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.
Competing Interest Statement
J.R.G. has consulted for Boehringer Ingelheim and has consulted for and received research support from Theravance Biopharma, Inc. J.L.D. is a SAB member for The Public Health Company, and a consultant for Allen & Company. C.J.Y. is a SAB member for and hold equity in Related Sciences and ImmunAI, a consultant for and hold equity in Maze Therapeutics, and a consultant for TRex Bio. C.J.Y. has received research support from Chan Zuckerberg Initiative, Chan Zuckerberg Biohub and Genentech.
Footnotes
↵# A list of authors and their affiliations can be found in the Supplementary Information
Data curation: MGPW, SEV, GCH, RB, JRG, RP, AO, AlyW, KK, GKF
Formal Analysis: MGPW, SEV, GCH, PB, TG, RB, JRG, AleW, YiS, AB
Funding acquisition: DJE, CRL, JLC, JLD, MSA, CJY
Investigation: MGPW, SEV, GCH, PB, TG, RB, JRG, DSL, YaS, PZ, QZ, AG, TLV
Project administration: YaS, AlyW, CSC, CH, MFK, PGW, CRL
Resources: SAM, KLL, CY, DVH, GC, CM, BG, MSL, PJN, LJD, KK, GFK, KK, CSF, CH
Supervision: MGPW, GKF, KK, CSF, DJE, CH, MFK, PGW CRL, JLC, JLD, MSA, CJY
Visualization: MGPW, SEV, GCH, RB
Writing – original draft: MGPW, SEV, GCH, CJY
Writing – review & editing: PB, JRG, GKF, CSC, DJE, CH, MFK, PGW, CRL, JLC, JLD, MSA
Anti-IFN antibodies in critical COVID-19 correlate with poor ISG response and upregulation of LAIR1 surface protein in PBMCs
https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE168453