Transcriptomes of classical monocytes in post-COVID patients suggest predisposing condition or innate memory from SARS-CoV-2 infection

Despite extensive global research efforts, predisposing conditions and mechanisms leading to post-COVID remain poorly understood. While age and sex have most frequently been cited as predispositions, perturbations of the peripheral immune system have been associated with its pathogenesis. To deepen the current knowledge, we here investigated the immunological landscapes of 44 post-COVID patients and 44 sex-, age-, and vaccine-matched convalescents using single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs). To validate the mRNA-based findings, we measured plasma cytokine levels via Luminex technology. Our analysis revealed only minor differences in immune cell composition between the cohorts. In contrast, we identified numerous differently expressed genes (DEGs) that allowed for a clear clustering of patients and controls. These transcriptomic changes were predominantly observed in classical monocytes and were characterized by the downregulation of inflammation-associated genes, including IL1B, CCL3, -4, and -20 as well as CXCL1, -2, -3, and -8. Further analysis of transcription factor activity hinted at reduced inflammasome activity via SNAI1 and impaired differentiation of classical monocytes due to reduced ATF2. RNA velocity corroborated the findings of pre-mature classical monocytes in post-COVID patients. Based on these results, we hypothesize that patients either developed a state of SARS-CoV-2-induced immune tolerance that contributed to subsequent symptoms, or they possessed a predisposition of impaired innate immunity prior to infection, that facilitated the development of post-COVID.