Impaired early type I interferon responses to influenza virus infection in aged mice are associated with subsequent increased pulmonary inflammation

Seasonal influenza is responsible for significant mortality and morbidity worldwide. Seventy to ninety percent of these deaths occur in those aged 65 or older. To determine the innate immune responses to influenza A virus (IAV) infection, young (12-week) and old (70-week) C57BL/6 J mice were infected intranasally (i.n.) with IAV PR8. Immune responses were determined by qRT-PCR and single-cell RNA sequencing (scRNA-seq). Old mice, as compared to young mice, had significantly higher viral loads and lower type I interferon (IFN) expression in the lung at 3 days post-infection (dpi). In contrast, at this time point aged mice had significantly higher amounts of type III IFN expression, which correlated with the higher viral loads observed. Histopathology revealed that IAV infection in old mice resulted in lower pathological scores early (at 5 dpi) and higher lung pathological scores of diseases later (at 7 dpi) than in young mice. scRNA-seq analysis revealed that, at 7 dpi, older mice exhibited sustained local inflammatory responses, with higher expression levels of Ddx58, Irf7, Il6, and Tnf across various immune cells, including macrophages, monocytes, Natural killer cells, dendritic cells, and granulocytes, compared to young mice. Our murine model of aging and influenza infection demonstrated that aging dysregulated early IFN responses to influenza infection resulting in enhanced viral replication. These altered IFN responses in old mice also result in enhanced lung inflammation late after infection and may increase the incidence of secondary bacterial infections seen in older individuals.