Researchers at University College London (UCL) Great Ormond Street Hospital for Children (GOSH) have built a new lab model of infant lungs to show why respiratory syncytial virus (RSV) makes infants so much sicker than adults, and to allow them to test new treatments. The miniature model of a baby’s airways was created using pediatric airway cells, blood vessel cells, and neutrophils (a type of white blood cell that acts as the immune system’s primary response to infection).
Studies using the new model suggest that future therapies for RSV should target both the virus and its immune response to ensure babies get the best possible outcomes. Research lead Claire Smith, PhD, at UCL Great Ormond Street Institute of Child Health, said, “This model allows us to watch early immune responses unfold and study them in a human setting that reflects the infant airway. That’s something animal models often struggle to capture, especially when it comes to age-specific effects.”
Senior and corresponding author Smith and colleagues reported on their findings in Nature Communications in a paper titled “Neutrophil myeloperoxidase as a functional biomarker for RSV severity: implications for in vitro therapeutic screening.” In their report they concluded, “These findings identify neutrophil–epithelial interactions as a useful target for intervention and support the use of physiologically relevant human models to accelerate the development of therapies that limit immunopathology while preserving antiviral defense.”
RSV is the biggest cause of severe respiratory tract infections in infants and young children, resulting in over three million hospital admissions worldwide every year. RSV infection causes wheezing and breathing difficulties, and in the worst cases infants end up in intensive care. Despite this, treatment options for severe RSV disease remain extremely limited. “The lack of accessible, effective therapies highlights the need for continued advancements in RSV treatment and prevention,” the authors wrote.
During RSV infection neutrophils are rapidly mobilized to the lungs and play a key role in virus-targeting host defenses, the investigators continued. However, excessive neutrophil infiltration and activation can also contribute to airway inflammation, epithelial damage, and disease severity. “Understanding neutrophil behavior and activation during RSV infection, including during their migration across the airway epithelial barrier, is crucial for developing therapeutic strategies to mitigate pathological inflammation without compromising the antiviral response,” they suggested.
For their reported study the team aimed to create an in vitro model that recapitulates key clinical outcomes of infants with RSV bronchiolitis. To do this they established an air-liquid interface (ALI) system that incorporated pediatric airway epithelial cells, endothelial cells, and neutrophils from adults, to mirror the blood-airway barrier. “Differentiated airway epithelial cells (AECs) cultured at the air–liquid interface (ALI) provide a physiologically relevant platform to study neutrophil migration and the effect of antiviral treatments on this process,” they note. To compare with an adult response to RSV, the research team also made a model of an adult’s airways.
When the models were infected with RSV, the team found that the pediatric airway cells attracted far more white blood cells than did the adult airway cells. This influx can block an infant’s small airways and make it harder for them to breathe.
Neutrophils normally circulate in the blood but enter lung tissue in response to infection. In the baby airway model, researchers found that the neutrophils that entered the lung tissue were more activated and triggered a stronger inflammatory reaction than in the adult model. This effect was dependent on the immune cells physically moving through the infected tissue, not just responding to chemical signals released by it, making this type of model essential for study.
The results suggest that it is the infant airway itself, not just the virus, that ramps up the immune response and causes damage to the lungs. First author Machaela Palor, PhD, at UCL Great Ormond Street Institute of Child Health, said: “These findings help explain why RSV is often much more severe in infants than in adults. The pediatric airway actively shapes how immune cells behave during the infection.”
The researchers tested two antiviral drugs (remdesivir and RSV604). they found that both stopped the virus from multiplying, but only RSV604 also calmed the overactive immune response, reducing levels of a key inflammatory protein myeloperoxidase (MPO) released by white blood cells—high levels of which are linked to more severe RSV disease in babies. Remdesivir had no effect on this, suggesting that not all antivirals are equal when it comes to protecting the infant airway from immune-driven damage. “While both drugs reduced viral load, only RSV604 attenuated MPO expression,” the team stated.
The findings suggest that treating severe RSV in babies may require more than just stopping the virus—it may also be important to calm an overactive immune response. “This model suggests that MPO could be useful as a readout of therapeutic efficacy,” the team stated. “Targeting neutrophil-driven inflammatory pathways may be critical for reducing pathology in infant RSV infection.”
The researchers hope their findings and the new approach to research on RSV will accelerate the development of treatments better tailored to infants. “Our model gives us a way to assess both sides of the problem at once,” Smith said. “We can not only ask whether the drug stops the virus but also whether it helps control immune response in the infant airway. “This work reinforces the idea that age matters in respiratory infection. Understanding how infant airways shape immune responses will be key to designing safer and more effective RSV treatments.”
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