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

• 成果类型: Article
• 署名作者: Topper, Michael J.; Guarnieri, Joseph W.; Haltom, Jeffrey A.; Chadburn, Amy; Cope, Henry; Frere, Justin; An, Julia; Borczuk, Alain; Sinha, Saloni; Kim, Jangkeun; Park, Jiwoon; Butler, Daniel; Meydan, Cem; Foox, Jonathan; Bram, Yaron; Richard, Stephanie A.; Epsi, Nusrat J.; Agan, Brian; Chenoweth, Josh G.; Simons, Mark P.; Tribble, David; Burgess, Timothy; Dalgard, Clifton; Heise, Mark T.; Moorman, Nathaniel J.; Baxter, Victoria K.; Madden, Emily A.; Taft-Benz, Sharon A.; Anderson, Elizabeth J.; Sanders, Wes A.; Dickmander, Rebekah J.; Beigel, Katherine; Widjaja, Gabrielle A.; Janssen, Kevin A.; Lie, Timothy; Murdock, Deborah G.; Angelin, Alessia; Albrecht, Yentli E. Soto; Olali, Arnold Z.; Cen, Zimu; Dybas, Joseph; Priebe, Waldemar; Emmett, Mark R.; Best, Sonja M.; Johnson, Maya Kelsey; Trovao, Nidia S.; Clark, Kevin B.; Zaksas, Victoria; Meller, Robert; Grabham, Peter; Schisler, Jonathan C.; Moraes-Vieira, Pedro M.; Pollett, Simon; Mason, Christopher E.; Wurtele, Eve Syrkin; Taylor, Deanne; Schwartz, Robert E.; Beheshti, Afshin; Wallace, Douglas C.; Baylin, Stephen B.
• 署名单位: Johns Hopkins University; Johns Hopkins Medicine; University of Pennsylvania; Pennsylvania Medicine; Childrens Hospital of Philadelphia; University of Pennsylvania; Pennsylvania Medicine; Childrens Hospital of Philadelphia; Cornell University; Weill Cornell Medicine; University of Nottingham; Icahn School of Medicine at Mount Sinai; Cornell University; Weill Cornell Medicine; Uniformed Services University of the Health Sciences - USA; Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc; Uniformed Services University of the Health Sciences - USA; University of North Carolina; University of North Carolina Chapel Hill; University of North Carolina School of Medicine; University of Pennsylvania; Pennsylvania Medicine; Childrens Hospital of Philadelphia; University of Pennsylvania; University of Texas System; University of Texas Medical Branch Galveston; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID); National Institutes of Health (NIH) - USA; NIH Fogarty International Center (FIC); Carnegie Mellon University; University of Chicago; Morehouse School of Medicine; Columbia University; Universidade Estadual de Campinas; Universidade de Sao Paulo; Iowa State University; Iowa State University; Iowa State University; University of Pennsylvania; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; University of Pennsylvania; Van Andel Institute
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12287
• DOI: 10.1073/pnas.2401968121
• 发表日期: 2024-12-03
• 关键词: bone-marrow fibrosis; mitochondrial-dna; t-cells; fibrin; deficiency

摘要

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.