Department of Microbiology and Immunology, University of Illinois College of Medicine, Chicago, Illinois, USA.
Aging Cell. 2023 Apr;22(4):e13796. doi: 10.1111/acel.13796. Epub 2023 Feb 17.
Advanced age is a significant risk factor during viral infection due to an age-associated decline in the immune response. Older individuals are especially susceptible to severe neuroinvasive disease after West Nile virus (WNV) infection. Previous studies have characterized age-associated defects in hematopoietic immune cells during WNV infection that culminate in diminished antiviral immunity. Situated amongst immune cells in the draining lymph node (DLN) are structural networks of nonhematopoietic lymph node stromal cells (LNSCs). LNSCs are comprised of numerous, diverse subsets, with critical roles in the coordination of robust immune responses. The contributions of LNSCs to WNV immunity and immune senescence are unclear. Here, we examine LNSC responses to WNV within adult and old DLNs. Acute WNV infection triggered cellular infiltration and LNSC expansion in adults. Comparatively, aged DLNs exhibited diminished leukocyte accumulation, delayed LNSC expansion, and altered fibroblast and endothelial cell subset composition, signified by fewer LECs. We established an ex vivo culture system to probe LNSC function. Adult and old LNSCs both recognized an ongoing viral infection primarily through type I IFN signaling. Gene expression signatures were similar between adult and old LNSCs. Aged LNSCs were found to constitutively upregulate immediate early response genes. Collectively, these data suggest LNSCs uniquely respond to WNV infection. We are the first to report age-associated differences in LNSCs on the population and gene expression level during WNV infection. These changes may compromise antiviral immunity, leading to increased WNV disease in older individuals.
年龄增长是病毒感染的一个重要危险因素，这是由于免疫系统随年龄增长而衰退。老年人在感染西尼罗河病毒（WNV）后尤其容易发生严重的神经侵袭性疾病。先前的研究已经描述了在 WNV 感染过程中与年龄相关的造血免疫细胞缺陷，最终导致抗病毒免疫力下降。在引流淋巴结（DLN）中的免疫细胞之间，存在着非造血性淋巴结基质细胞（LNSC）的结构网络。LNSC 由许多不同的亚群组成，在协调强大的免疫反应中起着关键作用。LNSC 对 WNV 免疫和免疫衰老的贡献尚不清楚。在这里，我们研究了 LNSC 对成年和老年 DLN 中 WNV 的反应。急性 WNV 感染引发了成年人中的细胞浸润和 LNSC 扩张。相比之下，老年 DLN 表现出白细胞积累减少、LNSC 扩张延迟以及成纤维细胞和内皮细胞亚群组成改变，以更少的 LEC 为特征。我们建立了一个体外培养系统来探究 LNSC 的功能。成年和老年 LNSC 都主要通过 I 型 IFN 信号识别正在进行的病毒感染。成年和老年 LNSC 的基因表达谱相似。发现老年 LNSC 持续上调即刻早期反应基因。总的来说，这些数据表明 LNSC 对 WNV 感染有独特的反应。我们首次报道了在 WNV 感染过程中，LNSC 在群体和基因表达水平上与年龄相关的差异。这些变化可能会损害抗病毒免疫，导致老年人中 WNV 疾病的增加。
