Journal
SCIENCE TRANSLATIONAL MEDICINE
Volume 13, Issue 612, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.abh2624
Keywords
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Categories
Funding
- National Institute of Allergy and Infectious Diseases (NIAID) [U19 AI1077439]
- Dutch Research Council [NWO-Veni 192.029]
- NSF under the Graduate Research Fellowship Program [1650113]
- National Institute of Diabetes, Digestive and Kidney Diseases [1F30DK123915-01]
- Chan Zuckerberg Biohub
- NIAID [5PO1AI118688-04]
- National Heart, Lung and Blood Institute [R35 HL140026]
- Veteran Affairs Office of Research and Development CSRD [IK2CX001034]
- National Heart Lung and Blood Institute [HL151552]
- Division of Intramural Research of the NIH
- PhD Program in Bioinformatics at UCSF
- NIH [R35-GM134922, R01AI088364, R01AR071522, R01AI136972, U01HG012192]
- U.S. Department of Energy Office of Science [17-SC-20-SC]
- National Nuclear Security Administration [17-SC-20-SC]
- Howard Hughes Medical Institute
- Rockefeller University
- St. Giles Foundation
- National Center for Advancing Translational Sciences (NCATS)
- NIH Clinical and Translational Science Award (CTSA) program [UL1 TR001866]
- Fast Grant from Emergent Ventures, Mercatus Center at George Mason University
- Yale Center for Mendelian Genomics
- GSP Coordinating Center - National Human Genome Research Institute (NHGRI) [UM1HG006504, U24HG008956]
- French National Research Agency (ANR) under the Investments for the Future program [ANR-10-IAHU-01]
- Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence [ANR-10-LABX-62-IBEID]
- French Foundation for Medical Research (FRM) [EQU201903007798]
- FRM
- ANR GENCOVID project [ANRS-COV05]
- Square Foundation
- Grandir-Fonds de solidarite pour l'enfance
- SCOR Corporate Foundation for Science
- Institut National de la Sante et de la Recherche Medicale (INSERM)
- University of Paris
- Intramural Research Program of the NIAID
- Intramural Research Program of the NIH
- MD-PhD program of the Imagine Institute ( the support of the Fondation Bettencourt-Schueller)
- Chan Zuckerberg Initiative at the Chan Zuckerberg Biohub
- Genentech (COMET Plus) [TSK-020586]
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Autoantibodies against type I interferons have been identified in some patients with critical COVID-19, with higher prevalence in severe cases. The longitudinal dynamics and functional effects of these antibodies on circulating leukocytes remain unclear.
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 disease and 6% of patients with severe disease. We found no type I IFN autoantibodies in individuals with moderate disease. 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 disease. This was especially evident in dendritic cell populations isolated from patients with critical disease producing type I IFN-specific autoantibodies. Moreover, we found elevated expression of the inhibitory receptor leukocyte-associated immunoglobulin-like receptor 1 (LAIR1) on the surface of monocytes isolated from patients with critical disease early in the disease course. LAIR1 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.
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