Respiratory syncytial virus (RSV) infection makes an impact on the epithelium that varies with age, promoting asthma in children and chronic obstructive pulmonary disease (COPD) in adults, according to new data presented at a global conference sponsored by the Respiratory Syncytial Virus Foundation.

RSV remains a major cause of hospitalizations in children and is associated with an increased risk of developing asthma. RSV also contributes to significant morbidity in adults with chronic respiratory conditions, such as COPD, but the molecular and cellular basis of age-specific responses to RSV infection are not well understood, according to lead author Anubama Rajan, MD, of the Medical Sciences and Technology, Indian Institute of Technology Madras, Medical Sciences and Technology, Chennai, India.

“Understanding how infants, children, and adults respond differently to RSV at the epithelial level is critical, especially in a landscape where effective vaccines and broadly accessible antivirals are still limited,” Rajan told Medscape Medical News. “Defining age-specific epithelial programs can directly inform the development of targeted preventive and therapeutic strategies tailored to vulnerable populations,” she said.

Understanding Epithelial Response

To investigate age-specific epithelial responses to RSV, Rajan and colleagues used lab-grown models of nasal tissue for adults and infants. They performed single-cell RNA sequencing on these human nasal organoids (HNOs) to compare mock controls and periods of peaks infection for two strains of RSV, RSV/A/Ontario and RSV/B/Buenos Aires.

The infant HNOs showed widespread overproduction of the primary mucus components MUC5AC and MUC5B, which is consistent with the hypersecretion of mucus often found in infants with RSV, the researchers noted. The genetic analysis showed that sets of genes related to antigen presentation (HLA-DRA, HLA-DRB1, HLA-DQA1) and type 2 inflammation (interleukin [IL]-13, IL-5, FCER1G) appeared more often than expected in the secretory and basal cells of the infant HNOs. These findings suggest a pathway for how overactive Th2 contributes to the chronic airway inflammation, mucus production, and wheezing that characterize asthma in children.

RSV infection significantly altered epithelial composition in an age-dependent manner. Infant HNOs exhibited broad upregulation of MUC5AC and MUC5B across multiple secretory cell subtypes, consistent with mucus hypersecretion commonly detected in infants infected with RSV. In addition, the protein CXCL10, associated with triggering inflammation, was elevated in mucus-producing goblet cells in the infant models, which suggests a proinflammatory goblet cell subtype, the researchers noted.

By contrast, in the adult models, the HNOs showed high levels of activity in genes related to COPD such as CXCL8 (IL-8), SERPINB2, PTGS2, and CREB3L1, especially in secretory and basal cells; this was consistent with the immune response and epithelial changes that occur with COPD exacerbations.

In both infant and adult organoid models, RSV mainly targeted the ciliated cells lining the airways that help clear mucus, notably the primary ciliated cells and mucociliary hybrid cells. However, the infant HNOs supported RSV replication in two rare epithelial subtypes, KRT23+ activated basal cells and FOXI1+ ionocytes, that are not usually infected in adults, the researchers wrote.

Unexpected Age Differences

“We were genuinely surprised by the extent of age-dependent epithelial permissiveness to RSV,” Rajan told Medscape Medical News. “In particular, pediatric and infant nasal organoid systems showed broader RSV tropism, including infection of activated basal cells and ionocytes, cell types not typically considered primary RSV targets,” she said. “This unexpected vulnerability suggests that early-life airway epithelium may be intrinsically more permissive to RSV, providing a mechanistic explanation for severe disease in infants,” Rajan added.

“Our data uncover distinct transcriptional programs induced by RSV in infant vs adult nasal epithelium, mirroring asthma- and COPD-like molecular signatures, respectively,” said Rajan. The findings provide a foundation for age-tailored therapies aimed at preventing or mitigating chronic airway diseases linked to RSV infection, she said.

Several key research questions remain, said Rajan. “It is critical to determine whether these age-specific responses reflect intrinsic differences in epithelial cell states or are purely driven by viral-host interactions,” she said. “Future studies should explore whether these responses are reversible, how they influence long-term airway remodeling, and how epithelial signals shape downstream immunity,” she said. “Importantly, our current data focus on epithelial responses; co-culture systems incorporating immune cells and longitudinal studies will be essential to fully understand RSV-driven immunopathogenesis,” Rajan added.

Support for Clinical Experience

“In recent years, recognition of RSV in adults has increased, in part because of broader respiratory viral testing that became more routine after the COVID-19 pandemic,” said Seyedmohammad (Omid) Pourshahid, MD, MPH, assistant professor of clinical thoracic medicine and surgery at the Lewis Katz School of Medicine at Temple University, Philadelphia. “Molecular-level studies of airway epithelium help clarify how RSV drives inflammation and exacerbations in adults, which is essential for improving prevention and treatment strategies, said Pourshahid, who also serves as medical director of pulmonary rehabilitation at Temple University Hospital.

“The molecular findings align with established clinical observations rather than contradicting them,” Pourshahid told Medscape Medical News. The adult inflammatory patterns described in the current study are consistent with what is known clinically that RSV is associated with COPD exacerbations and neutrophil-predominant airway inflammation in adults, he said.

The study findings support consideration of RSV as a clinically meaningful adult respiratory pathogen, particularly in older adults and those with chronic cardiopulmonary disease, and disease prevention is critical, said Pourshahid. Current CDC guidance recommends RSV vaccination for all adults aged 75 years or older, and for adults aged 50-74 years who are at increased risk, including those with chronic lung disease, he added.

Prospective studies in adults are needed to link molecular airway responses to clinical outcomes such as hospitalization, exacerbation frequency, and lung function decline, said Pourshahid. “Integrating mechanistic data with longitudinal clinical follow-up will help determine whether modifying RSV risk through vaccination or future therapies changes disease trajectories,” he said.

The study was funded by grants from the National Institutes of Health (NIH) and an India Alliance-DBT Wellcome grant. The study also received support from the Baylor College of Medicine Genomic/RNA Profiling, Cytometry, and Integrated Microscopy Cores grants, which are supported by NIH.

The researchers and Pourshahid disclosed having no financial conflicts of interest.