COVID-19 International Research Team, Medford, MA 02155.
Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287.
Proc Natl Acad Sci U S A. 2024 Dec 3;121(49):e2401968121. doi: 10.1073/pnas.2401968121. Epub 2024 Nov 27.
Lethal COVID-19 outcomes are attributed to classic cytokine storm. We revisit this using RNA sequencing of nasopharyngeal and 40 autopsy samples from patients dying of SARS-CoV-2. Subsets of the 100 top-upregulated genes in nasal swabs are upregulated in the heart, lung, kidney, and liver, but not mediastinal lymph nodes. Twenty-two of these are "noncanonical" immune genes, which we link to components of the renin-angiotensin-activation-system that manifest as increased fibrin deposition, leaky vessels, thrombotic tendency, PANoptosis, and mitochondrial dysfunction. Immunohistochemistry of mediastinal lymph nodes reveals altered architecture, excess collagen deposition, and pathogenic fibroblast infiltration. Many of the above findings are paralleled in animal models of SARS-CoV-2 infection and human peripheral blood mononuclear and whole blood samples from individuals with early and later SARS-CoV-2 variants. We then redefine cytokine storm in lethal COVID-19 as driven by upstream immune gene and mitochondrial signaling producing downstream RAAS (renin-angiotensin-aldosterone system) overactivation and organ damage, including compromised mediastinal lymph node function.
COVID-19 的致命后果归因于经典的细胞因子风暴。我们使用来自死于 SARS-CoV-2 的患者的鼻咽和 40 个尸检样本的 RNA 测序重新研究了这一点。鼻拭子中上调的前 100 个上调基因的子集在心脏、肺、肾和肝中上调，但纵隔淋巴结没有上调。其中 22 个是“非典型”免疫基因，我们将其与肾素-血管紧张素-激活系统的成分联系起来，这些成分表现为纤维蛋白沉积增加、血管渗漏、血栓倾向、PANoptosis 和线粒体功能障碍。纵隔淋巴结的免疫组织化学显示出改变的结构、过多的胶原蛋白沉积和病理性成纤维细胞浸润。上述许多发现与 SARS-CoV-2 感染的动物模型以及个体早期和晚期 SARS-CoV-2 变异的外周血单核细胞和全血样本中存在的情况相平行。然后，我们将致命 COVID-19 中的细胞因子风暴重新定义为上游免疫基因和线粒体信号驱动的，导致下游 RAAS（肾素-血管紧张素-醛固酮系统）过度激活和器官损伤，包括纵隔淋巴结功能受损。
