The coronavirus disease 2019 (COVID-19) is accompanied by a cytokine storm with the release of many proinflammatory factors and development of respiratory syndrome. Several SARS-CoV-2 lineages have been identified, and the Delta variant (B.1.617), linked with high mortality risk, has become dominant in many countries. Understanding the immune responses associated with COVID-19 lineages may therefore aid the development of therapeutic and diagnostic strategies. Multiple single-cell gene expression studies revealed innate and adaptive immunological factors and pathways correlated with COVID-19 severity. Additional investigations covering host–pathogen response characteristics for infection caused by different lineages are required. Here, we performed single-cell transcriptome profiling of blood mononuclear cells from the individuals with different severity of the COVID-19 and virus lineages to uncover variant specific molecular factors associated with immunity. We identified significant changes in lymphoid and myeloid cells. Our study highlights that an abundant population of monocytes with specific gene expression signatures accompanies Delta lineage of SARS-CoV-2 and contributes to COVID-19 pathogenesis inferring immune components for targeted therapy.

Transposable elements (TEs) are key regulators of immunity in both health and disease. It has been proven that the activity and transcriptional expression levels of TEs increase during viral infections, correlating with the antiviral response. This study investigates non-LTR TE (LINE, SINE, and SVA) transcriptomic signatures in human PBMCs during infections caused by influenza A virus, HIV, and SARS-CoV-2 (Delta/Omicron variants) using single-cell RNA sequencing (scRNA-seq) data from 98 patients. In the HIV and SARS-CoV-2 patient cohorts, unique cell-specific TE expression patterns were identified that allow for the differentiation of disease severity, prediction of disease progression, and assessment of the therapy’s efficacy. The expression of LINE elements was found to be more dependent on the nature and course of the disease than that of SINE elements. The most variable TE expression profile was observed in precursor cytotoxic T-lymphocytes (T CD8+ Naive cells), which depended on the virus type and the severity of the viral disease. For this cell type, a bioinformatic analysis of the co-expression regulation of TE transcriptional networks and transcription factors during viral infections was performed. This analysis identified key players among those most involved in virus-specific responses, which could serve as diagnostic biomarkers or therapeutic targets for treating diseases caused by influenza A virus, HIV, and SARS-CoV-2. This work confirms the involvement of non-LTR TEs in mediating antiviral responses. Further research into the mechanisms of TE participation in antiviral defense is necessary to recommend them as potential biomarkers for the diagnosis, monitoring, and assessment of antiviral therapy, or as therapeutic targets for viral infections of various origins.