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Multiplatform analyses reveal distinct drivers of systemic pathogenesis in adult versus pediatric severe acute COVID-19.

ABSTRACT: The pathogenesis of multi-organ dysfunction associated with severe acute SARS-CoV-2 infection remains poorly understood. Endothelial damage and microvascular thrombosis have been identified as drivers of COVID-19 severity, yet the mechanisms underlying these processes remain elusive. Here we show alterations in fluid shear stress-responsive pathways in critically ill COVID-19 adults as compared to non-COVID critically ill adults using a multiomics approach. Mechanistic in-vitro studies, using microvasculature-on-chip devices, reveal that plasma from critically ill COVID-19 adults induces fibrinogen-dependent red blood cell aggregation that mechanically damages the microvascular glycocalyx. This mechanism appears unique to COVID-19, as plasma from non-COVID sepsis patients demonstrates greater red blood cell membrane stiffness but induces less significant alterations in overall blood rheology. Multiomics analyses in pediatric patients with acute COVID-19 or the post-infectious multi-inflammatory syndrome in children (MIS-C) demonstrate little overlap in plasma cytokine and metabolite changes compared to adult COVID-19 patients. Instead, pediatric acute COVID-19 and MIS-C patients show alterations strongly associated with cytokine upregulation. These findings link high fibrinogen and red blood cell aggregation with endotheliopathy in adult COVID-19 patients and highlight differences in the key mediators of pathogenesis between adult and pediatric populations.

SUBMITTER: Druzak S

PROVIDER: S-EPMC10073144 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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Multiplatform analyses reveal distinct drivers of systemic pathogenesis in adult versus pediatric severe acute COVID-19.

Druzak Samuel S Iffrig Elizabeth E Roberts Blaine R BR Zhang Tiantian T Fibben Kirby S KS Sakurai Yumiko Y Verkerke Hans P HP Rostad Christina A CA Chahroudi Ann A Schneider Frank F Wong Andrew Kam Ho AKH Roberts Anne M AM Chandler Joshua D JD Kim Susan O SO Mosunjac Mario M Mosunjac Marina M Geller Rachel R Albizua Igor I Stowell Sean R SR Arthur Connie M CM Anderson Evan J EJ Ivanova Anna A AA Ahn Jun J Liu Xueyun X Maner-Smith Kristal K Bowen Thomas T Paiardini Mirko M Bosinger Steve E SE Roback John D JD Kulpa Deanna A DA Silvestri Guido G Lam Wilbur A WA Ortlund Eric A EA Maier Cheryl L CL

Nature communications 20230404 1

The pathogenesis of multi-organ dysfunction associated with severe acute SARS-CoV-2 infection remains poorly understood. Endothelial damage and microvascular thrombosis have been identified as drivers of COVID-19 severity, yet the mechanisms underlying these processes remain elusive. Here we show alterations in fluid shear stress-responsive pathways in critically ill COVID-19 adults as compared to non-COVID critically ill adults using a multiomics approach. Mechanistic in-vitro studies, using mi ...[more]

PMID: 37015925

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Multiplatform analyses reveal distinct drivers of systemic pathogenesis in adult versus pediatric severe acute COVID-19.

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Multiplatform analyses reveal distinct drivers of systemic pathogenesis in adult versus pediatric severe acute COVID-19.

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