title: Cytotoxic cells kill intracellular bacteria through granulysin-mediated delivery of granzymes.
abstract: When killer lymphocytes recognize infected cells, perforin delivers cytotoxic proteases (granzymes) into the target cell to trigger apoptosis. What happens to intracellular bacteria during this process is unclear. Human, but not rodent, cytotoxic granules also contain granulysin, an antimicrobial peptide. Here, we show that granulysin delivers granzymes into bacteria to kill diverse bacterial strains. In Escherichia coli, granzymes cleave electron transport chain complex I and oxidative stress defense proteins, generating reactive oxygen species (ROS) that rapidly kill bacteria. ROS scavengers and bacterial antioxidant protein overexpression inhibit bacterial death. Bacteria overexpressing a GzmB-uncleavable mutant of the complex I subunit nuoF or strains that lack complex I still die, but more slowly, suggesting that granzymes disrupt multiple vital bacterial pathways. Mice expressing transgenic granulysin are better able to clear Listeria monocytogenes. Thus killer cells play an unexpected role in bacterial defense.
authors.affiliation: Cellular and Molecular Medicine Program, Boston Children's Hospital, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA. Electronic address: michael.walch@unifr.ch.
authors.forename: Michael
authors.initials: M
authors.lastname: Walch
authors.affiliation: Cellular and Molecular Medicine Program, Boston Children's Hospital, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Farokh
authors.initials: F
authors.lastname: Dotiwala
authors.affiliation: Cellular and Molecular Medicine Program, Boston Children's Hospital, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Sachin
authors.initials: S
authors.lastname: Mulik
authors.affiliation: Cellular and Molecular Medicine Program, Boston Children's Hospital, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Jerome
authors.initials: J
authors.lastname: Thiery
authors.affiliation: Cellular and Molecular Medicine Program, Boston Children's Hospital, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Tomas
authors.initials: T
authors.lastname: Kirchhausen
authors.affiliation: Feinberg School of Medicine, Northwestern University, 420E Superior Street, Chicago, IL 60611, USA.
authors.forename: Carol
authors.initials: C
authors.lastname: Clayberger
authors.affiliation: Feinberg School of Medicine, Northwestern University, 420E Superior Street, Chicago, IL 60611, USA.
authors.forename: Alan M
authors.initials: AM
authors.lastname: Krensky
authors.affiliation: Cellular and Molecular Medicine Program, Boston Children's Hospital, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Denis
authors.initials: D
authors.lastname: Martinvalet
authors.affiliation: Cellular and Molecular Medicine Program, Boston Children's Hospital, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA. Electronic address: judy.lieberman@childrens.harvard.edu.
authors.forename: Judy
authors.initials: J
authors.lastname: Lieberman
mesh_terms: D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism*; D001424:Bacterial Infections / Q000276:immunology*; D004926:Escherichia coli; D053804:Granzymes / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology* / Q000378:metabolism; D008089:Listeria monocytogenes; D051379:Mice; D008807:Mice, Inbred BALB C; D054353:Perforin / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013211:Staphylococcus aureus
chemical_list: D000945:Antigens, Differentiation, T-Lymphocyte; C075005:GNLY protein, human; D017382:Reactive Oxygen Species; D054353:Perforin; D053804:Granzymes