane V Havlir¹⁶, Gabriel Chamie¹⁶, Carina Marquez¹⁶, Bryan Greenhouse¹⁶, Michail S Lionakis¹⁷, Philip J Norris^{15

18

19}, Larry J Dumont^{20

21

22}, Kathleen Kelly²⁰, Peng Zhang¹⁰, Qian Zhang¹⁰, Adrian Gervais^{9

10}, Tom Le Voyer^{9

10}, Alexander Whatley²³, Yichen Si²⁴, Ashley Byrne¹⁴, Alexis J Combes^{11

25

26}, Arjun Arkal Rao^{11

25

26}, Yun S Song^{14

23

27}; UCSF COMET consortium; Gabriela K Fragiadakis^{3

11

26}, Kirsten Kangelaris²⁸, Carolyn S Calfee²⁹, David J Erle^{2

11

15}, Carolyn Hendrickson²⁹, Matthew F Krummel^{11

25}, Prescott G Woodruff^{11

29}, Charles R Langelier²⁸, Jean-Laurent Casanova^{8

9

10

30}, Joseph L Derisi^{7

14}, Mark S Anderson^{6

31}, Chun Jimmie Ye^{2

3

11

14

32

33

34}

Affiliations

¹ Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
² Institute of Human Genetics, University of California, San Francisco, CA, USA.
³ Division of Rheumatology, Department of Medicine, University of California, San Francisco, California, USA.
⁴ Medical Scientist Training Program, University of California. San Francisco, CA, USA.
⁵ Tetrad Graduate Program, University of California, San Francisco, CA, USA.
⁶ Diabetes Center, University of California, San Francisco, CA, USA.
⁷ Department of Biochemistry and Biophysics, University of California, San Francisco, CA, USA.
⁸ Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France.
⁹ University of Paris, Imagine Institute, Paris, France.
¹⁰ St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA.
¹¹ ImmunoX Initiative, University of California, San Francisco, CA, USA.
¹² Department of Medicine, San Francisco VA Health Care System, University of California, San Francisco, CA, USA.
¹³ School of Medicine, University of California, San Francisco, San Francisco, California, USA.
¹⁴ Chan Zuckerberg Biohub, San Francisco, CA, USA.
¹⁵ Zuckerberg San Francisco General, San Francisco, CA, USA.
¹⁶ Division of HIV, Infectious Disease and Global Medicine, Department of Medicine, University of California, San Francisco, CA, USA.
¹⁷ 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.
¹⁸ Department of Laboratory Medicine, University of California, San Francisco, CA, USA.
¹⁹ Vitalant Research Institute, San Francisco, CA, USA.
²⁰ Vitalant Research Institute, Denver, CO, USA.
²¹ University of Colorado School of Medicine, Aurora, CO, USA.
²² Geisel School of Medicine at Dartmouth, Lebanon, NH, USA.
²³ Department of Electrical Engineering and Computer Sciences, University of California, Berkeley, CA, USA.
²⁴ Department of Biostaticstics, University of Michigan.
²⁵ Department of Pathology, University of California, San Francisco, CA, USA.
²⁶ UCSF CoLabs, University of California, San Francisco, CA, USA.
²⁷ Department of Statistics, University of California, Berkeley, CA, USA.
²⁸ Division of Infectious Disease, Department of Medicine, University of California, San Francisco, CA, USA.
²⁹ Division of Pulmonary and Critical Care Medicine, Department of Medicine and the Cardiovascular Research Institute, University of California, San Francisco, CA, USA.
³⁰ Howard Hughes Medical Institute, New York, NY, USA.
³¹ Endocrine Division, Department of Medicine, University of California, San Francisco, CA, USA.
³² Departments of Epidemiology and Biostatistics, Bioengineering and Therapeutic Sciences.
³³ Bakar Computational Health Sciences Institute, University of California, San Francisco, CA, USA.
³⁴ Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA.

Abstract

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.

Keywords: COVID-19; IFN; ISG; SARS-CoV2; autoantibodies; peripheral blood mononuclear cells; scRNA-seq.

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Preprint

Abstract

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