Systems-Level Insights into Age-Dependent Innate Immune Responses in Influenza B Infection
Aging is known to alter innate immune function, increasing susceptibility to viral infections, yet its specific effects on Influenza B virus (IBV) infection remain poorly characterized. To address this gap, we developed a preclinical mouse model using a clinically relevant IBV strain Inf/B/Phuket/3073/2013 to compare innate immune responses between young adult and aged mice, with a particular focus on age-related transcriptional and proteomic alterations in lungs during infection. Bulk RNA sequencing and proteomics analysis of lung tissue harvested post-infection revealed distinct age-dependent transcriptional profiles. In young adult mice, IBV infection induced 170 differentially expressed genes (DEGs) compared to age-matched controls, whereas aged mice showed a markedly heightened response with 4,195 DEGs, reflecting widespread transcriptional dysregulation. Functional enrichment of these DEGs indicated perturbations in innate immune signalling, apoptosis, and pathways related to cellular stress and DNA damage in aged mice. There are several differentially expressed proteins have been identified in young adult and aged influenza B infection. Among these differentially expressed proteins, some commonly co-expressed proteins have a role in virus entry, signalling pathways, and interferon response. Real-time PCR analysis confirmed altered expression of key innate immune genes, including Toll-like receptors (TLRs), interferon regulatory factors (IRF7 and IRF9), and type I and II interferons (IFN-alpha, IFN-beta, IFN-gamma). Notably, young adult mice exhibited a more coordinated and robust activation of antiviral pathways, whereas aged mice demonstrated delayed and aberrant immune responses, characterized by excessive inflammation and impaired interferon signalling.