The Annual Review of Research 2024 (ARR2024), organized by inStem (Institute for Stem Cell Science and Regenerative Medicine), brought together some of the brightest minds in biotechnology to discuss cutting-edge research and its potential impact on health sciences. Dr. Anubama Rajan presented her pioneering research on Respiratory Syncytial Virus (RSV) in a talk titled “Age-Related Differences and Unique Tropism of RSV in Human Nasal Organoids.”

RSV is a leading cause of infant mortality worldwide, particularly affecting young children due to their heightened vulnerability. Dr. Rajan’s research aimed to uncover why children experience more severe infections and how age-related differences play a critical role in RSV’s impact on the airway epithelium.

During her talk, Dr. Rajan discussed her team’s innovative approach using human nasal organoids (HNOs) to study RSV infection. By employing single-cell transcriptomic analysis on both adult and pediatric HNOs, the research identified key differences in cellular responses to RSV between age groups. 

Understanding RSV and Its Impact on Different Age Groups

Respiratory Syncytial Virus (RSV) is recognized globally as a leading cause of infant mortality, particularly affecting young children with greater severity. Dr. Rajan’s research delves into why the infection manifests more aggressively in pediatric patients compared to adults. The crux of her study lies in exploring how RSV interacts with various cell types within the human airway epithelium and how these interactions differ with age.

Innovative Use of Human Nasal Organoids

To investigate these age-related differences, Dr. Rajan’s team utilized human nasal organoids (HNOs) derived from both adult and pediatric donors. These organoids mimic the complex structure and function of the human nasal epithelium, providing a sophisticated model to study viral infections at a cellular level.

Key Findings from Single-Cell Transcriptomic Analysis

Employing single-cell transcriptomic analysis, the research uncovered significant disparities in how adult and pediatric HNOs respond to RSV infection:

• Cellular Differentiation and Proliferation: There were notable differences in gene expression related to how cells differentiate and proliferate between the two age groups.
• Innate Immune Response: Pediatric HNOs exhibited a lower and more dysregulated innate immune response to RSV, potentially explaining the increased severity of infections in young children.
• Cell Type Susceptibility: While RSV is known to primarily infect ciliated cells, the study identified the primary ciliary cells as the most susceptible subtype. Unexpectedly, in pediatric HNOs, RSV also infected other cell types like basal cells and ionocytes/tuft cells, which had not been prominently associated with RSV infection before.

Implications for Therapeutic and Vaccine Development

These findings are groundbreaking as they provide the first comprehensive HNO cell atlas detailing RSV infection at a single-cell level. Further, the study highlights the importance of age-specific cellular responses in RSV infections. It also identifies new target cells for therapeutic intervention, which could lead to the development of more effective treatments and vaccines tailored for pediatric patients.

The objective of the study was to address two key questions:
1. Are there differences in RSV infection/tropism between an adult and a pediatric HNO?
2. What happens to the apical ciliated cells during RSV infection and are they the only cell type susceptible to RSV infection?

Key Findings:

• Model System: Human Nose Organoids, retaining individual genetic backgrounds, were used to mimic the respiratory epithelium, allowing detailed study of RSV infection through single-cell RNA sequencing.
• Cellular Differences: Pediatric nasal epithelium exhibits more cell clusters and a higher proportion of proliferative basal stem cells than adults, indicating a more active growth phase and potentially explaining increased RSV severity in children.
• Target Cells: RSV primarily infects primary ciliary cells in both adults and children. However, in children, RSV also targets basal cells and ionocytes, unlike in adults.
• Novel Discoveries: New RSV tropism for activated basal cells and ionocytes in pediatric samples was identified, highlighting the complex nature of RSV infection.

Conclusion:
Dr. Rajan’s research provided valuable insights into the cellular mechanisms underlying RSV infection severity in children. By using advanced organoid models and single-cell sequencing, her team has uncovered critical differences in RSV tropism and cellular responses between adults and pediatric patients. These findings pave the way for developing targeted therapeutic strategies to combat RSV in children, potentially leading to more effective treatments and better clinical outcomes.