The oxidative stress alters the endothelial permeability via downregulation of ZO-1 during group A streptococcal infection

  • 朱 建州

Student thesis: Doctoral Thesis

Abstract

Group A streptococcal (GAS) infections which caused by Streptococcus pyogenes range from self-limiting cutaneous illness to life-threatening invasive diseases including necrotizing fasciitis sepsis and streptococcal toxic shock syndrome The infected cells can release reactive oxygen species (ROS) to eliminate intracellular pathogens Among them NAPDH oxidases (NOX)-derived ROS involve in not only host defense but signal transduction In previous studies epithelial cells infected with GAS undergo ROS-regulated apoptosis to inhibit the colonization However it has been shown that GAS can invade survive and multiply in endothelial cells and the conquest of oxidative stress which may lead to endothelial dysfunction Therefore GAS-infected blood vessel endothelium may play a key role in the pathogenesis of invasive bacteremia and sepsis In this study excess ROS induced by GAS infection leading to endothelial barrier disruption was explored The ROS-altered signal transduction can turn off the canonical autophagy via activating PI3k/Akt pathway Degradation of tight junction protein zona occludens 1 (ZO-1) may be attributed to a non-canonical autophagy LC3-associated phagocytosis (LAP) which was induced by NOX2-derived ROS Treatment with a NOX inhibitor dextromethorphan (DM) decreased the oxidative stress restored the protein expression level of ZO-1 and protected ZO-1 from disassembly Treatment with lysosomal acidification inhibitor chloroquine (CQ) attenuated the degradation of ZO-1 protein and maintained the barrier integrity Taken together NOX-derived ROS might trigger LAP formation to engulf tight junction protein ZO-1 followed by degradation leading to endothelial hyperpermeability
Date of Award2021
Original languageEnglish
SupervisorChing-Chuan Liu (Supervisor)

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