Transcriptome analysis of classical blood cells reveals downregulation of pro-inflammatory genes in the classical monocytes of long COVID patients.

Introduction: Despite extensive research, the pathogenesis and predispositions underlying long COVID (long-term coronavirus disease 2019) remain poorly understood. Methods: To address this, we analyzed the immunological landscapes of 44 patients with long COVID and 44 matched convalescents using single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs) and validated the findings with plasma cytokine measurements via Luminex technology. Results: While the immune cell compositions showed minimal quantitative differences only among natural killer (NK) cells, the transcriptome analyses identified distinct gene expression patterns, particularly in classical monocytes: patients with long COVID exhibited downregulation of the inflammation-associated genes, including IL1B and CXCL2. Imputation of the transcription factor activity hinted at a reduced inflammasome activity (via SNAI1) and an impaired monocyte differentiation (via ATF2) in long COVID. The RNA velocity data supported the presence of immature classical monocytes in these patients. Discussion: These findings show that monocytes might be dysregulated and/or exhausted in patients with long COVID.