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PLoS Pathog. 2014 Mar 13;10(3):e1003939. doi: 10.1371/journal.ppat.1003939. eCollection 2014 Mar.

VE-cadherin cleavage by LasB protease from Pseudomonas aeruginosa facilitates type III secretion system toxicity in endothelial cells.

Author information

1
INSERM, U1036, Biology of Cancer and Infection, Grenoble, France; CNRS, ERL 5261, Bacterial Pathogenesis and Cellular Responses, Grenoble, France; Université Joseph Fourier-Grenoble I, Grenoble, France; CEA, DSV/iRTSV, Grenoble, France.
2
CNRS and Aix-Marseille Univ, Laboratoire d'Ingénierie des Systèmes Macromoléculaires (UMR7255), Marseille, France.

Abstract

Infection of the vascular system by Pseudomonas aeruginosa (Pa) occurs during bacterial dissemination in the body or in blood-borne infections. Type 3 secretion system (T3SS) toxins from Pa induce a massive retraction when injected into endothelial cells. Here, we addressed the role of type 2 secretion system (T2SS) effectors in this process. Mutants with an inactive T2SS were much less effective than wild-type strains at inducing cell retraction. Furthermore, secretomes from wild-types were sufficient to trigger cell-cell junction opening when applied to cells, while T2SS-inactivated mutants had minimal activity. Intoxication was associated with decreased levels of vascular endothelial (VE)-cadherin, a homophilic adhesive protein located at endothelial cell-cell junctions. During the process, the protein was cleaved in the middle of its extracellular domain (positions 335 and 349). VE-cadherin attrition was T3SS-independent but T2SS-dependent. Interestingly, the epithelial (E)-cadherin was unaffected by T2SS effectors, indicating that this mechanism is specific to endothelial cells. We showed that one of the T2SS effectors, the protease LasB, directly affected VE-cadherin proteolysis, hence promoting cell-cell junction disruption. Furthermore, mouse infection with Pa to induce acute pneumonia lead to significant decreases in lung VE-cadherin levels, whereas the decrease was minimal with T2SS-inactivated or LasB-deleted mutant strains. We conclude that the T2SS plays a pivotal role during Pa infection of the vascular system by breaching the endothelial barrier, and propose a model in which the T2SS and the T3SS cooperate to intoxicate endothelial cells.

PMID:
24626230
PMCID:
PMC3953407
DOI:
10.1371/journal.ppat.1003939
[Indexed for MEDLINE]
Free PMC Article

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