title: Metabolic Reprogramming of Host Cells by Virulent Francisella tularensis for Optimal Replication and Modulation of Inflammation.
abstract: A shift in macrophage metabolism from oxidative phosphorylation to aerobic glycolysis is a requirement for activation to effectively combat invading pathogens. Francisella tularensis is a facultative intracellular bacterium that causes an acute, fatal disease called tularemia. Its primary mechanism of virulence is its ability to evade and suppress inflammatory responses while replicating in the cytosol of macrophages. The means by which F. tularensis modulates macrophage activation are not fully elucidated. In this study, we demonstrate that virulent F. tularensis impairs production of inflammatory cytokines in primary macrophages by preventing their shift to aerobic glycolysis, as evidenced by the downregulation of hypoxia inducible factor 1α and failure to upregulate pfkfb3 We also show that Francisella capsule is required for this process. In addition to modulating inflammatory responses, inhibition of glycolysis in host cells is also required for early replication of virulent Francisella Taken together, our data demonstrate that metabolic reprogramming of host cells by F. tularensis is a key component of both inhibition of host defense mechanisms and replication of the bacterium.
authors.affiliation: Immunity to Pulmonary Pathogens Section, Laboratory of Bacteriology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840;
authors.forename: Elliott V
authors.initials: EV
authors.lastname: Wyatt
authors.affiliation: Immunity to Pulmonary Pathogens Section, Laboratory of Bacteriology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840;
authors.forename: Karina
authors.identifier: 0000-0002-4215-242X
authors.initials: K
authors.lastname: Diaz
authors.affiliation: Immunity to Pulmonary Pathogens Section, Laboratory of Bacteriology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840;
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Griffin
authors.affiliation: Department of Microbiology, University of Iowa Carver College of Medicine, Iowa City, IA 52242;
authors.forename: Jed A
authors.identifier: 0000-0002-4947-8246
authors.initials: JA
authors.lastname: Rasmussen
authors.affiliation: Immunity to Pulmonary Pathogens Section, Laboratory of Bacteriology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840;
authors.forename: Deborah D
authors.initials: DD
authors.lastname: Crane
authors.affiliation: Department of Microbiology, University of Iowa Carver College of Medicine, Iowa City, IA 52242; Genetics Program, University of Iowa Carver College of Medicine, Iowa City, IA 52242; and Midwest Regional Center for Excellence in Biodefense and Emerging Infectious Disease Research, University of Iowa Carver College of Medicine, Iowa City, IA 52242.
authors.forename: Bradley D
authors.initials: BD
authors.lastname: Jones
authors.affiliation: Immunity to Pulmonary Pathogens Section, Laboratory of Bacteriology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840; bosioc@niaid.nih.gov.
authors.forename: Catharine M
authors.initials: CM
authors.lastname: Bosio
mesh_terms: D000818:Animals; D016667:Bacterial Capsules / Q000276:immunology*; D065150:Cellular Reprogramming; D016207:Cytokines / Q000276:immunology; D015536:Down-Regulation; D005604:Francisella tularensis / Q000472:pathogenicity*; D006019:Glycolysis; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007249:Inflammation / Q000276:immunology*; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D025481:Phosphofructokinase-2 / Q000378:metabolism; D014406:Tularemia / Q000276:immunology; D014774:Virulence
chemical_list: D016207:Cytokines; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C000595376:PFKFB3 protein, mouse; D025481:Phosphofructokinase-2