Proc Natl Acad Sci U S A . Lethal COVID-19 associates with RAAS-induced inflammation for multiple organ damage including mediastinal lymph nodes

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

Michael J Topper[SUP] #[/SUP][SUP] 1 2 [/SUP], Joseph W Guarnieri[SUP] #[/SUP][SUP] 1 3 4 [/SUP], Jeffrey A Haltom[SUP] 1 3 4 [/SUP], Amy Chadburn[SUP] 5 [/SUP], Henry Cope[SUP] 6 [/SUP], Justin Frere[SUP] 7 [/SUP], Julia An[SUP] 1 2 [/SUP], Alain Borczuk[SUP] 8 [/SUP], Saloni Sinha[SUP] 8 [/SUP], JangKeun Kim[SUP] 8 [/SUP], Jiwoon Park[SUP] 8 [/SUP], Daniel Butler[SUP] 8 [/SUP], Cem Meydan[SUP] 8 [/SUP], Jonathan Foox[SUP] 8 [/SUP], Yaron Bram[SUP] 8 [/SUP], Stephanie A Richard[SUP] 9 10 [/SUP], Nusrat J Epsi[SUP] 9 10 [/SUP], Brian Agan[SUP] 9 10 [/SUP], Josh G Chenoweth[SUP] 10 [/SUP], Mark P Simons[SUP] 9 [/SUP], David Tribble[SUP] 9 [/SUP], Timothy Burgess[SUP] 9 [/SUP], Clifton Dalgard[SUP] 11 [/SUP], Mark T Heise[SUP] 12 [/SUP], Nathaniel J Moorman[SUP] 12 [/SUP], Victoria K Baxter[SUP] 12 [/SUP], Emily A Madden[SUP] 12 [/SUP], Sharon A Taft-Benz[SUP] 12 [/SUP], Elizabeth J Anderson[SUP] 12 [/SUP], Wes A Sanders[SUP] 12 [/SUP], Rebekah J Dickmander[SUP] 12 [/SUP], Katherine Beigel[SUP] 1 3 13 [/SUP], Gabrielle A Widjaja[SUP] 1 3 4 [/SUP], Kevin A Janssen[SUP] 1 3 4 [/SUP], Timothy Lie[SUP] 1 3 4 [/SUP], Deborah G Murdock[SUP] 1 3 4 [/SUP], Alessia Angelin[SUP] 1 3 4 [/SUP], Yentli E Soto Albrecht[SUP] 1 3 4 14 [/SUP], Arnold Z Olali[SUP] 1 3 4 [/SUP], Zimu Cen[SUP] 1 3 4 [/SUP], Joseph Dybas[SUP] 1 3 [/SUP], Waldemar Priebe[SUP] 1 15 [/SUP], Mark R Emmett[SUP] 1 16 [/SUP], Sonja M Best[SUP] 1 17 [/SUP], Maya Kelsey Johnson[SUP] 1 2 [/SUP], Nidia S Trovao[SUP] 1 18 [/SUP], Kevin B Clark[SUP] 1 19 20 [/SUP], Victoria Zaksas[SUP] 1 21 22 [/SUP], Robert Meller[SUP] 1 23 [/SUP], Peter Grabham[SUP] 1 24 [/SUP], Jonathan C Schisler[SUP] 1 12 [/SUP], Pedro M Moraes-Vieira[SUP] 1 25 [/SUP], Simon Pollett[SUP] 9 10 [/SUP], Christopher E Mason[SUP] 1 8 26 [/SUP], Eve Syrkin Wurtele[SUP] 1 27 28 29 [/SUP], Deanne Taylor[SUP] 1 3 4 13 30 [/SUP], Robert E Schwartz[SUP] 1 8 [/SUP], Afshin Beheshti[SUP] #[/SUP][SUP] 1 31 32 33 [/SUP], Douglas C Wallace[SUP] #[/SUP][SUP] 1 3 4 34 [/SUP], Stephen B Baylin[SUP] #[/SUP][SUP] 1 2 35 [/SUP]



Affiliations

• PMID: 39602262
• DOI: 10.1073/pnas.2401968121

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.

Keywords: COVID-19; fibrosis; renin angiotensin aldosterone system.

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