title: Granzyme A impairs host defense during Streptococcus pneumoniae pneumonia.
abstract: Streptococcus pneumoniae is the most common causative pathogen in community-acquired pneumonia (CAP). Granzyme A (GzmA) is a serine protease produced by a variety of cell types involved in the immune response. We sought to determine the role of GzmA on the host response during pneumococcal pneumonia. GzmA was measured in bronchoalveolar lavage fluid (BALF) harvested from CAP patients from the infected and contralateral uninfected side and in lung tissue slides from CAP patients and controls. In CAP patients, GzmA levels were increased in BALF obtained from the infected lung. Human lungs showed constitutive GzmA expression by both parenchymal and nonparenchymal cells. In an experimental setting, pneumonia was induced in wild-type (WT) and GzmA-deficient (GzmA(-/-)) mice by intranasal inoculation of S. pneumoniae In separate experiments, WT and GzmA(-/-) mice were treated with natural killer (NK) cell depleting antibodies. Upon infection with S. pneumoniae, GzmA(-/-) mice showed a better survival and lower bacterial counts in BALF and distant body sites compared with WT mice. Although NK cells showed strong GzmA expression, NK cell depletion did not influence bacterial loads in either WT or GzmA(-/-) mice. These results implicate that GzmA plays an unfavorable role in host defense during pneumococcal pneumonia by a mechanism that does not depend on NK cells.
authors.affiliation: Center for Experimental and Molecular Medicine (CEMM), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; f.e.vandenboogaard@amc.nl.
authors.forename: Florry E
authors.initials: FE
authors.lastname: van den Boogaard
authors.affiliation: Laboratory of Experimental Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory, Amsterdam, The Netherlands;
authors.forename: Klaas P J M
authors.initials: KP
authors.lastname: van Gisbergen
authors.affiliation: Department of Respiratory Medicine, University Maastricht, The Netherlands;
authors.forename: Juanita H
authors.initials: JH
authors.lastname: Vernooy
authors.affiliation: Center for Experimental and Molecular Medicine (CEMM), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Laboratory of Experimental Oncology and Radiobiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands;
authors.forename: Jan P
authors.initials: JP
authors.lastname: Medema
authors.affiliation: Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands;
authors.forename: Joris J T H
authors.initials: JJ
authors.lastname: Roelofs
authors.affiliation: Center for Experimental and Molecular Medicine (CEMM), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands;
authors.forename: Marieke A D
authors.initials: MA
authors.lastname: van Zoelen
authors.affiliation: Department of Internal Medicine, St. Antonius Hospital, Nieuwegein, The Netherlands;
authors.forename: Henrik
authors.initials: H
authors.lastname: Endeman
authors.affiliation: Department of Internal Medicine, St. Antonius Hospital, Nieuwegein, The Netherlands;
authors.forename: Douwe H
authors.initials: DH
authors.lastname: Biesma
authors.affiliation: Bioceros, Utrecht, The Netherlands; and.
authors.forename: Louis
authors.initials: L
authors.lastname: Boon
authors.affiliation: Center for Experimental and Molecular Medicine (CEMM), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands;
authors.forename: Cornelis
authors.initials: C
authors.lastname: Van't Veer
authors.affiliation: Center for Experimental and Molecular Medicine (CEMM), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands;
authors.forename: Alex F
authors.initials: AF
authors.lastname: de Vos
authors.affiliation: Center for Experimental and Molecular Medicine (CEMM), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Department of Medicine, Division of Infectious Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Tom
authors.initials: T
authors.lastname: van der Poll
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D016022:Case-Control Studies; D005260:Female; D053804:Granzymes / Q000502:physiology*; D006801:Humans; D007111:Immunity, Cellular; D007694:Killer Cells, Natural / Q000502:physiology; D008168:Lung / Q000201:enzymology / Q000276:immunology / Q000382:microbiology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D020556:Neutrophil Infiltration; D011018:Pneumonia, Pneumococcal / Q000201:enzymology* / Q000276:immunology / Q000382:microbiology; D013296:Streptococcus pneumoniae / Q000276:immunology*
chemical_list: D053804:Granzymes; C509212:GZMA protein, human
keywords: Streptococcus pneumoniae; granzyme A; inflammation; pneumonia