1. Lethal COVID-19 associates with RAAS-induced inflammation for multiple organ damage including mediastinal lymph nodes.
- Author
-
Topper MJ, Guarnieri JW, Haltom JA, Chadburn A, Cope H, Frere J, An J, Borczuk A, Sinha S, Kim J, Park J, Butler D, Meydan C, Foox J, Bram Y, Richard SA, Epsi NJ, Agan B, Chenoweth JG, Simons MP, Tribble D, Burgess T, Dalgard C, Heise MT, Moorman NJ, Baxter VK, Madden EA, Taft-Benz SA, Anderson EJ, Sanders WA, Dickmander RJ, Beigel K, Widjaja GA, Janssen KA, Lie T, Murdock DG, Angelin A, Soto Albrecht YE, Olali AZ, Cen Z, Dybas J, Priebe W, Emmett MR, Best SM, Kelsey Johnson M, Trovao NS, Clark KB, Zaksas V, Meller R, Grabham P, Schisler JC, Moraes-Vieira PM, Pollett S, Mason CE, Syrkin Wurtele E, Taylor D, Schwartz RE, Beheshti A, Wallace DC, and Baylin SB
- Subjects
- Humans, Animals, Inflammation pathology, Cytokine Release Syndrome pathology, Mediastinum pathology, Male, Mice, COVID-19 pathology, COVID-19 immunology, COVID-19 virology, COVID-19 metabolism, Renin-Angiotensin System, Lymph Nodes pathology, Lymph Nodes metabolism, SARS-CoV-2
- 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., Competing Interests: Competing interests statement:R.E.S. is on the scientific advisory of Miromatrix, Inc. and Lime Therapeutics and is a consultant for Alnylam, Inc. D.C.W. is on the scientific advisory boards of Pano Therapeutics, Inc., and Medical Excellent Capital.
- Published
- 2024
- Full Text
- View/download PDF