Multiplatform analyses reveal distinct drivers of systemic pathogenesis in adult versus pediatric severe acute COVID-19, 2023, Samuel Druzak

[Mij]

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.

https://www.nature.com/articles/s41467-023-37269-3

 

[Sean]

alterations in fluid shear stress-responsive pathways

Now that is interesting.

 

[SNT Gatchaman]

See also Monocyte Adhesion and Transmigration Through Endothelium Following Cardiopulmonary Bypass Shearing is Mediated by IL-8 Signaling (2023, Preprint: BioRxiv)

With this study to our knowledge, we are the first to show that CPB shear stress activated monocytes adhere to and migrate through an intact and unstimulated endothelial monolayer. [...] This was accompanied by the disruption of adherens junction and reorganization of cytoskeleton in the endothelial cells.

In flow conditions IL-8 stimulates adhesion to E-selectin expressing endothelial cells and promotes monocytes polarization toward an M1 pro-inflammatory phenotype. In our system, it appears that IL-8 promoted endothelial specific processes facilitating monocyte adhesion that was strongly inhibited by blocking the IL-8 receptors on endothelial cells. Further studies will be necessary to assess direct effects of IL-8 on CPB shear stress activated monocytes

In addition, endothelial cells have been shown to express the IL-8 receptors CXCR1 and CXCR2 and respond to IL-8 by activating angiogenesis processes, including proliferation, survival, tube morphogenesis and MMP production. The binding of IL-8 on endothelial cells can induce cytoskeletal reorganization through Rho and Rac signaling pathways, which are correlated to the clustering of E-selectin, intercellular adhesion molecules, and vascular cell adhesion molecules.

IL-8 treatment increases the permeability of the endothelium, likely facilitating the subsequent transmigration of monocytes. Accordingly, our studies also show that IL-8 is a strong inducer of ICAM-1 and VCAM-1 RNA expression in the microvascular endothelial cells. We also observed IL-8 dependent endothelial cell cytoskeleton rearrangement and VE-cadherin disruption.