Infants display reduced NK cell responses in RSV and increased inflammatory responses in SARS-CoV-2 infections.

Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infection hospitalizations in infants and poses a significantly higher risk of respiratory failure than SARS-CoV-2. The mechanisms underlying these differences remain unclear. We analyzed blood samples from infants (median age 2.3 months) with SARS-CoV-2 (n = 30), RSV (n = 19), and healthy controls (n = 17) using single-cell transcriptomics and epigenomics, and cytokine profiling. Both viruses triggered comparable interferon responses across PBMC subsets but differed in NK cell and inflammatory responses. Severe RSV cases showed reduced NK cell frequencies, lower expression, and decreased chromatin accessibility at T-BET and EOMES binding sites. RSV infections were also associated with increased CD4 T, memory T and transitional B cells. In contrast, SARS-CoV-2 was characterized by stronger pro-inflammatory signatures, including increased NFKB pathway activity and higher serum TNF concentrations. These findings highlight distinct immune responses to RSV and SARS-CoV-2, providing insights that may inform clinical decisions.