A systems immunology approach reveals divergent immune profiles of RSV and SARS-CoV-2 infections in infants

Respiratory syncytial virus (RSV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in infants differ substantially in their clinical presentations and outcomes. RSV is the leading cause of severe lower respiratory tract infection in infants, whereas SARS-CoV-2 infections are typically milder and do not necessarily involve the lower respiratory tract. To uncover immune mechanisms associated with these differences, we analyzed blood samples from infants (median age, 2.3 months) infected with RSV (<i>n</i> = 19) or SARS-CoV-2 (<i>n</i> = 30), as well as healthy control infants (<i>n</i> = 17), using cytokine profiling, single-cell transcriptomics, and epigenomics. Both viruses induced comparable interferon-stimulated gene signatures but displayed disease-specific signatures in the individual cell types analyzed. Specifically, RSV was associated with increased CD4⁺ terminal effector memory T cell and memory regulatory T cell frequencies in the peripheral blood. Infants with severe RSV had reduced natural killer cell frequencies in the blood, lower <i>IFNG</i> expression in CD56^dim natural killer cells, and diminished chromatin accessibility at T-BET and EOMES binding sites in CD56^dim and CD56^bright natural killer cells. In contrast, infants infected with SARS-CoV-2 showed heightened proinflammatory responses in the blood, including higher nuclear factor κB pathway activity and serum tumor necrosis factor concentrations. These results highlight the distinct nature of infant immune responses to RSV and SARS-CoV-2 infections, offering insights that may help explain differences in the clinic and guide therapies.