Temporal multi-omic analysis of COVID-19 in end-stage kidney disease

Patients with end-stage kidney disease (ESKD) are at high risk of severe COVID-19. We performed longitudinal single cell multi-omic immune profiling of ESKD patients with COVID- 19, sampled during two waves of the pandemic. Uniquely, for a subset of patients, we obtained samples before and during acute infection, allowing intra-individual comparison. Using single- cell transcriptome, surface proteome and immunoreceptor sequencing of 580,040 high-quality cells, derived from 187 longitudinal samples from 61 patients, we demonstrate widespread changes following infection. We identified gene expression signatures of severity, with the majority of pathways differentiating mild from severe disease in B cells and monocytes. For example, gene expression of PLAC8 , a receptor known to modulate SARS-CoV-2 entry to cells, was a marker of severity in CD14+ monocytes. Longitudinal profiling demonstrated distinct temporal molecular trajectories in severe versus mild disease, including type 1 and type 2 interferon signalling, MHC gene expression and, in B cells, a proliferative signature ( KRAS and MYC ). Evaluation of clonal T cell dynamics showed that the fastest expanding clones were significantly enriched in known SARS-CoV-2 specific sequences and shared across multiple patients. Our analyses revealed novel TCR clones likely reactive to SARS- CoV-2. Finally, we identified a population of transcriptionally distinct monocytes that emerged in peripheral blood following glucocorticoid treatment. Overall, our data delineate the temporal dynamics of the immune response in COVID-19 in a high-risk population and provide a valuable open-access resource.