Aging is associated with an insufficient early inflammatory response of lung endothelial cells in SARS-CoV-2 infection

作者：Saravanan Subramaniam, Devin Kenney, Archana Jayaraman, Aoife K. O’Connell, Sarah Walachowski, Paige Montanaro, Christoph Reinhardt, Giuseppe Colucci, Nicholas A. Crossland, Florian Douam, Markus Bosmann · 发表于：Frontiers in Immunology · 年份：2024 · DOI：10.3389/fimmu.2024.1397990 · 被引用次数：8 · 研究领域：Inflammation biomarkers and pathways、COVID-19 Clinical Research Studies、Long-Term Effects of COVID-19

Advanced age is associated with an increased susceptibility to Coronavirus Disease (COVID)-19 and more severe outcomes, although the underlying mechanisms are understudied. The lung endothelium is located next to infected epithelial cells and bystander inflammation may contribute to thromboinflammation and COVID-19-associated coagulopathy. Here, we investigated age-associated SARS-CoV-2 pathogenesis and endothelial inflammatory responses using humanized K18-hACE2 mice. Survival was reduced to 20% in aged mice (85–112 weeks) versus 50% in young mice (12–15 weeks) at 10 days post infection (dpi). Bulk RNA-sequencing of endothelial cells from mock and infected mice at 2dpi of both age groups (aged: 72–85 weeks; young: 15 weeks) showed substantially lower significant differentially regulated genes in infected aged mice than in young mice (712 versus 2294 genes). Viral recognition and anti-viral pathways such as RIG-I-like receptor signaling, NOD-like receptor signaling and interferon signaling were regulated in response to SARS-CoV-2. Young mice showed several fold higher interferon responses ( Ifitm3 , Ifit1 , Isg15, Stat1 ) and interferon-induced chemokines ( Cxcl10 and Cxcl11 ) than aged mice. Endothelial cells from infected young mice displayed elevated expression of chemokines ( Cxcl9 , Ccl2 ) and leukocyte adhesion markers ( Icam1 ) underscoring that inflammation of lung endothelium during infection could facilitate leukocyte adhesion and thromboinflammation. TREM1 and acut...