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

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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Publication Details

Journal
Proceedings of the National Academy of Sciences
Published
2024-11-27
DOI
https://doi.org/10.1073/pnas.2401968121
Citations
13
Primary Topic
COVID-19 Clinical Research Studies
Type
article
Field-Weighted Citation Impact
5.06

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article

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

Saloni Sinha, Brian K. Agan, Cem Meydan, Alain Borczuk et al.
13 citations
Proceedings of the National Academy of Sciences
COVID-19 Clinical Research Studies
5.06
article

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

Saloni Sinha, Brian K. Agan, Cem Meydan, Alain Borczuk, Jiwoon Park, Victoria Zaksas, Timothy H. Burgess, Nusrat J Epsi, Stephanie A Richard, Clifton L. Dalgard, Deanne Taylor, Joseph W. Guarnieri, Mark T. Heise, Simon Pollett, Jeffrey Haltom, Elizabeth J. Anderson, Emily A. Madden, JangKeun Kim, Joseph M. Dybas, Yaron Bram, Rebekah J. Dickmander, Mark R. Emmett, Robert E. Schwartz, Nathaniel J. Moorman, Kevin B. Clark, Alessia Angelin, Mark P. Simons, Deborah G. Murdock, Eve Syrkin Wurtele, Sonja M. Best, Justin J. Frere, Stephen B. Baylin, Michael J. Topper, Kevin A. Janssen, Waldemar Priebe, Amy Chadburn, Sharon Taft-Benz, Henry Cope, Peter Grabham, Timothy Lie, Robert Meller, Josh Chenoweth, Arnold Z. Olali, Jonathan Foox, Yentli E. Soto Albrecht, Jonathan C. Schisler, Pedro M. Moraes‐Vieira, Afshin Beheshti, Nídia S. Trovão, Victoria K. Baxter, Julia An, Daniel Butler, Douglas C. Wallace, Christopher E. Mason, David R. Tribble, Wes Sanders, Gabrielle A. Widjaja, Katherine Beigel, Zimu Cen, Maya Kelsey Johnson
article en
13 citations

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.

Proceedings of the National Academy of SciencesVol. 121(49)
Broad Institute (US), University of North Carolina at Chapel Hill (US), Henry M. Jackson Foundation (US), Van Andel Institute (US), Children's Hospital of Philadelphia (US), The University of Texas MD Anderson Cancer Center (US), University of Nottingham (GB), Johns Hopkins University (US), Uniformed Services University of the Health Sciences (US), University of Pittsburgh (US), Iowa State University (US), Universidade Estadual de Campinas (UNICAMP) (BR), Cornell University (US), University of Chicago (US), Cures Within Reach (US), National Institute of Allergy and Infectious Diseases (US), Blue Marble Space (US), New York Genome Center (US), Blue Marble Space Institute of Science (US), McGowan Institute for Regenerative Medicine (US), Sidney Kimmel Comprehensive Cancer Center (US), Weill Cornell Medicine (US), The University of Texas Medical Branch at Galveston (US), Morehouse School of Medicine (US), Massachusetts Institute of Technology (US), Carnegie Mellon University (US), Columbia University (US), University of Pennsylvania (US), Fogarty International Center (US), Icahn School of Medicine at Mount Sinai (US)
U.S. Department of Defense, Bill and Melinda Gates Foundation, Division of Intramural Research, National Institute of Allergy and Infectious Diseases
Good health and well-being
Openalex Percentile: Top 4%
COVID-19 Clinical Research Studies
5.06
DOIOpen Access PDFOpenAlex
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