Klebsiella pneumoniae disrupts vasodilation by targeting eNOS post translational modifications via the type VI secretion system and the capsule polysaccharide

Rheman, S.; sa-Pessoa Graca Santos, J.; Buckley, C.; Lancaster, R.; Ross, C.; Zhang, X.; McCarron, J.; Curtis, T.; Bengoechea, J.

doi:10.1101/2025.02.05.636584

bioRxiv · 10.1101/2025.02.05.636584

Klebsiella pneumoniae disrupts vasodilation by targeting eNOS post translational modifications via the type VI secretion system and the capsule polysaccharide

Rheman, S.·sa-Pessoa Graca Santos, J.·Buckley, C.·Lancaster, R.·Ross, C.·Zhang, X.·McCarron, J.·Curtis, T.·Bengoechea, J.

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Abstract

Vasodilation is a crucial protective response to inflammation and infection. Endothelial cells control vasodilation through the bioavailability of eNOS-produced nitric oxide (NO), and the generation of endothelium-dependent hyperpolarization (EDH). Here, we demonstrate that Klebsiella pneumoniae, one of the most prevalent blood stream infection pathogens, inhibits agonist-induced vasodilation by blunting the NO-dependent pathway and attenuating the EDH pathway. The type VI secretion system (T6SS) effector VgrG4 licences the kinase PKC{beta} in an NLRX1-controlled mitochondria reactive oxygen species (mtROS)-dependent manner to phosphorylate the eNOS inhibitory site Thr495, effectively dampening eNOS activity. The capsule polysaccharide, on the other hand, limits the phosphorylation of the eNOS activation site Ser1177 by inducing the phosphatase PP2Ac upon activation of an EGF receptor-dependent pathway. VgrG4-induced mtROS attenuates the EDH pathway. Overall, this work reveals a new anti-host activity of the T6SS and illustrates how pathogens can control vascular biology by targeting eNOS post translational modifications.

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Rheman, S., sa-Pessoa Graca Santos, J., Buckley, C., Lancaster, R., Ross, C., Zhang, X., McCarron, J., Curtis, T., Bengoechea, J.. 2025-02-05. Klebsiella pneumoniae disrupts vasodilation by targeting eNOS post translational modifications via the type VI secretion system and the capsule polysaccharide. https://doi.org/10.1101/2025.02.05.636584

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