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

van der Wijst, Monique G.P.; Vazquez, Sara E.; Hartoularos, George C.; Bastard, Paul; Grant, Tianna; Bueno, Raymund; Lee, David S.; Greenland, John R.; Sun, Yang; Perez, Richard; Ogorodnikov, Anton; Ward, Alyssa; Mann, Sabrina A.; Lynch, Kara L.; Yun, Cassandra; Havlir, Diane V.; Chamie, Gabriel; Marquez, Carina; Greenhouse, Bryan; Lionakis, Michail S.; Norris, Philip J.; Dumont, Larry J.; Kelly, Kathleen; Zhang, Peng; Zhang, Qian; Gervais, Adrian; Le Voyer, Tom; Whatley, Alexander; Si, Yichen; Byrne, Ashley; Combes, Alexis J.; Rao, Arjun Arkal; Song, Yun S.; Fragiadakis, Gabriela K.; Kangelaris, Kirsten; Calfee, Carolyn S.; Erle, David J.; Hendrickson, Carolyn; Krummel, Matthew F.; Woodruff, Prescott G.; Langelier, Charles R.; Casanova, Jean-Laurent; Derisi, Joseph L.; Anderson, Mark S.; Ye, Chun Jimmie

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.