{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T18:32:57Z","timestamp":1768501977019,"version":"3.49.0"},"posted":{"date-parts":[[2023,1,5]]},"group-title":"Immunology","reference-count":45,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,1,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  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\n                  <jats:italic>ex vivo<\/jats:italic>\n                  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.\n                <\/jats:p>","DOI":"10.1101\/2023.01.05.522898","type":"posted-content","created":{"date-parts":[[2023,1,7]],"date-time":"2023-01-07T05:41:28Z","timestamp":1673070088000},"source":"Crossref","is-referenced-by-count":0,"title":["Type I IFN stimulates lymph node stromal cells from adult and old mice during a West Nile virus infection"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3376-8329","authenticated-orcid":false,"given":"Allison K.","family":"Bennett","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5344-118X","authenticated-orcid":false,"given":"Michelle","family":"Richner","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Madeline D.","family":"Mun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Justin M.","family":"Richner","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2023010822300722000_2023.01.05.522898v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cyto.2010.01.009"},{"key":"2023010822300722000_2023.01.05.522898v1.2","unstructured":"Babraham Bioinformatics\u2014FastQC A Quality Control tool for High Throughput Sequence Data. (n.d.). Retrieved January 24, 2022, from https:\/\/www.bioinformatics.babraham.ac.uk\/projects\/fastqc\/"},{"key":"2023010822300722000_2023.01.05.522898v1.3","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.jbior.2016.05.001","article-title":"Gene regulation in the immediate-early response process","volume":"62","year":"2016","journal-title":"Advances in Biological Regulation"},{"issue":"9","key":"2023010822300722000_2023.01.05.522898v1.4","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1038\/s43587-021-00114-7","article-title":"SARS-CoV-2, COVID-19 and the aging immune system","volume":"1","year":"2021","journal-title":"Nature Aging"},{"issue":"1","key":"2023010822300722000_2023.01.05.522898v1.5","first-page":"15D.3.1","article-title":"Propagation, Quantification, Detection, and Storage of West Nile Virus","volume":"31","year":"2013","journal-title":"Current Protocols in Microbiology"},{"key":"2023010822300722000_2023.01.05.522898v1.6","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20090222"},{"key":"2023010822300722000_2023.01.05.522898v1.7","unstructured":"Centers for Disease Control and Prevention (CDC). (2019, October 19). Average annual incidence of West Nile virus neuroinvasive disease reported to CDC by age group, 1999-2018. West Nile Virus. https:\/\/www.cdc.gov\/westnile\/statsmaps\/cumMapsData.html"},{"key":"2023010822300722000_2023.01.05.522898v1.8","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkp427"},{"key":"2023010822300722000_2023.01.05.522898v1.9","doi-asserted-by":"crossref","unstructured":"Cho, H. , Proll, S. C. , Szretter, K. J. , Katze, M. G. , Gale, M. , & Diamond, M. S. (2013). Differential innate immune response programs in neuronal subtypes determine susceptibility to infection in the brain by positive-stranded RNA viruses. 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