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

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

doi:10.1073/pnas.2401968121

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

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

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

1 Scopus 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.

Original language	English
Article number	e2401968121
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	121
Issue number	49
DOIs	https://doi.org/10.1073/pnas.2401968121
State	Published - 3 Dec 2024

Keywords

COVID-19
fibrosis
renin angiotensin aldosterone system

Access to Document

10.1073/pnas.2401968121

Cite this

Topper, M. J., Guarnieri, J. W., Haltom, J. A., Chadburn, A., Cope, H., Frere, J., An, J., Borczuk, A., Sinha, S., Kim, J. K., Park, J., Butler, D., Meydan, C., Foox, J., Bram, Y., Richard, S. A., Epsi, N., Agan, B., Chenoweth, J. G., ... Baylin, S. B. (2024). Lethal COVID-19 associates with RAAS-induced inflammation for multiple organ damage including mediastinal lymph nodes. Proceedings of the National Academy of Sciences of the United States of America, 121(49), Article e2401968121. https://doi.org/10.1073/pnas.2401968121

@article{226831eb9f8b4947a797434c17ae5e8e,

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

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",

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

note = "Publisher Copyright: Copyright {\textcopyright} 2024 the Author(s).",

year = "2024",

month = dec,

day = "3",

doi = "10.1073/pnas.2401968121",

language = "English",

volume = "121",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

issn = "0027-8424",

number = "49",

}

Topper, MJ, Guarnieri, JW, Haltom, JA, Chadburn, A, Cope, H, Frere, J, An, J, Borczuk, A, Sinha, S, Kim, JK, Park, J, Butler, D, Meydan, C, Foox, J, Bram, Y, Richard, SA , Epsi, N , 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, Albrecht, YES, Olali, AZ, Cen, Z, Dybas, J, Priebe, W, Emmett, MR, Best, SM, Johnson, MK, Trovao, NS, Clark, KB, Zaksas, V, Meller, R, Grabham, P, Schisler, JC, Moraes-Vieira, PM, Pollett, S, Mason, CE, Wurtele, ES, Taylor, D, Schwartz, RE, Beheshti, A, Wallace, DC & Baylin, SB 2024, 'Lethal COVID-19 associates with RAAS-induced inflammation for multiple organ damage including mediastinal lymph nodes', Proceedings of the National Academy of Sciences of the United States of America, vol. 121, no. 49, e2401968121. https://doi.org/10.1073/pnas.2401968121

Lethal COVID-19 associates with RAAS-induced inflammation for multiple organ damage including mediastinal lymph nodes. / Topper, Michael J.; Guarnieri, Joseph W.; Haltom, Jeffrey A. et al.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 121, No. 49, e2401968121, 03.12.2024.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Lethal COVID-19 associates with RAAS-induced inflammation for multiple organ damage including mediastinal lymph nodes

AU - Topper, Michael J.

AU - Guarnieri, Joseph W.

AU - Haltom, Jeffrey A.

AU - Chadburn, Amy

AU - Cope, Henry

AU - Frere, Justin

AU - An, Julia

AU - Borczuk, Alain

AU - Sinha, Saloni

AU - Kim, Jang Keun

AU - Park, Jiwoon

AU - Butler, Daniel

AU - Meydan, Cem

AU - Foox, Jonathan

AU - Bram, Yaron

AU - Richard, Stephanie A.

AU - Epsi, Nusrat

AU - Agan, Brian

AU - Chenoweth, Josh G.

AU - Simons, Mark P.

AU - Tribble, David

AU - Burgess, Timothy

AU - Dalgard, Clifton

AU - Heise, Mark T.

AU - Moorman, Nathaniel J.

AU - Baxter, Victoria K.

AU - Madden, Emily A.

AU - Taft-Benz, Sharon A.

AU - Anderson, Elizabeth J.

AU - Sanders, Wes A.

AU - Dickmander, Rebekah J.

AU - Beigel, Katherine

AU - Widjaja, Gabrielle A.

AU - Janssen, Kevin A.

AU - Lie, Timothy

AU - Murdock, Deborah G.

AU - Angelin, Alessia

AU - Albrecht, Yentli E.Soto

AU - Olali, Arnold Z.

AU - Cen, Zimu

AU - Dybas, Joseph

AU - Priebe, Waldemar

AU - Emmett, Mark R.

AU - Best, Sonja M.

AU - Johnson, Maya Kelsey

AU - Trovao, Nidia S.

AU - Clark, Kevin B.

AU - Zaksas, Victoria

AU - Meller, Robert

AU - Grabham, Peter

AU - Schisler, Jonathan C.

AU - Moraes-Vieira, Pedro M.

AU - Pollett, Simon

AU - Mason, Christopher E.

AU - Wurtele, Eve Syrkin

AU - Taylor, Deanne

AU - Schwartz, Robert E.

AU - Beheshti, Afshin

AU - Wallace, Douglas C.

AU - Baylin, Stephen B.

PY - 2024/12/3

Y1 - 2024/12/3

N2 - 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.

AB - 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.

KW - COVID-19

KW - fibrosis

KW - renin angiotensin aldosterone system

UR - http://www.scopus.com/inward/record.url?scp=85211073743&partnerID=8YFLogxK

U2 - 10.1073/pnas.2401968121

DO - 10.1073/pnas.2401968121

M3 - Article

C2 - 39602262

AN - SCOPUS:85211073743

SN - 0027-8424

VL - 121

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 49

M1 - e2401968121

ER -