Single-cell analysis reveals SARS-CoV-2 modulation of monocyte differentiation and immune response during Omicron BA.1 in vitro stimulation

Single-cell technologies provide valuable insights into heterogeneous immune cell populations. To investigate how SARS-CoV-2 shapes host immunity, we employed a high-throughput single-cell approach on HLA-DR enriched human peripheral blood mononuclear cells stimulated in vitro with the Omicron BA.1 variant. This analysis yielded integrated data on protein and gene expression at a single-cell resolution. RNA-seq data and pathway analysis of differentially regulated genes revealed intricate regulatory patterns in monocytes, natural killer cells, plasmacytoid and conventional dendritic cells. Among all cell types, monocytes were most strongly affected in terms of their differentiation status, expression of adhesion markers, cytokine and chemokine signaling and antigen processing and presentation. We further investigated the effect of viral entry on the stimulated cells by aligning the Omicron BA.1 genome to single-cell reads and found that, although SARS-CoV-2 RNA was detected across all cell types, CD14+ and CD16+ monocytes were preferentially virus-positive. Genes upregulated in virus-positive monocytes were associated with cellular responses to stress and infection, inflammation and metabolism, while genes related to antiviral alpha-beta interferon signaling and antigen processing and presentation appeared to be downregulated. This study gives new insights on intersection between SARS-CoV-2 dynamics and host innate immunity and further elucidate mechanisms that potentially contribute to the invasion of immune cells by SARS-CoV-2 leading to control and/or pathogenesis of the infection.