title: Granzymes A and B Regulate the Local Inflammatory Response during Klebsiella pneumoniae Pneumonia.
abstract: Klebsiella pneumoniae is a common cause of hospital-acquired pneumonia. Granzymes (gzms), mainly found in cytotoxic lymphocytes, have been implicated as mediators of infection and inflammation. We here sought to investigate the role of gzmA and gzmB in the host response to K. pneumoniae-induced airway infection and sepsis. For this purpose, pneumonia was induced in wild-type (WT) and gzmA-deficient (gzmA-/-), gzmB-/- and gzmAxB-/- mice by intranasal infection with K. pneumoniae. In WT mice, gzmA and gzmB were mainly expressed by natural killer cells. Pneumonia was associated with reduced intracellular gzmA and increased intracellular gzmB levels. Gzm deficiency had little impact on antibacterial defence: gzmA-/- and gzmAxB-/- mice transiently showed modestly higher bacterial loads in the lungs but not in distant organs. GzmB-/- and, to a larger extent, gzmAxB-/- mice displayed transiently increased lung inflammation, reflected in the semi-quantitative histology scores and levels of pro-inflammatory cytokines and chemokines. Most differences between gzm-deficient and WT mice had disappeared during late-stage pneumonia. Gzm deficiency did not impact on distant organ injury or survival. These results suggest that gzmA and gzmB partly regulate local inflammation during early pneumonia but eventually play an insignificant role during pneumosepsis by the common human pathogen K. pneumoniae.
authors.affiliation: Center for Experimental and Molecular Medicine (CEMM), Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: M Isabel
authors.initials: MI
authors.lastname: García-Laorden
authors.forename: Ingrid
authors.initials: I
authors.lastname: Stroo
authors.forename: Dana C
authors.initials: DC
authors.lastname: Blok
authors.forename: Sandrine
authors.initials: S
authors.lastname: Florquin
authors.forename: Jan Paul
authors.initials: JP
authors.lastname: Medema
authors.forename: Alex F
authors.initials: AF
authors.lastname: de Vos
authors.forename: Tom
authors.initials: T
authors.lastname: van der Poll
mesh_terms: D000818:Animals; D001433:Bacteriolysis; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D053804:Granzymes / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D056747:Immunomodulation; D018836:Inflammation Mediators / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology* / Q000382:microbiology; D007710:Klebsiella Infections / Q000276:immunology*; D007711:Klebsiella pneumoniae / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011014:Pneumonia / Q000276:immunology*
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D053804:Granzymes