Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI, 53226, USA.
Blood Research Institute, Versiti Wisconsin, Milwaukee, WI, 53226, USA.
Nat Commun. 2023 Oct 18;14(1):6597. doi: 10.1038/s41467-023-42021-y.
Influenza virus infection causes increased morbidity and mortality in the elderly. Aging impairs the immune response to influenza, both intrinsically and because of altered interactions with endothelial and pulmonary epithelial cells. To characterize these changes, we performed single-cell RNA sequencing (scRNA-seq), spatial transcriptomics, and bulk RNA sequencing (bulk RNA-seq) on lung tissue from young and aged female mice at days 0, 3, and 9 post-influenza infection. Our analyses identified dozens of key genes differentially expressed in kinetic, age-dependent, and cell type-specific manners. Aged immune cells exhibited altered inflammatory, memory, and chemotactic profiles. Aged endothelial cells demonstrated characteristics of reduced vascular wound healing and a prothrombotic state. Spatial transcriptomics identified novel profibrotic and antifibrotic markers expressed by epithelial and non-epithelial cells, highlighting the complex networks that promote fibrosis in aged lungs. Bulk RNA-seq generated a timeline of global transcriptional activity, showing increased expression of genes involved in inflammation and coagulation in aged lungs. Our work provides an atlas of high-throughput sequencing methodologies that can be used to investigate age-related changes in the response to influenza virus, identify novel cell-cell interactions for further study, and ultimately uncover potential therapeutic targets to improve health outcomes in the elderly following influenza infection.
流感病毒感染会导致老年人发病率和死亡率增加。衰老会损害对流感的免疫反应，这既源于内在因素，也源于与内皮细胞和肺上皮细胞相互作用的改变。为了描述这些变化，我们对年轻和老年雌性小鼠在流感感染后 0、3 和 9 天的肺部组织进行了单细胞 RNA 测序（scRNA-seq）、空间转录组学和批量 RNA 测序（bulk RNA-seq）。我们的分析确定了数十个在动力学、年龄依赖性和细胞类型特异性方面差异表达的关键基因。衰老的免疫细胞表现出改变的炎症、记忆和趋化特性。衰老的内皮细胞表现出血管愈合减少和促血栓形成状态的特征。空间转录组学鉴定了上皮细胞和非上皮细胞表达的新型促纤维化和抗纤维化标记物，突出了促进老年肺部纤维化的复杂网络。批量 RNA-seq 生成了一个全局转录活性的时间线，显示出衰老肺部中与炎症和凝血相关的基因表达增加。我们的工作提供了一个高通量测序方法的图谱，可以用于研究流感病毒感染后对年龄相关变化的反应，确定进一步研究的新的细胞-细胞相互作用，并最终发现改善流感感染后老年人健康结果的潜在治疗靶点。
