Why RSV Hits Infants Harder Than COVID-19: Immune Suppression, Not Hyperinflammation
Why do infants hospitalized with RSV so often become sicker than those admitted with COVID-19? The two viruses are both respiratory RNA pathogens. Both infect the lungs. Both can require intensive care. Yet clinicians have observed for years that RSV consistently produces more severe outcomes in young infants. An explanation has now emerged from single-cell analysis of blood samples taken from hospitalized babies.
The study, published February 25 in Science Translational Medicine, compared immune responses across 19 infants with RSV, 30 infants with SARS-CoV-2, and 17 healthy controls. Most participants were approximately 2 months old. What researchers from St. Jude Children's Research Hospital and The Jackson Laboratory found reversed a key assumption: RSV does not trigger dangerous inflammation. It suppresses the immune response.
Natural killer cells: depleted and dysfunctional
Both viruses triggered similar rises in most interferons - the antiviral signaling molecules that inhibit viral replication. That surface similarity masked a sharp divergence underneath. Infants with RSV had significantly fewer natural killer (NK) cells in circulation compared to both COVID-19 patients and healthy controls. The NK cells that remained were also functionally impaired: they produced less interferon-gamma, a cytokine critical for antiviral defense. The degree of interferon-gamma suppression correlated directly with disease severity - the sicker the infant, the less functional the NK cell response.
Co-corresponding author Duygu Ucar, PhD, Professor at JAX, noted an additional dimension: "RSV appears to reprogram parts of the infant immune system at the epigenetic level - which are molecular switches that control how genes are turned on or off." This epigenetic reprogramming means RSV may not only suppress the immediate immune response but alter how immune genes can be expressed in the future. The implications for infant health beyond the acute infection are not yet understood.
SARS-CoV-2 takes the opposite approach
SARS-CoV-2 produced immune dysregulation of a different character: hyperinflammation. Infants with COVID-19 showed elevated TNF-alpha signaling and heightened NF-kB activity - pro-inflammatory pathways that drive tissue damage when chronically activated.
The clinical implications follow directly. Anti-inflammatory steroids dampen NF-kB and related pathways. In severe COVID-19 patients, that dampening is beneficial. In RSV patients, whose immune responses are already suppressed, adding corticosteroids may further impair the NK cell activity that is struggling to control the virus. "One very practical implication of our work is that we should not routinely give steroids to infants with RSV," said co-first author Asuncion Mejias, MD, PhD.
Limitations and next steps
The study enrolled 19 RSV patients and 30 SARS-CoV-2 patients - a modest sample appropriate for intensive single-cell work but not for definitive clinical conclusions. The analysis captures a snapshot during hospitalization; longitudinal studies are needed to understand how immune profiles evolve across illness and how prior exposures shape responses. The epigenetic reprogramming finding is intriguing but preliminary. RSV remains the leading cause of infant hospitalization worldwide, making the mechanistic understanding established here directly relevant to developing better treatments.