Centers and Institutes
Published November 27, 2024 | Version v1
Journal article Open

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

Creators

  • 1. Johns Hopkins University
  • 2. The Children's Hospital of Philadelphia
  • 3. Cornell University
  • 4. University of Nottingham
  • 5. Mount Sinai
  • 6. Uniformed Services University
  • 7. Henry M. Jackson Foundation for the Advancement of Military Medicine
  • 8. University of Chicago

Description

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.

Notes

Due to the large number of authors, only the first 20 and the University of Chicago authors are included on the above author list. Please download the article for the complete list of authors.

Data availability

The published article includes all datasets generated and analyzed during this study. Processed bulk RNA-seq data for the human-related data from the nasopharyngeal and autopsy data is available online with dbGaP Study Accession No.: phs002258.v1.p1 and online here at: https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs002258.v1.p1 (117) and also https://covidgenes.weill.cornell.edu/. The murine RNA-seq data are deposited on the gene expression omnibus (GEO) repository with Accession No. GSE221510 and can be found here: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE221510 (118). Additionally, the murine RNA-seq data were also deposited in the NCBI BioProject database (https://www.ncbi.nlm.nih.gov/bioproject/) under the BioProject accession number PRJNA803057. The hamster RNA-seq data are also deposited on the GEO repository with Accession No. GSE203001 and can be found here: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE203001 (119). The RNA-seq data from the miR-2392 mimic 3D HUVEC tissue model data is available via the NASA Open Science Data Repository’s (OSDR) Biological Data Management Environment (https://osdr.nasa.gov/bio/repo) with Accession No.: OSD-577 and https://doi.org/10.26030/rs3g-e189 (120). This study did not generate new unique reagents. RNA-seq data will be deposited. All other data are included in the manuscript and/or SI Appendix. Previously published data were used for this work (4, 113–116).

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topper-et-al-2024-lethal-covid-19-associates-with-raas-induced-inflammation-for-multiple-organ-damage-including.pdf

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Additional details

Identifiers

DOI
10.1073/pnas.2401968121
Other
oai:uchicago.tind.io:14184

Funding

National Institute of Allergy and Infectious Diseases
HU00011920111
U.S. Department of Defense
W81XWH-21-1-0128
Bill & Melinda Gates Foundation
INV-046722
Adelson Medical Research Foundation
Hodson Scholar Foundation
Samuel Waxman Research Foundation
Unknown funder
The Evelyn Grollman Glick Scholar Award
Defense Health Program
HU00012020067
Defense Health Program
HU00012120103
USU
RESPONSE award
Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc.
National Institute of Allergy and Infectious Diseases
Y1-AI-5072

UChicago Information

Division(s)
Institutes & Centers
Center(s) or Institute(s)
Center for Translational Data Science