Single-Cell Omics Reveals Dyssynchrony of the Innate and Adaptive Immune System in Progressive COVID-19

Unterman, A.; Sumida, T. S.; Nouri, N.; Yan, X.; Zhao, A. Y.; Gasque, V.; Schupp, J. C.; Asashima, H.; Liu, Y.; Cosme, C.; Deng, W.; Chen, M.; Brickman Raredon, M. S.; Hoehn, K.; Wang, G.; Wang, Z.; Deiuliis, G.; Ravindra, N. G.; Li, N.; Castaldi, C.; Wong, P.; Fournier, J.; Bermejo, S.; Sharma, L.; Casanovas-Massana, A.; Vogels, C. B. F.; Wyllie, A. L.; Grubaugh, N. D.; Melillo, A.; Meng, H.; Minasyan, M.; The Yale IMPACT research team,; Niklason, L. E.; Ko, A. I.; Montgomery, R. R.; Farhadian, S. F.; Iwasaki, A.; Shaw, A. C.; van Dijk, D.; Zhao, H.; Kleinstein, S. H.; Hafler, D. A.; Kamins,

A dysregulated immune response against the SARS-CoV-2 virus plays a critical role in severe COVID-19. However, the molecular and cellular mechanisms by which the virus causes lethal immunopathology are poorly understood. Here, we utilize multi-omics single-cell analysis to probe dynamic immune responses in patients with stable or progressive manifestations of COVID-19, and assess the effects of tocilizumab, an anti-IL-6 receptor monoclonal antibody. Coordinated profiling of gene expression and cell lineage protein markers reveals a prominent type-1 interferon response across all immune cells, especially in progressive patients. An anti-inflammatory innate immune response and a pre-exhaustion phenotype in activated T cells are hallmarks of progressive disease. Skewed T cell receptor repertoires in CD8 T cells and uniquely enriched V(D)J sequences are also identified in COVID-19 patients. B cell repertoire and somatic hypermutation analysis are consistent with a primary immune response, with possible contribution from memory B cells. Our in-depth immune profiling reveals dyssynchrony of the innate and adaptive immune interaction in progressive COVID-19, which may contribute to delayed virus clearance and has implications for therapeutic intervention.