Patientswho recover frompneumonia 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 bacterium Pseudomonas aeruginosa, a common cause of hospital-acquired pneumonia, as a model for investigating this phenomenon. We show that infection of pulmonary endothelial cells by P. aeruginosa induces production and release of a cytotoxic amyloidmolecule 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-induceddeath by stimulation of signal transduction pathways that are linked to prion protein.Analysis of bronchoalveolar lavage fluid collected fromhuman patientswith P. aeruginosa pneumonia demonstrated cytotoxic activity, andlavage fluidcontainedamyloidmolecules, including oligomeric t andAb.Demonstrationof long-lived cytotoxic agents after Pseudomonas infectionmay establish a molecular link to the high rates of death as a result of end-organ damage in the months after recovery frompneumonia, and modulation of signal transduction pathways that have been linked to prion protein may provide a mechanism for intervention.