Pro-Coagulant Endothelial Dysfunction Results from EHEC Shiga Toxins and Host Damage-Associated Molecular Patterns

• Published in: Frontiers in immunology 2015-04, Vol.6, p.155-155
• Main Authors: Mayer, Chad L, Parello, Caitlin S L, Lee, Benjamin C, Itagaki, Kiyoshi, Kurosawa, Shinichiro, Stearns-Kurosawa, Deborah J
• Format: Article
• Language: English
• Subjects: damage-associated molecular patterns (DAMPs); endothelial cells; hemolytic uremic syndrome (HUS); Immunology; Protein C; Shiga Toxin 1; Shiga Toxin 2
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2015.00155

Hemolytic uremic syndrome (HUS) from enterohemorrhagic Escherichia coli infection is a leading cause of kidney failure in otherwise healthy U.S. children. The bacterial Shiga toxins (Stx) induce the characteristic coagulopathy of HUS, but the damage to toxin-receptor expressing cells and organ injury due to ischemia likely also releases inflammatory damage-associated molecular patterns (DAMPs), which may exacerbate injury along with the toxins. To examine this, human aortic and renal glomerular cell anti-coagulant and barrier functions were studied after in vitro challenge with Stx1, Stx2, and DAMPs. There was significant loss of surface anti-coagulant protein C pathway molecules, increased expression of pro-thrombotic PAR1 and reduced protein C activation capability by 15-27%. Histones nearly completely prevented the activated protein C protection of endothelial cells from thrombin-induced permeability. In mice, lethal Stx2 challenge elevated plasma HMGB1 (day 2, 321 ± 118%; p