Transcriptomic analysis of neonatal vs. adult lung early responses to RSV reveals key roles for DC and type I IFN in controlling immunopathologic imprinting.
Résumé
The human respiratory syncytial virus (hRSV) causes severe bronchiolitis in infants worldwide. However, despite decades of research, immunological factors responsible for RSV susceptibility in infants are still poorly understood. Recently, we have characterized the neonatal lung environment in BALB/c mice at steady state, showing both the scarcity of lung dendritic cells (DC) and a pattern of cytokines and transcription factors suggestive of a Th2 bias [1]. We decided to use a global transcriptomic approach to gain more insight into neonatal innate immunity to RSV. The gene expression profile of neonatal versus adult lung, 2 days after an RSV or mock infection was analyzed using whole mouse genome agilent microarrays. Interestingly we found major differences in gene expression profile upon RSV infection according to age. Newborn mice were deficient for major pathways like interferon, had delayed DC recruitment and showed airway remodelling. Transcriptomic data were confirmed and extended by real-time PCR, ELISA, flow cytometry and immunohistological assays. Treatment with Flt3-L during the neonatal period prior to RSV infection, increased lung DC number, and partly restored the IFN pathways up to an “adult-like” response. The pathological imprinting of an RSV neonatal infection is revealed by enhanced airway pathology upon reinfection at adult age [2]. Neonates treated with Flt3-L prior to the primary RSV infection were protected against enhanced weight loss and airway inflammation upon reinfection. Thus we reveal a key role for lung DC and IFN pathway deficiency in immunopathological response of neonates to RSV infection.