title: Protective Role for Macrophages in Respiratory Francisella tularensis Infection.
abstract: Francisella tularensiscauses lethal pneumonia following infection of the lungs by targeting macrophages for intracellular replication; however, macrophages stimulated with interferon gamma (IFN-γ) can resist infectionin vitroWe therefore hypothesized that the protective effect of IFN-γ againstF. tularensisin vivorequires macrophages receptive to stimulation. We found that the lethality of pulmonaryF. tularensisLVS infection was exacerbated under conditions of alveolar macrophage depletion and in mice with a macrophage-specific defect in IFN-γ signaling (termed mice with macrophages insensitive to IFN-γ [MIIG mice]). We previously found that treatment with exogenous interleukin 12 (IL-12) protects againstF. tularensisinfection; this protection was lost in MIIG mice. MIIG mice also exhibited reduced neutrophil recruitment to the lungs following infection. Systemic neutrophil depletion was found to render wild-type mice highly sensitive to respiratoryF. tularensisinfection, and depletion beginning at 3 days postinfection led to more pronounced sensitivity than depletion beginning prior to infection. Furthermore, IL-12-mediated protection required NADPH oxidase activity. These results indicate that lung macrophages serve a critical protective role in respiratoryF. tularensisLVS infection. Macrophages require IFN-γ signaling to mediate protection, which ultimately results in recruitment of neutrophils to further aid in survival from infection.
authors.affiliation: Department of Immunology and Microbial Disease, Albany Medical College, Albany, New York, USA.
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Steiner
authors.affiliation: Department of Immunology and Microbial Disease, Albany Medical College, Albany, New York, USA.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Furuya
authors.affiliation: Division of Immunobiology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.|Division of Bone Marrow Transplantation and Immune Deficiency, Department of Pediatrics, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Jordan
authors.affiliation: Department of Immunology and Microbial Disease, Albany Medical College, Albany, New York, USA metzged@mail.amc.edu.
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Metzger
mesh_terms: D000818:Animals; D005604:Francisella tularensis / Q000472:pathogenicity; D007371:Interferon-gamma / Q000276:immunology*; D018664:Interleukin-12 / Q000494:pharmacology*; D008168:Lung / Q000382:microbiology; D016676:Macrophages, Alveolar / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D019255:NADPH Oxidases / Q000378:metabolism; D009504:Neutrophils / Q000276:immunology; D018410:Pneumonia, Bacterial / Q000276:immunology; D014406:Tularemia / Q000276:immunology*
chemical_list: D018664:Interleukin-12; D007371:Interferon-gamma; D019255:NADPH Oxidases
keywords: interferons; lung defense; lung infection; macrophages; neutrophils; tularemia