Respiratory syncytial virus (RSV) is one of the leading causes of hospitalization and mortality during the first year of life. In infants, it frequently causes bronchiolitis and pneumonia, often requiring inpatient care and intensive therapy. SARS-CoV-2 infection in infants is generally milder and less likely to result in severe outcomes. In addition, RSV is associated with recurrent wheezing and increased risk of asthma later in life, whereas SARS-CoV-2 only occasionally leads to multisystem inflammatory syndrome in children (MIS-C) or long COVID. These clinical differences suggest distinct immune responses in early life.
Both infections increase circulating monocyte numbers. However, RSV is often associated with lymphocytosis, whereas SARS-CoV-2 is more commonly associated with lymphopenia. Studies have shown that children with mild RSV exhibit higher interferon (IFN) gene activity and plasma cell signatures, alongside lower expression of inflammation- and neutrophil-associated genes, compared with those with severe RSV. Mild and moderate RSV are associated with increased Ki67 expression in cytotoxic and central memory CD8 T cells. Severe RSV is characterized by increased frequencies of HLA-DR^low monocytes, attenuated IFN responses, and reduced circulating NK cell numbers.
In young children with mild COVID-19, interferon-stimulated genes (ISGs) are activated without systemic inflammation. In more severe SARS-CoV-2 cases, serum inflammatory cytokines increase, and ISGs are activated across multiple immune cell types.
Although interferon responses are characteristic of both infections, their magnitude, cellular distribution, and relationship to disease severity remain incompletely defined. Epigenetic regulation has been largely unexplored.
The researchers hypothesized that direct comparison of the two infections would clarify differences in infant immune responses. They included infants with RSV and SARS-CoV-2 of varying severity, as well as healthy controls. Single-cell gene activity, regulatory landscapes, and protein profiles were analyzed, enabling identification of shared and disease-specific immune mechanisms in early life.
Shared Features And Key Differences In Immune Responses
Both viruses induced sustained interferon responses in peripheral blood mononuclear cells (PBMC), reflecting antiviral activation. However, the infections differed across four principal dimensions:
- intensity of inflammation;
- epigenetic regulation;
- NK cell responses;
- adaptive immune responses.
Inflammatory Intensity
The most prominent differences concerned inflammatory activity. SARS-CoV-2 triggered a robust proinflammatory response, with elevated serum TNF and activation of NF-κB–associated genes and regulatory regions in PBMC. These findings are consistent with adult data.
RSV, by contrast, was associated with more restrained inflammation. In severe cases, IL1B expression in CD14 monocytes declined, and serum TNF levels were lower than in COVID-19. Previous studies have reported an inverse relationship between RSV severity and innate cytokine levels, including TNF, in upper airway samples and plasma.
Epigenetic Changes And The Role Of NK Cells
Epigenetic profiling revealed disease-specific regulatory differences. In infants with severe RSV, peripheral blood NK cells exhibited reduced expression of IFNG and IFNG-AS1, along with decreased chromatin accessibility at binding sites for NK maturation factors and regulators of IFN-γ production, including T-BET and EOMES. These alterations likely impair NK cell activity.
NK cells act early during infection and perform several critical functions:
- production of IFN-γ;
- regulation of myeloid cell activity;
- modulation of epithelial inflammation;
- interaction with innate immune populations.
Impairment of these functions can significantly influence disease trajectory.
In contrast, infants recovering from SARS-CoV-2 displayed epigenetic changes enriched at ISG-associated loci. Some overlapped with CD14 monocyte signatures observed in adults during convalescence. RSV infection also showed increased accessibility of IRF-binding regions in certain monocyte subsets compared with SARS-CoV-2.
Adaptive Immune Responses
Adaptive responses also differed. RSV infection was associated with increased frequencies of CD4 TEMRA cells in PBMC, a population that may contribute to viral clearance. Prior adult studies have shown that accumulation of CD8 T cells beneath bronchial epithelium correlates with more severe RSV disease. In infants with RSV, proliferating T cell frequencies increased. Strong ISG responses were detected in circulating T cells during both infections.
These T cell responses may partially compensate for reduced NK-derived IFN-γ at later stages. However, extensive evidence indicates that early IFN-γ production plays a protective role in RSV. When IFN-γ responses are attenuated and NK cell numbers decline in blood, disease severity tends to increase.
Even robust T cell responses do not fully compensate for impaired NK cell function in shaping early antiviral and inflammatory responses during RSV infection. Differences in activation timing, tissue localization, and intercellular communication likely limit the capacity of CD8 T cell–derived IFN-γ to substitute for early NK activity.
Unlike RSV, SARS-CoV-2 was associated with enhanced inflammatory activity in naïve CD4 and CD8 T cells in peripheral blood.
Conclusion
Features of systemic immunosuppression characterized severe RSV: weakened inflammatory and innate responses, reduced IL1B expression in CD14 monocytes, decreased IFNG and IFNG-AS1 expression, and altered gene regulation in NK cells. These findings may explain why anti-inflammatory therapies, including corticosteroids, have shown limited efficacy in RSV.
SARS-CoV-2, in contrast, induced stronger inflammatory responses, consistent with the established use of anti-inflammatory treatment in severe COVID-19. In the study cohort, only a small number of infants received corticosteroids; in these cases, interferon responses were attenuated rather than completely suppressed, highlighting the need to balance inflammation control with preservation of antiviral defence.
These findings suggest potential therapeutic strategies to restore or enhance early innate immune responses and NK cell function. A clearer understanding of immune differences between RSV and SARS-CoV-2 may support more targeted treatment approaches for severe disease in infants.
