Bennett Allison K, Richner Michelle, Mun Madeline D, Richner Justin M
bioRxiv. 2023 Jan 5:2023.01.05.522898. doi: 10.1101/2023.01.05.522898.
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 adult. 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 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.
由于免疫反应随年龄增长而下降，高龄是病毒感染期间的一个重要风险因素。老年人在感染西尼罗河病毒（WNV）后尤其易患严重的神经侵袭性疾病。先前的研究已经描述了WNV感染期间造血免疫细胞中与年龄相关的缺陷，这些缺陷最终导致抗病毒免疫力下降。位于引流淋巴结（DLN）中的免疫细胞之间的是非造血淋巴结基质细胞（LNSC）的结构网络。LNSC由众多不同的亚群组成，在协调强大的免疫反应中起关键作用。LNSC对WNV免疫和免疫衰老的贡献尚不清楚。在这里，我们研究了成年和老年DLN中LNSC对WNV的反应。急性WNV感染引发了成年DLN中的细胞浸润和LNSC扩增。相比之下，老年DLN表现出白细胞积累减少、LNSC扩增延迟以及成纤维细胞和内皮细胞亚群组成改变，表现为LEC减少。我们建立了一个培养系统来探究LNSC的功能。成年和老年LNSC主要通过I型干扰素信号识别正在进行的病毒感染。成年和老年LNSC之间的基因表达特征相似。发现老年LNSC组成性上调立即早期反应基因。总体而言，这些数据表明LNSC对WNV感染有独特的反应。我们是第一个报告WNV感染期间LNSC在群体水平和基因表达水平上与年龄相关差异的。这些变化可能会损害抗病毒免疫力，导致老年人的WNV疾病增加。
