Wu Wenxin, Alexander Jeremy S, Booth J Leland, Huang Chaoqun, Liu Lin, Miller Craig A, Drevets Douglas A, Metcalf Jordan P
Pulmonary, Critical Care & Sleep Medicine, Department of Medicine, University of Oklahoma Health Sciences Center, Room 425, 800 N. Research Pkwy, Oklahoma City, OK, 73104, USA.
The Lundberg-Kienlen Lung Diseases and Infection Laboratory, Department of Physiological Sciences, Oklahoma State University, Stillwater, OK, USA.
Geroscience. 2025 Sep 23. doi: 10.1007/s11357-025-01892-3.
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.
季节性流感在全球范围内导致了严重的死亡率和发病率。其中70%至90%的死亡发生在65岁及以上的人群中。为了确定对甲型流感病毒（IAV）感染的先天免疫反应，将年轻（12周龄）和年老（70周龄）的C57BL/6 J小鼠经鼻内（i.n.）感染IAV PR8。通过qRT-PCR和单细胞RNA测序（scRNA-seq）确定免疫反应。与年轻小鼠相比，年老小鼠在感染后3天（dpi）时肺部的病毒载量显著更高，I型干扰素（IFN）表达更低。相反，在这个时间点，老年小鼠的III型IFN表达量显著更高，这与观察到的更高病毒载量相关。组织病理学显示，与年轻小鼠相比，老年小鼠的IAV感染在早期（5 dpi）导致更低的病理评分，而在后期（7 dpi）导致更高的肺部疾病病理评分。scRNA-seq分析显示，在7 dpi时，与年轻小鼠相比，老年小鼠表现出持续的局部炎症反应，在包括巨噬细胞、单核细胞、自然杀伤细胞、树突状细胞和粒细胞在内的各种免疫细胞中，Ddx58、Irf7、Il6和Tnf的表达水平更高。我们的衰老和流感感染小鼠模型表明，衰老会使对流感感染的早期IFN反应失调，从而导致病毒复制增强。老年小鼠中这些改变的IFN反应还会导致感染后期肺部炎症增强，并可能增加老年个体中继发细菌感染的发生率。
