title: Dipeptidyl peptidase I controls survival from Klebsiella pneumoniae lung infection by processing surfactant protein D.
abstract: Prior work established that a deficiency in the cysteine protease dipeptidyl peptidase I (DPPI) improves survival following polymicrobial septic peritonitis. To test whether DPPI regulates survival from severe lung infections, DPPI(-/-) mice were studied in a Klebsiella pneumoniae lung infection model, finding that survival in DPPI(-/-) mice is significantly better than in DPPI(+/+) mice 8d after infection. DPPI(-/-) mice have significantly fewer bacteria in the lung than infected DPPI(+/+) mice, but no difference in lung histopathology, lung injury, or cytokine levels. To explore mechanisms of enhanced bacterial clearance in DPPI(-/-) mice, we examined the status of pulmonary collectins, finding that levels of surfactant protein D, but not of surfactant protein A, are higher in DPPI(-/-) than in DPPI(+/+) BAL fluid, and that DPPI(-/-) BAL fluid aggregate bacteria more effectively than control BAL fluid. Sequencing of the amino terminus of surfactant protein D revealed two or eight additional amino acids in surfactant protein D isolated from DPPI(-/-) mice, suggesting processing by DPPI. These results establish that DPPI is a major determinant of survival following Klebsiella pneumoniae lung infection and suggest that the survival disadvantage in DPPI(+/+) mice is in part due to processing of surfactant protein D by DPPI.
authors: Department of Medicine and The Cardiovascular Research Institute, University of California, San Francisco, CA 94143-0111.
authors: Rachel E
authors: RE
authors: Sutherland
authors: Department of Medicine and The Cardiovascular Research Institute, University of California, San Francisco, CA 94143-0111.
authors: Sophia S
authors: SS
authors: Barry
authors: Department of Medicine and The Cardiovascular Research Institute, University of California, San Francisco, CA 94143-0111.
authors: Joanna S
authors: JS
authors: Olsen
authors: Department of Medicine and The Cardiovascular Research Institute, University of California, San Francisco, CA 94143-0111.
authors: D Brenda
authors: DB
authors: Salantes
authors: Department of Medicine and The Cardiovascular Research Institute, University of California, San Francisco, CA 94143-0111.
authors: George H
authors: GH
authors: Caughey
authors: Department of Medicine and The Cardiovascular Research Institute, University of California, San Francisco, CA 94143-0111.
authors: Paul J
authors: PJ
authors: Wolters
mesh_terms: D000818:Animals; D020789:Cathepsin C / Q000235:genetics / Q000378:metabolism*; D007710:Klebsiella Infections / Q000378:metabolism* / Q000382:microbiology; D007711:Klebsiella pneumoniae / Q000378:metabolism*; D008168:Lung / Q000378:metabolism* / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D037663:Pulmonary Surfactant-Associated Protein D / Q000378:metabolism*; D015996:Survival Rate; D014018:Tissue Distribution
chemical_list: D037663:Pulmonary Surfactant-Associated Protein D; D020789:Cathepsin C
keywords: Bacterial killing; Collectin; Innate immunity; Pulmonary inflammation