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

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 PKCβ in an NLRX1-controlled mitochondria reactive oxygen species (mtROS)-dependent manner to phosphorylate the eNOS inhibitory site Thr ⁴⁹⁵ , effectively dampening eNOS activity. The capsule polysaccharide, on the other hand, limits the phosphorylation of the eNOS activation site Ser ¹¹⁷⁷ 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.