title: Acidosis increases the susceptibility of respiratory epithelial cells toPseudomonas aeruginosa-induced cytotoxicity.
abstract: Bacterial infection can lead to acidosis of the local microenvironment, which is believed to exacerbate disease pathogenesis; however, the mechanisms by which changes in pH alter disease progression are poorly understood. We test the hypothesis that acidosis enhances respiratory epithelial cell death in response to infection withPseudomonas aeruginosaOur findings support the idea that acidosis in the context ofP. aeruginosainfection results in increased epithelial cell cytotoxicity due to ExoU intoxication. Importantly, enforced maintenance of neutral pH duringP. aeruginosainfection demonstrates that cytotoxicity is dependent on the acidosis. Investigation of the underlying mechanisms revealed that host cell cytotoxicity correlated with increased bacterial survival during an acidic infection that was due to reduced bactericidal activity of host-derived antimicrobial peptides. These findings extend previous reports that the activities of antimicrobial peptides are pH-dependent and provide novel insights into the consequences of acidosis on infection-derived pathology. Therefore, this report provides the first evidence that physiological levels of acidosis increase the susceptibility of epithelial cells to acutePseudomonasinfection and demonstrates the benefit of maintaining pH homeostasis during a bacterial infection.
authors.affiliation: Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire.
authors.forename: Iviana M
authors.initials: IM
authors.lastname: Torres
authors.affiliation: Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire.
authors.forename: Sally
authors.initials: S
authors.lastname: Demirdjian
authors.affiliation: Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Vargas
authors.affiliation: Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire.
authors.forename: Britton C
authors.initials: BC
authors.lastname: Goodale
authors.affiliation: Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire brent.berwin@dartmouth.edu.
authors.forename: Brent
authors.initials: B
authors.lastname: Berwin
mesh_terms: D000072283:A549 Cells; D000138:Acidosis / Q000382:microbiology* / Q000473:pathology; D023181:Antimicrobial Cationic Peptides / Q000494:pharmacology; D001426:Bacterial Proteins / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D004847:Epithelial Cells / Q000382:microbiology* / Q000473:pathology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008168:Lung / Q000473:pathology*; D050296:Microbial Viability / Q000187:drug effects; D011552:Pseudomonas Infections / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000502:physiology*
chemical_list: D023181:Antimicrobial Cationic Peptides; D001426:Bacterial Proteins
keywords: Pseudomonas aeruginosa; acidosis; cell death; epithelial cells