Lethal COVID-19 associates with RAAS-induced inflammation for multiple organ damage including mediastinal lymph nodes

2024/11/27 by Michael J. Topper, Joseph W. Guarnieri, Jeffrey Haltom +57 · 2 voices · 21 citations
Biochemistry, Genetics and Molecular Biology · Medicine · #Biology #COVID-19 Clinical Research Studies #Cancer #Coronavirus disease 2019 (COVID-19) #Cytokine storm #Dermatological and COVID-19 studies #Immune system #Immunology #Inflammasome and immune disorders #Inflammation #Internal medicine #Lung #Lymph #Lymph node #Mediastinal lymph node #Medicine #Pathology

paper · pdf · doi:10.1073/pnas.2401968121

published in Proceedings of the National Academy of Sciences 121(49), e2401968121 (National Academy of Sciences)

openalex publication_date 2024/11/27 · openalex created_date 2025/10/10 · openalex updated_date 2026/08/01

Abstract

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.

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Discussions

• This study shows how severe COVID causes widespread organ damage, driven by immune & mitochondrial dysfunction that disrupts systems like the RAAS pathway. It highlights lymph node fibrosis, which wea [bsky, 122 points, 4 comments]
• Lethal COVID-19 associates with RAAS-induced inflammation for multiple organ damage including mediastinal lymph nodes PNAS doi.org/10.1073/pnas... [bsky, 0 points, 0 comments]

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