Pseudomonas aeruginosainfection liberates transmissible, cytotoxic prion amyloids.
Patients who recover from pneumonia subsequently have elevated rates of death after hospital discharge as a result of secondary organ damage, the causes of which are unknown. We used the bacteriumPseudomonas aeruginosa, a common cause of hospital-acquired pneumonia, as a model for investigating this phenomenon. We show that infection of pulmonary endothelial cells byP. aeruginosainduces production and release of a cytotoxic amyloid molecule with prion characteristics, including resistance to various nucleases and proteases. This cytotoxin was self-propagating, was neutralized by anti-amyloid Abs, and induced death of endothelial cells and neurons. Moreover, the cytotoxin induced edema in isolated lungs. Endothelial cells and isolated lungs were protected from cytotoxin-induced death by stimulation of signal transduction pathways that are linked to prion protein. Analysis of bronchoalveolar lavage fluid collected from human patients withP. aeruginosapneumonia demonstrated cytotoxic activity, and lavage fluid contained amyloid molecules, including oligomeric τ and Aβ. Demonstration of long-lived cytotoxic agents afterPseudomonasinfection may establish a molecular link to the high rates of death as a result of end-organ damage in the months after recovery from pneumonia, and modulation of signal transduction pathways that have been linked to prion protein may provide a mechanism for intervention.-Balczon, R., Morrow, K. A., Zhou, C., Edmonds, B., Alexeyev, M., Pittet, J.-F., Wagener, B. M., Moser, S. A., Leavesley, S., Zha, X., Frank, D. W., Stevens, T.Pseudomonas aeruginosainfection liberates transmissible, cytotoxic prion amyloids.
Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, Alabama, USA; rbalczon@southalabama.edu.|Center for Lung Biology, College of Medicine, University of South Alabama, Mobile, Alabama, USA.
Ron
R
Balczon
Center for Lung Biology, College of Medicine, University of South Alabama, Mobile, Alabama, USA.|Department of Physiology and Cell Biology, College of Medicine, University of South Alabama, Mobile, Alabama, USA.
K Adam
KA
Morrow
Center for Lung Biology, College of Medicine, University of South Alabama, Mobile, Alabama, USA.|Department of Physiology and Cell Biology, College of Medicine, University of South Alabama, Mobile, Alabama, USA.
Chun
C
Zhou
Center for Lung Biology, College of Medicine, University of South Alabama, Mobile, Alabama, USA.
Bradley
B
Edmonds
Center for Lung Biology, College of Medicine, University of South Alabama, Mobile, Alabama, USA.|Department of Physiology and Cell Biology, College of Medicine, University of South Alabama, Mobile, Alabama, USA.
Mikhail
M
Alexeyev
Department of Anesthesia and Perioperative Medicine, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, USA.
Jean-Francois
JF
Pittet
Department of Anesthesia and Perioperative Medicine, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, USA.
Brant M
BM
Wagener
Department of Pathology, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, USA.
Stephen A
SA
Moser
Center for Lung Biology, College of Medicine, University of South Alabama, Mobile, Alabama, USA.|Department of Chemical and Biomedical Engineering, College of Medicine, University of South Alabama, Mobile, Alabama, USA.
Silas
S
Leavesley
Center for Lung Biology, College of Medicine, University of South Alabama, Mobile, Alabama, USA.|Department of Physiology and Cell Biology, College of Medicine, University of South Alabama, Mobile, Alabama, USA.
Xiangming
X
Zha
Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
Dara W
DW
Frank
Center for Lung Biology, College of Medicine, University of South Alabama, Mobile, Alabama, USA.|Department of Physiology and Cell Biology, College of Medicine, University of South Alabama, Mobile, Alabama, USA.
Troy
T
Stevens
D000818:Animals; D003603:Cytotoxins / Q000378:metabolism*; D004487:Edema; D042783:Endothelial Cells / Q000382:microbiology; D006801:Humans; D051379:Mice; D009474:Neurons / Q000382:microbiology; D018410:Pneumonia, Bacterial / Q000382:microbiology / Q000473:pathology; D000072002:Prion Proteins / Q000378:metabolism / Q000633:toxicity*; D011552:Pseudomonas Infections / Q000378:metabolism* / Q000473:pathology; D011550:Pseudomonas aeruginosa; D051381:Rats
D003603:Cytotoxins; D000072002:Prion Proteins