Viral Sepsis in Children

Gupta, Neha; Richter, Robert; Robert, Stephen; Kong, Michele

Circulating viral particles may also induce endothelial cell structural changes that lead to barrier disruption and further vascular leak. Endothelial cells are anchored to each other through adherens junctions comprised predominantly of vascular endothelial (VE)-cadherin, which is attached to the endothelial cytoskeleton through beta-catenin and p120catenin (55, 56) . In human endothelial cells, pathogenic strains of hantavirus appear to bind to cellular surface β3-integrins, thereby promoting VE-cadherin internalization and adherens junction destabilization (57) . VE-cadherin destabilization may also be mediated through the cellular membrane Tie2 receptor. Tie2 receptor is activated by angiopoietin-1 (Agpt-1) that is derived by periendothelial cells (58, 59) . When activated, the Tie2 receptor activates PI3K/Akt cell-survival signaling and Rac1mediated cytoskeletal stabilization (60) . Inflammatory mediators, such as thrombin (61), reactive oxygen species (62) , and VEGF (63), stimulate endothelial cell Weibel-Palade body exocytosis, releasing the Tie2 antagonist Agpt-2 (64). Agpt-2 acts in an autocrine fashion to inhibit Tie2 signaling, thereby promoting RhoA kinase activity and VE-cadherin destabilization (60) . Mice infected with a pathogenic strain of H3N2 influenza virus develop acute lung injury that is rescued by the Tie2 agonist vasculotide (65) , suggesting that the Tie2 receptor is integral in the development of endotheliopathy during viral sepsis. The exact mechanisms each virus employs to induce endothelial cell dysfunction are not clear; however, the typical presentation of capillary leak with viral sepsis suggests a common pathway by which endothelial integrity is compromised.