Differential Antiviral Effects and Immune Responses in Nasal and Airway Organoid During RSV Infection: Implications for Interferon Therapy

Linmei Wang¹Lina Chen¹Lin Yang¹Yanan Hu^1,2Danli Lu¹You Duan³Li Qiu¹Yan Li¹Rui Zhang¹Hanmin Liu^1*Wenhao Yang^1*

• ¹Department of Pediatric Pulmonology and Immunology, Sichuan University West China Second University Hospital, Chengdu, China
• ²NHC Key Laboratory of Chronobiology, Sichuan University, Chengdu, China
• ³Key Laboratory of Birth Defects and Related Diseases of Women and Children,Ministry of Education,, Sichuan University, Chengdu, China

Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infections in infants and young children, and it constitutes a significant risk factor for the development of bronchiolitis and subsequent childhood asthma. The severity of the disease is notably higher in infants compared to adults, underscoring the urgent need for effective therapeutic interventions. In our study, we utilized pediatric nasal and airway epithelial organoids to demonstrate that both type I and type III interferons (IFNs) markedly reduce viral load and downregulate key inflammatory mediators, including IL-6, CXCL8, IL-1α, and TNF, during RSV infection. Through transcriptome sequencing and multiplex cytokine profiling of 46 immune mediators, we observed a more robust immune response in the nasal epithelium compared to the airway epithelium. Notably, IFN-λ1 was most effective in suppressing inflammation in the nasal epithelium, whereas IFN-β did not exacerbate inflammatory responses in the airway epithelium. These findings provide novel insights for optimizing clinical IFN therapy, particularly in terms of selecting the appropriate interferon type, delivery site, and dosing strategy.