학술논문
Multiplatform analyses reveal distinct drivers of systemic pathogenesis in adult versus pediatric severe acute COVID-19
Document Type
Original Paper
Author
Druzak, Samuel; Iffrig, Elizabeth; Roberts, Blaine R.; Zhang, Tiantian; Fibben, Kirby S.; Sakurai, Yumiko; Verkerke, Hans P.; Rostad, Christina A.; Chahroudi, Ann; Schneider, Frank; Wong, Andrew Kam Ho; Roberts, Anne M.; Chandler, Joshua D.; Kim, Susan O.; Mosunjac, Mario; Mosunjac, Marina; Geller, Rachel; Albizua, Igor; Stowell, Sean R.; Arthur, Connie M.; Anderson, Evan J.; Ivanova, Anna A.; Ahn, Jun; Liu, Xueyun; Maner-Smith, Kristal; Bowen, Thomas; Paiardini, Mirko; Bosinger, Steve E.; Roback, John D.; Kulpa, Deanna A.; Silvestri, Guido; Lam, Wilbur A.; Ortlund, Eric A.; Maier, Cheryl L.
Source
Nature Communications. 14(1)
Subject
Language
English
ISSN
2041-1723
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.
In this work, authors take a multiomics and microfluidics-based approach to elucidate the mechanism of endothelial damage in critical illness associated with SARS-CoV-2.
In this work, authors take a multiomics and microfluidics-based approach to elucidate the mechanism of endothelial damage in critical illness associated with SARS-CoV-2.