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.