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<p>Vasodilation is a defence mechanism during inflammation and infection that is regulated by nitric oxide produced by endothelial nitric oxide synthase (eNOS) and the generation of endothelium-dependent hyperpolarization. Several viral infections have been shown to alter vascular biology, but effects of bacterial pathogens are unclear. Here using an ex vivo blood vessel model and human primary endothelial cells, we show that <i>Klebsiella pneumoniae</i>, a prevalent bloodstream pathogen, inhibits vasodilation pathways. The type VI secretion system (T6SS) effector VgrG4 activates the mitochondrial receptor NLRX1, which leads to increased mitochondrial reactive oxygen species and phosphorylation of the eNOS inhibitory site by the kinase PKCβ, which in turn reduces eNOS activity. <i>K.</i> <i>pneumoniae</i> capsule polysaccharide also activates the phosphatase PP2Ac, which reduces phosphorylation of the eNOS activation site. VgrG4-induced mitochondrial reactive oxygen species attenuate endothelium-dependent hyperpolarization by impairing signalling of the Ca<sup>2+</sup>-activated K<sup>+</sup> channel axis. This work reveals that T6SS activity can modulate host vascular biology by targeting eNOS post-translational modifications.</p>

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Klebsiella pneumoniae inhibits vasodilation through capsule and T6SS-dependent pathways

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月21日

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  • Safi Rehman,
  • Joana Sa-Pessoa,
  • Charlotte Buckley,
  • Rachel L. Lee,
  • Karolina Wojtania,
  • Alix Lee,
  • Rebecca Lancaster,
  • Josy Augustine,
  • Peter Barabas,
  • Ciara Ross,
  • Xun Zhang,
  • John G. McCarron,
  • Tim M. Curtis,
  • Jose A. Bengoechea

摘要

Vasodilation is a defence mechanism during inflammation and infection that is regulated by nitric oxide produced by endothelial nitric oxide synthase (eNOS) and the generation of endothelium-dependent hyperpolarization. Several viral infections have been shown to alter vascular biology, but effects of bacterial pathogens are unclear. Here using an ex vivo blood vessel model and human primary endothelial cells, we show that Klebsiella pneumoniae, a prevalent bloodstream pathogen, inhibits vasodilation pathways. The type VI secretion system (T6SS) effector VgrG4 activates the mitochondrial receptor NLRX1, which leads to increased mitochondrial reactive oxygen species and phosphorylation of the eNOS inhibitory site by the kinase PKCβ, which in turn reduces eNOS activity. K. pneumoniae capsule polysaccharide also activates the phosphatase PP2Ac, which reduces phosphorylation of the eNOS activation site. VgrG4-induced mitochondrial reactive oxygen species attenuate endothelium-dependent hyperpolarization by impairing signalling of the Ca2+-activated K+ channel axis. This work reveals that T6SS activity can modulate host vascular biology by targeting eNOS post-translational modifications.