Study Reveals Distinct Infant Immune Responses to RSV and SARS-CoV-2

RSV Causes More Severe Illness in Infants Than SARS-CoV-2, Study Reveals

A new study by scientists from St. Jude Children's Research Hospital and The Jackson Laboratory (JAX) has found that young infants hospitalized with respiratory syncytial virus (RSV) often experience more severe illness compared to those infected with SARS-CoV-2. Published in Science Translational Medicine, the research indicates that these two respiratory viruses trigger distinct immune responses in infants, which may account for the varying clinical outcomes and suggest different treatment strategies.

"The study revealed how two respiratory viruses, RSV and SARS-CoV-2, induce different types of immune dysregulation in young infants at chemical, cellular, and epigenetic levels." – Octavio Ramilo, chair of the St. Jude Department of Infectious Diseases and a co-corresponding author.

Unpacking the Study: Methodology and Observations

During the COVID-19 pandemic, physicians observed that infants admitted with RSV infection frequently exhibited more severe symptoms than those hospitalized with SARS-CoV-2. To investigate these differences, researchers compared the immune responses of 19 infants hospitalized with RSV, 30 with SARS-CoV-2, and 17 healthy, age-matched infants. Most participants were approximately two months old.

The study employed single-cell analysis, measuring proteins, genes, and epigenetic signatures in blood samples. This methodology aimed to identify specific immune cells and signals contributing to the observed distinctions in immune responses.

Distinct Immune Response Profiles Emerge

The research identified unique immune response profiles associated with each virus, highlighting fundamental differences in how infants' bodies react.

Severe RSV in infants was linked to:

• Lower levels of systemic inflammation.
• A poorly coordinated early immune response, primarily involving natural killer cells.
• Significantly fewer natural killer cells compared to infants with SARS-CoV-2 infections.
• Reduced production of interferon-gamma by natural killer cells, with this reduction correlating with disease severity. Interferon-gamma is a molecule involved in antiviral responses.
• Lower interferon-gamma expression.
• Reduced activity of key inflammatory signals, including IL-1B and NF-KB.
• Epigenetic reprogramming of parts of the infant immune system, influencing gene activation and deactivation.

Ultimately, RSV was described as contributing to an immunosuppressive state in infants.

In contrast, SARS-CoV-2 generally induced:

• Significant immune dysregulation across multiple cell types.
• A substantial increase in pro-inflammatory molecules, such as TNF alpha and NF-κB activity.

This response was characterized as hyperinflammatory.

Clinical Implications for Treatment

The differing immune responses have profound potential clinical implications for treatment strategies, suggesting that a one-size-fits-all approach may not be effective for young infants battling these viruses.

For SARS-CoV-2, the hyperinflammatory response observed in infected infants may explain why anti-inflammatory treatments, such as steroids, can benefit some patients with severe COVID-19.

However, for RSV, steroids have not been effective for patients and may even be detrimental. Asunción Mejías, from the St. Jude Department of Infectious Diseases and a co-first author, stated that routine administration of steroids to infants with RSV is not advisable because the virus itself is immunosuppressive, and further immune suppression could impair the natural killer cell response.

RSV remains a leading cause of infant hospitalizations and a significant cause of infant mortality globally. The study's findings and methodology provide a crucial framework for enhancing the understanding of infant immunity and could potentially improve outcomes for children who die from infection before age five.

Study Contributors and Funding

Co-corresponding authors of the study include Duygu Ucar and Jacques Banchereau from The Jackson Laboratory, and Asunción Mejías and Octavio Ramilo from St. Jude Children's Research Hospital. Other authors listed include Djamel Nehar-Belaid, Radu Marches, Giray Eryilmaz, and Silke Paust (The Jackson Laboratory); Zhaohui Xu, Steven Josefowicz, and Virginia Pascual (Weill Cornell Medicine); and Bart Jones and Marie Wehenkel (St. Jude).

Funding for the research was provided by grants from the National Institutes of Health (U01 AI131386, U19 AI168632, and U01 AI165452) and the American Lebanese Syrian Associated Charities (ALSAC).