Post by Nadica (She/Her) on Dec 4, 2024 3:41:19 GMT
Lethal COVID-19 associates with RAAS-induced inflammation for multiple organ damage including mediastinal lymph nodes - Published Nov 27, 2024
Significance
This work defines across multiple large, independent patient cohorts the downstream implications of cytokine storm in lethal COVID-19 as driven by upstream immune gene and mitochondrial signaling producing RAAS overactivation and subsequent organ damage. Furthermore, we delineate a lymphoid organ fibrosis phenotype occurring in severe COVID-19, which has potential implications in mediating the chronic B and T cell dysfunction prevalent in long COVID. Correlations between tissue findings and circulating markers suggest this last possibility.
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.
Significance
This work defines across multiple large, independent patient cohorts the downstream implications of cytokine storm in lethal COVID-19 as driven by upstream immune gene and mitochondrial signaling producing RAAS overactivation and subsequent organ damage. Furthermore, we delineate a lymphoid organ fibrosis phenotype occurring in severe COVID-19, which has potential implications in mediating the chronic B and T cell dysfunction prevalent in long COVID. Correlations between tissue findings and circulating markers suggest this last possibility.
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.