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Two recent studies utilizing multi-omics single-cell analyses provide new insights into potential immunopathogenesis associated with severe COVID-19. In Nature Medicine, Stephenson et al. performed gene expression analysis on peripheral blood mononuclear cells obtained from a cohort of patients with COVID-19 of varying severity. Notably, they identify a C1Q-expressing CD16+ monocyte subset associated with more severe disease. C1q+CD16+ monocytes had increased interaction with platelets, a finding that is linked with increased platelet activation and increased frequencies of mobilized megakaryocyte precursors in patients’ blood. In Nature, Delorey et al. present a single-cell and spatial cell atlas of gene expression in lung samples obtained at autopsy of patients with critical COVID-19. They show severe reductions in lung AT2 epithelial cells along with reduced surfactant production and perturbations in the regeneration of AT1 epithelial cells, which ultimately lead to compromised lung function. Both studies can serve as rich dataset resources for further hypothesis-driven investigations of COVID-19-associated immunopathology.