title: Pseudomonas aeruginosa exoenzymes U and Y induce a transmissible endothelial proteinopathy.
abstract: We tested the hypothesis that Pseudomonas aeruginosa type 3 secretion system effectors exoenzymes Y and U (ExoY and ExoU) induce release of a high-molecular-weight endothelial tau, causing transmissible cell injury characteristic of an infectious proteinopathy. Both the bacterial delivery of ExoY and ExoU and the conditional expression of an activity-attenuated ExoU induced time-dependent pulmonary microvascular endothelial cell gap formation that was paralleled by the loss of intracellular tau and the concomitant appearance of high-molecular-weight extracellular tau. Transfer of the high-molecular-weight tau in filtered supernatant to naïve endothelial cells resulted in intracellular accumulation of tau clusters, which was accompanied by cell injury, interendothelial gap formation, decreased endothelial network stability in Matrigel, and increased lung permeability. Tau oligomer monoclonal antibodies captured monomeric tau from filtered supernatant but did not retrieve higher-molecular-weight endothelial tau and did not rescue the injurious effects of tau. Enrichment and transfer of high-molecular-weight tau to naïve cells was sufficient to cause injury. Thus we provide the first evidence for a pathophysiological stimulus that induces release and transmissibility of high-molecular-weight endothelial tau characteristic of an endothelial proteinopathy.
authors.affiliation: Department of Physiology and Cell Biology, University of South Alabama, Mobile, Alabama; Center for Lung Biology, University of South Alabama, Mobile, Alabama;
authors.forename: K Adam
authors.initials: KA
authors.lastname: Morrow
authors.affiliation: Physician-Scientist Training Program, Department of Medicine, University of Texas-Southwestern Medical Center, Dallas, Texas; Division of Pulmonary and Critical Care, University of Texas-Southwestern Medical Center, Dallas, Texas;
authors.forename: Cristhiaan D
authors.initials: CD
authors.lastname: Ochoa
authors.affiliation: Department of Biochemistry and Molecular Biology, University of South Alabama, Mobile, Alabama; Center for Lung Biology, University of South Alabama, Mobile, Alabama;
authors.forename: Ron
authors.initials: R
authors.lastname: Balczon
authors.affiliation: Department of Physiology and Cell Biology, University of South Alabama, Mobile, Alabama; Center for Lung Biology, University of South Alabama, Mobile, Alabama;
authors.forename: Chun
authors.initials: C
authors.lastname: Zhou
authors.affiliation: Department of Physiology and Cell Biology, University of South Alabama, Mobile, Alabama; Center for Lung Biology, University of South Alabama, Mobile, Alabama;
authors.forename: Laura
authors.initials: L
authors.lastname: Cauthen
authors.affiliation: Department of Biochemistry and Molecular Biology, University of South Alabama, Mobile, Alabama; Center for Lung Biology, University of South Alabama, Mobile, Alabama;
authors.forename: Mikhail
authors.initials: M
authors.lastname: Alexeyev
authors.affiliation: Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin; Division of Hematology/Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin;
authors.forename: Katherine M
authors.initials: KM
authors.lastname: Schmalzer
authors.affiliation: Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, Wisconsin; and Center for Infectious Disease Research, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Dara W
authors.initials: DW
authors.lastname: Frank
authors.affiliation: Department of Physiology and Cell Biology, University of South Alabama, Mobile, Alabama; Department of Medicine, University of South Alabama, Mobile, Alabama; Center for Lung Biology, University of South Alabama, Mobile, Alabama; tstevens@southalabama.edu.
authors.forename: Troy
authors.initials: T
authors.lastname: Stevens
mesh_terms: D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism / Q000382:microbiology*; D008168:Lung / Q000201:enzymology / Q000382:microbiology; D055806:Microvessels / Q000378:metabolism; D011552:Pseudomonas Infections / Q000382:microbiology / Q000635:transmission*; D011550:Pseudomonas aeruginosa / Q000201:enzymology*; D051381:Rats
chemical_list: D000242:Cyclic AMP
keywords: aggregation; infection; microtubules; pneumonia; proteinopathy