Comparative Single-Cell Analyses in Infants Revealed RSV-Specific Declines in NK Cell Responses and COVID-19-Specific Increases in Inflammatory Responses [COVID_RSV_snATAC]

The clinical phenotype of infants infected with respiratory syncytial virus (RSV) differs from that of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. RSV is the leading cause of hospitalization for lower respiratory tract infection and carries a significant higher risk of respiratory failure compared to SARS-CoV-2, which has been generally linked to fever and croup in young infants. The underlying mechanisms these differences remain unclear. We analyzed peripheral blood mononuclear cells (PBMCs) and serum from infants infected with SARS-CoV-2 (n=30), RSV (n=19), and healthy controls (n=17) using single-cell RNA sequencing, single-nucleus ATAC sequencing and cytokine profiling. Both viruses triggered type I interferon responses across PBMC subsets but differed in their NK cell and inflammatory responses. Severe RSV cases were characterized by lower NK cell percentages, lower IFNG expression and diminished chromatin accessibility at T-BET and EOMES binding sites in NK cells. Furthermore, RSV infections were associated with increased frequencies of CD4+ TEMRA and memory Treg cells. In contrast, SARS-CoV-2 infections were marked by more pronounced pro-inflammatory signatures, including increased transcriptional and epigenetic activity at NFKB factors and higher serum TNF concentrations. These findings highlight distinct immune response pathways in RSV and SARS-CoV-2 infections that may inform future therapeutic strategies.