The markedly reduced pathogenicity of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Omicron variant in comparison to earlier strains has raised critical questions regarding its underlying mechanisms. To elucidate the host immune responses driving these differences, we performed single-cell transcriptomic profiling of lung and blood samples from human angiotensin-converting enzyme 2 (hACE2) transgenic mice infected with either the SARS-CoV-2 prototype strain or the Omicron BA.1 variant at 5 days post-inoculation. Both strains induced a reduction in lung cell numbers, with capillary endothelial cells showing the highest number of differentially expressed genes (DEGs). Shared transcriptional responses included upregulation of chemokine (e.g. Gnaq, Lyn, Ccl5) and IL-17 signaling pathways. Notably, Omicron BA.1 infection resulted in downregulation of Txnip, a key gene involved in oxidative stress responses. Genes associated with neutrophil granules and pro-inflammatory functions (Mmp8, S100a8, S100a9) were also downregulated, whereas wound healing pathways were upregulated in immature neutrophils. Additionally, Omicron BA.1 altered gene expression associated with neutrophil migration from blood to lung, and decreased the activation of cell chemotaxis, cytokine-mediated signaling, IL-17 and NF-κB pathways in pro-inflammatory monocytes and pulmonary interstitial macrophages. These findings highlight distinct immunological signatures contributing to the attenuated pathogenicity of Omicron BA.1, particularly through the modulation of neutrophil and monocyte-macrophage responses.
Keywords: Omicron BA.1 variant; SARS-CoV-2 prototype strain; monocyte-macrophage; neutrophil; pathogenicity differences; single-cell transcriptome.