title: Antioxidant Defenses of Francisella tularensis Modulate Macrophage Function and Production of Proinflammatory Cytokines.
abstract: Francisella tularensis, the causative agent of a fatal human disease known as tularemia, has been used in the bioweapon programs of several countries in the past, and now it is considered a potential bioterror agent. Extreme infectivity and virulence of F. tularensis is due to its ability to evade immune detection and to suppress the host's innate immune responses. However, Francisella-encoded factors and mechanisms responsible for causing immune suppression are not completely understood. Macrophages and neutrophils generate reactive oxygen species (ROS)/reactive nitrogen species as a defense mechanism for the clearance of phagocytosed microorganisms. ROS serve a dual role; at high concentrations they act as microbicidal effector molecules that destroy intracellular pathogens, and at low concentrations they serve as secondary signaling messengers that regulate the expression of various inflammatory mediators. We hypothesized that the antioxidant defenses of F. tularensis maintain redox homeostasis in infected macrophages to prevent activation of redox-sensitive signaling components that ultimately result in suppression of pro-inflammatory cytokine production and macrophage microbicidal activity. We demonstrate that antioxidant enzymes of F. tularensis prevent the activation of redox-sensitive MAPK signaling components, NF-κB signaling, and the production of pro-inflammatory cytokines by inhibiting the accumulation of ROS in infected macrophages. We also report that F. tularensis inhibits ROS-dependent autophagy to promote its intramacrophage survival. Collectively, this study reveals novel pathogenic mechanisms adopted by F. tularensis to modulate macrophage innate immune functions to create an environment permissive for its intracellular survival and growth.
authors.affiliation: From the Department of Microbiology and Immunology, New York Medical College, Valhalla, New York 10595.
authors.forename: Seham M
authors.initials: SM
authors.lastname: Rabadi
authors.affiliation: From the Department of Microbiology and Immunology, New York Medical College, Valhalla, New York 10595.
authors.forename: Belkys C
authors.initials: BC
authors.lastname: Sanchez
authors.affiliation: From the Department of Microbiology and Immunology, New York Medical College, Valhalla, New York 10595.
authors.forename: Mrudula
authors.initials: M
authors.lastname: Varanat
authors.affiliation: the Department of Basic and Social Sciences, Albany College of Pharmacy and Health Sciences, Albany, New York 12208, and.
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Ma
authors.affiliation: the Department of Basic and Social Sciences, Albany College of Pharmacy and Health Sciences, Albany, New York 12208, and.
authors.forename: Sally V
authors.initials: SV
authors.lastname: Catlett
authors.affiliation: the Colleges of Nanoscale Science and Engineering, State University of New York Polytechnic Institute, Albany, New York 12203.
authors.forename: Juan Andres
authors.initials: JA
authors.lastname: Melendez
authors.affiliation: the Department of Basic and Social Sciences, Albany College of Pharmacy and Health Sciences, Albany, New York 12208, and Meenakshi.Malik@acphs.edu.
authors.forename: Meenakshi
authors.initials: M
authors.lastname: Malik
authors.affiliation: From the Department of Microbiology and Immunology, New York Medical College, Valhalla, New York 10595, Shekhar_Bakshi@nymc.edu.
authors.forename: Chandra Shekhar
authors.initials: CS
authors.lastname: Bakshi
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D005604:Francisella tularensis / Q000235:genetics / Q000472:pathogenicity*; D006706:Homeostasis; D007113:Immunity, Innate; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D016207:Cytokines; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D048051:p38 Mitogen-Activated Protein Kinases
keywords: bacterial pathogenesis; cytokine induction; immunosuppression; p38 MAPK; redox signaling