title: Elucidating sources and roles of granzymes A and B during bacterial infection and sepsis.
abstract: During bacterial sepsis, proinflammatory cytokines contribute to multiorgan failure and death in a process regulated in part by cytolytic cell granzymes. When challenged with a sublethal dose of the identified mouse pathogen Brucella microti, wild-type (WT) and granzyme A (gzmA)(-/-) mice eliminate the organism from liver and spleen in 2 or 3 weeks, whereas the bacteria persist in mice lacking perforin or granzyme B as well as in mice depleted of Tc cells. In comparison, after a fatal challenge, only gzmA(-/-) mice exhibit increased survival, which correlated with reduced proinflammatory cytokines. Depletion of natural killer (NK) cells protects WT mice from sepsis without influencing bacterial clearance and the transfer of WT, but not gzmA(-/-) NK, cells into gzmA(-/-) recipients restores the susceptibility to sepsis. Therefore, infection-related pathology, but not bacterial clearance, appears to require gzmA, suggesting the protease may be a therapeutic target for the prevention of bacterial sepsis without affecting immune control of the pathogen.
authors.affiliation: Cell Immunity in Cancer, Inflammation and Infection Group, Department of Biochemistry and Molecular and Cell Biology, Biomedical Research Centre of Aragon (CIBA), IIS Aragon/University of Zaragoza, Zaragoza 50009, Spain.
authors.forename: Maykel A
authors.initials: MA
authors.lastname: Arias
authors.affiliation: Unidad de Tecnología en Producción y Sanidad Animal, Centro de Investigación y Tecnología Agroalimentaria (CITA), Gobierno de Aragón, Zaragoza 50059, Spain.
authors.forename: María P
authors.initials: MP
authors.lastname: Jiménez de Bagües
authors.affiliation: Grupo de Genética de Micobacterias, Departamento Microbiología, Medicina Preventiva y Salud Pública, Universidad de Zaragoza, Zaragoza 50009, Spain.
authors.forename: Nacho
authors.initials: N
authors.lastname: Aguiló
authors.affiliation: Department of Clinical Biochemistry and Molecular Biology, H.C.U. Lozano Blesa, Zaragoza 50009, Spain.
authors.forename: Sebastián
authors.initials: S
authors.lastname: Menao
authors.affiliation: CIMA, Gene Therapy and Hepatology Unit, University of Navarra, Pamplona 31008, Spain.
authors.forename: Sandra
authors.initials: S
authors.lastname: Hervás-Stubbs
authors.affiliation: Unidad de Anatomía Patológica, IIS Aragón, Zaragoza 50009, Spain.
authors.forename: Alba
authors.initials: A
authors.lastname: de Martino
authors.affiliation: College of Veterinary Medicine, Western University of Health Sciences, Pomona, CA 91766-1854, USA.
authors.forename: Ana
authors.initials: A
authors.lastname: Alcaraz
authors.affiliation: Former Member of Metschnikoff Laboratory, Max-Planck-Institute for Immunology and Epigenetics, Freiburg 79108, Germany.
authors.forename: Markus M
authors.initials: MM
authors.lastname: Simon
authors.affiliation: TheraTest Labs, Inc., Lombard, IL 60148, USA; NorthShore University Research Institute, Evanston, IL 60201, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Froelich
authors.affiliation: Cell Immunity in Cancer, Inflammation and Infection Group, Department of Biochemistry and Molecular and Cell Biology, Biomedical Research Centre of Aragon (CIBA), IIS Aragon/University of Zaragoza, Zaragoza 50009, Spain; Nanoscience Institute of Aragon (INA), University of Zaragoza, Zaragoza 50018, Spain; Aragon I+D Foundation, Zaragoza 20018, Spain. Electronic address: pardojim@unizar.es.
authors.forename: Julián
authors.initials: J
authors.lastname: Pardo
mesh_terms: D000818:Animals; D016470:Bacteremia / Q000378:metabolism*; D002002:Brucella; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D053804:Granzymes / Q000235:genetics / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D013154:Spleen / Q000378:metabolism / Q000473:pathology
chemical_list: D016207:Cytokines; D053804:Granzymes; C509214:Gzmb protein, mouse; C000597315:granzyme A, mouse