Young infants hospitalized with respiratory syncytial virus (RSV) often experience more severe symptoms compared to those infected with SARS-CoV-2, the virus responsible for COVID-19. A study published on February 25, 2026, in Science Translational Medicine by researchers from St. Jude Children’s Research Hospital and The Jackson Laboratory (JAX) reveals that the two respiratory viruses elicit distinct immune responses. Understanding these differences could illuminate why clinical outcomes vary significantly between RSV and SARS-CoV-2 and inform tailored treatment strategies.
Physicians noted during the COVID-19 pandemic that infants admitted with RSV displayed more alarming symptoms than those with SARS-CoV-2, prompting researchers to investigate the underlying immune mechanisms. The study involved a comparative analysis of immune responses from infants hospitalized with either virus, examining blood samples at a single-cell level to identify specific immune cells and signaling pathways involved.
According to co-corresponding author Octavio Ramilo, MD, chair of the St. Jude Department of Infectious Diseases, this research provides the first evidence that RSV and SARS-CoV-2 induce markedly different types of immune dysregulation in young infants. The study revealed that the body’s response to each virus varies at the chemical, cellular, and even epigenetic levels.
Immune Responses Compared
The researchers discovered that severe cases of RSV in infants were associated with unexpectedly low levels of systemic inflammation and a disorganized early immune response, particularly involving a specialized group of immune cells known as natural killer cells. In contrast, infants with SARS-CoV-2 infection exhibited a hyperinflammatory immune response.
Duygu Ucar, PhD, another co-corresponding author and professor at JAX, noted that while antiviral responses appeared similar at first glance, further examination revealed significant differences in immune gene regulation. RSV seems to reprogram certain aspects of the infant immune system at the epigenetic level, which are the molecular switches that control gene activation.
Study Details and Findings
The study involved blood samples from 19 infants with RSV infections, 30 infants with SARS-CoV-2 infections, and 17 healthy age-matched infants, with most participants around two months old. Comprehensive single-cell analysis indicated that both viruses triggered a similar increase in most interferons—antiviral molecules crucial for immune defense. However, notable disparities emerged. Infants with RSV had significantly fewer natural killer cells compared to those infected with SARS-CoV-2. These natural killer cells were also found to produce less interferon-gamma, a critical molecule for viral defense, which correlated closely with disease severity.
Asa Thibodeau, PhD, an associate computational scientist at JAX, emphasized that the integration of advanced computational methods with single-cell technologies allowed the team to identify unique immune response signatures and associate gene expression with potential epigenetic regulators.
Clinical Implications of the Research
The differences in immune responses have considerable clinical implications. The RSV infection was characterized by lower interferon-gamma expression and diminished activity of key inflammatory signals such as IL-1B and NF-κB, which typically aid in fighting infections. Conversely, SARS-CoV-2 was associated with significant immune dysregulation across various cell types, leading to increased levels of pro-inflammatory molecules like TNF alpha and heightened NF-κB activity.
This disparity helps explain why anti-inflammatory treatments, including steroids, can be beneficial for some severe COVID-19 patients but have not proven effective for RSV and may even be detrimental. As co-first author Asunción Mejías, MD, PhD, stated, the findings suggest that steroids should not routinely be administered to infants with RSV, as these drugs could further suppress the already weakened immune response.
The Broader Impact of RSV
RSV remains a leading cause of hospitalization among infants and is the second leading cause of infant mortality globally. The study highlights the pressing require for effective treatments and preventive strategies. Ramilo pointed out that approximately five million children die before the age of five each year, with many of these deaths occurring in the first months of life due to infections that arise before they can receive vaccinations. The insights gleaned from this research may pave the way for improved interventions and outcomes for vulnerable infants.
The study involved contributions from several co-authors, including Jacques Banchereau from JAX and researchers from Weill Cornell Medicine. Funding for the research was provided by the National Institutes of Health and the American Lebanese Syrian Associated Charities (ALSAC).
This research not only enhances our understanding of infant immunity but also sets the stage for future studies aimed at improving treatment protocols for severe viral infections in young children. As researchers continue to explore these immune responses, the hope is to develop more effective therapies and preventative measures to safeguard infant health.
As the scientific community delves deeper into the intricacies of immune responses among infants, this study serves as a crucial step toward uncovering effective interventions for RSV and other respiratory viruses. Readers are encouraged to share their thoughts and experiences regarding this critical health issue.
