A study found that infant immune systems respond very differently to RSV and SARS-CoV-2, with important treatment implications.
RT’s Three Key Takeaways:
Distinct Immune Responses: A study in Science Translational Medicine by researchers at St. Jude Children’s Research Hospital and The Jackson Laboratory found that RSV and SARS-CoV-2 trigger fundamentally different immune responses in young infants, helping explain their differing severity and treatment needs.
RSV Suppresses Key Defenses: Infants hospitalized with RSV showed fewer natural killer cells, lower interferon-gamma levels, and reduced inflammatory signaling—indicating an immunosuppressive response that was strongly linked to more severe disease.
Treatment Implications Differ: While SARS-CoV-2 infections in infants were marked by hyperinflammation that may respond to steroids, RSV’s already suppressed immune profile suggests steroids could be ineffective or harmful, underscoring the need for virus-specific treatment strategies.
Young infants hospitalized with respiratory syncytial virus (RSV) often become much sicker compared to those infected with SARS-CoV-2, the virus that causes COVID-19. In a study published in Science Translational Medicine, scientists from St. Jude Children’s Research Hospital and The Jackson Laboratory (JAX) report that the two respiratory viruses trigger different immune responses. Those differences might explain why these two diseases have different clinical outcomes and require different treatment strategies.
During the COVID-19 pandemic, physicians observed that infants admitted with RSV infection often had more severe symptoms than those hospitalized with SARS-CoV-2, despite both being respiratory RNA viruses. To understand these differences, the researchers compared the immune responses of infants hospitalized with either virus to those of healthy infants at a single-cell level. Measurements of proteins, genes and epigenetic signatures in the blood revealed the specific immune cells and signals central to these differences.
“We showed, for the first time, that two similar respiratory viruses, RSV and SARS-CoV-2, cause very different types of immune dysregulation in young infants,” said co-corresponding author Octavio Ramilo, MD, St. Jude Department of Infectious Diseases chair. “The host response differs depending on the infecting virus at the chemical, cellular and even epigenetic level.”
The researchers found that severe RSV in infants was linked to unexpectedly low levels of systemic inflammation and a poorly coordinated early immune response, primarily by a special set of immune cells called natural killer cells. This pattern contrasts with the hyperinflammatory immune response profile observed in infants with SARS-CoV-2 infection.
“What surprised us most was that the antiviral responses looked similar at first glance, but when we examined how immune genes were regulated, we saw striking differences,” said co-corresponding author Duygu Ucar, PhD, Professor at JAX. “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.”
“These changes may help explain why RSV can lead to more severe disease and possibly influence how the immune system responds in the future,” Ucar concluded.
RSV suppresses immune response, increasing its severity
To find these differences, the researchers compared immune cells and proteins from blood samples derived from 19 infants hospitalized with RSV infections, 30 infants hospitalized with SARS-CoV-2 infections, and 17 healthy age-matched infants. Most infants in the study were around 2 months old.
Comprehensive single-cell analysis of the infants’ immune responses revealed that both viruses cause a similar rise in most interferons, antiviral molecules that interfere with viruses, but the analysis also revealed drastic differences.
“Most strikingly, we saw infants with RSV had significantly fewer numbers of natural killer cells, compared to those with SARS-CoV-2 infections,” said co-first author Asunción Mejías, MD, PhD, MsCS, St. Jude Department of Infectious Diseases. “In those patients, these cells also made less interferon-gamma, a key molecule to defend against viruses, which was strongly correlated with disease severity.”
“Integrating single cell technologies using advanced computational methods enabled us to not only identify immune response signatures in specific immune cell types but also associate gene expression with potential epigenetic regulators,” said co-first author Asa Thibodeau, PhD, Associate Computational Scientist at JAX. “Understanding immune differences at the transcriptional and epigenetic level will guide future studies and better treatments.”
The RSV response was also marked by lower interferon-gamma expression and reduced activity of key inflammatory signals (IL-1B, NF-KB) that normally help fight infection.
Providing clinical guidance through contrast with SARS-CoV-2
In contrast to RSV, SARS-CoV-2 generally causes significant immune dysregulation across multiple cell types. The researchers observed a significant increase in many pro-inflammatory molecules in these infants, such as TNF alpha and NF-κB activity. Clinically, this may explain why anti-inflammatory treatments, such as steroids, help some patients with severe COVID-19, while they have not helped patients with RSV, and may even be harmful.
“One very practical implication of our work is that we should not routinely give steroids to infants with RSV,” Mejías said. “RSV is already immunosuppressive; giving steroids that also suppress immunity may further impair the natural killer cell response combating the virus.”
RSV remains the primary cause of infant hospitalizations and the number two cause of infant mortality worldwide. The study’s results and methodology provide a blueprint for better understanding infant immunity in general.
“Globally, five million children die before the age of 5, half occurring in the first months of life due to infection, before vaccines are given,” Ramilo said. “With the tools we have developed, we have shown that we can start to uncover what’s happening in that early immunological window to begin improving those odds.”
