» Articles » PMID: 24705722

The Pseudomonas Aeruginosa Exoenzyme Y Impairs Endothelial Cell Proliferation and Vascular Repair Following Lung Injury

Abstract

Exoenzyme Y (ExoY) is a Pseudomonas aeruginosa toxin that is introduced into host cells through the type 3 secretion system (T3SS). Once inside the host cell cytoplasm, ExoY generates cyclic nucleotides that cause tau phosphorylation and microtubule breakdown. Microtubule breakdown causes interendothelial cell gap formation and tissue edema. Although ExoY transiently induces interendothelial cell gap formation, it remains unclear whether ExoY prevents repair of the endothelial cell barrier. Here, we test the hypothesis that ExoY intoxication impairs recovery of the endothelial cell barrier following gap formation, decreasing migration, proliferation, and lung repair. Pulmonary microvascular endothelial cells (PMVECs) were infected with P. aeruginosa strains for 6 h, including one possessing an active ExoY (PA103 exoUexoT::Tc pUCPexoY; ExoY(+)), one with an inactive ExoY (PA103ΔexoUexoT::Tc pUCPexoY(K81M); ExoY(K81M)), and one that lacks PcrV required for a functional T3SS (ΔPcrV). ExoY(+) induced interendothelial cell gaps, whereas ExoY(K81M) and ΔPcrV did not promote gap formation. Following gap formation, bacteria were removed and endothelial cell repair was examined. PMVECs were unable to repair gaps even 3-5 days after infection. Serum-stimulated growth was greatly diminished following ExoY intoxication. Intratracheal inoculation of ExoY(+) and ExoY(K81M) caused severe pneumonia and acute lung injury. However, whereas the pulmonary endothelial cell barrier was functionally improved 1 wk following ExoY(K81M) infection, pulmonary endothelium was unable to restrict the hyperpermeability response to elevated hydrostatic pressure following ExoY(+) infection. In conclusion, ExoY is an edema factor that chronically impairs endothelial cell barrier integrity following lung injury.

Citing Articles

Urinary tract infections and catheter-associated urinary tract infections caused by .

El Husseini N, Carter J, Lee V Microbiol Mol Biol Rev. 2024; 88(4):e0006622.

PMID: 39431861 PMC: 11653733. DOI: 10.1128/mmbr.00066-22.


ExoY infection of pulmonary microvascular endothelial cells releases cyclic nucleotides into the extracellular compartment.

Stone M, Choi C, Dey N, Swain G, Stevens T, Sayner S Am J Physiol Lung Cell Mol Physiol. 2024; 327(5):L756-L768.

PMID: 39316682 PMC: 11560077. DOI: 10.1152/ajplung.00038.2024.


cUMP elicits interendothelial gap formation during infection.

deWeever A, Paudel S, Zhou C, Francis C, Tambe D, Frank D Am J Physiol Lung Cell Mol Physiol. 2024; 327(3):L395-L405.

PMID: 39076085 PMC: 11444506. DOI: 10.1152/ajplung.00164.2023.


Lung endothelium, tau, and amyloids in health and disease.

Balczon R, Lin M, Voth S, Nelson A, Schupp J, Wagener B Physiol Rev. 2023; 104(2):533-587.

PMID: 37561137 PMC: 11281824. DOI: 10.1152/physrev.00006.2023.


Cytotoxins: Mechanisms of Cytotoxicity and Impact on Inflammatory Responses.

Wood S, Goldufsky J, Seu M, Dorafshar A, Shafikhani S Cells. 2023; 12(1).

PMID: 36611990 PMC: 9818787. DOI: 10.3390/cells12010195.


References
1.
El-Solh A, Hattemer A, Hauser A, Alhajhusain A, Vora H . Clinical outcomes of type III Pseudomonas aeruginosa bacteremia. Crit Care Med. 2011; 40(4):1157-63. PMC: 3288436. DOI: 10.1097/CCM.0b013e3182377906. View

2.
Nakamura M, Ito H, Wate R, Nakano S, Hirano A, Kusaka H . Phosphorylated Smad2/3 immunoreactivity in sporadic and familial amyotrophic lateral sclerosis and its mouse model. Acta Neuropathol. 2008; 115(3):327-34. DOI: 10.1007/s00401-007-0337-z. View

3.
Vance R, Rietsch A, Mekalanos J . Role of the type III secreted exoenzymes S, T, and Y in systemic spread of Pseudomonas aeruginosa PAO1 in vivo. Infect Immun. 2005; 73(3):1706-13. PMC: 1064930. DOI: 10.1128/IAI.73.3.1706-1713.2005. View

4.
Balczon R, Prasain N, Ochoa C, Prater J, Zhu B, Alexeyev M . Pseudomonas aeruginosa exotoxin Y-mediated tau hyperphosphorylation impairs microtubule assembly in pulmonary microvascular endothelial cells. PLoS One. 2013; 8(9):e74343. PMC: 3762819. DOI: 10.1371/journal.pone.0074343. View

5.
Sayner S, Frank D, King J, Chen H, Vandewaa J, Stevens T . Paradoxical cAMP-induced lung endothelial hyperpermeability revealed by Pseudomonas aeruginosa ExoY. Circ Res. 2004; 95(2):196-203. DOI: 10.1161/01.RES.0000134922.25721.d9. View