title: The Mycobacterium avium ssp. paratuberculosis specific mptD gene is required for maintenance of the metabolic homeostasis necessary for full virulence in mouse infections.
abstract: Mycobacterium avium subspecies paratuberculosis (MAP) causes Johne's disease, a chronic granulomatous enteritis in ruminants. Furthermore, infections of humans with MAP have been reported and a possible association with Crohn's disease and diabetes type I is currently discussed. MAP owns large sequence polymorphisms (LSPs) that were exclusively found in this mycobacteria species. The relevance of these LSPs in the pathobiology of MAP is still unclear. The mptD gene (MAP3733c) of MAP belongs to a small group of functionally uncharacterized genes, which are not present in any other sequenced mycobacteria species. mptD is part of a predicted operon (mptABCDEF), encoding a putative ATP binding cassette-transporter, located on the MAP-specific LSP14. In the present study, we generated an mptD knockout strain (MAPΔmptD) by specialized transduction. In order to investigate the potential role of mptD in the host, we performed infection experiments with macrophages. By this, we observed a significantly reduced cell number of MAPΔmptD early after infection, indicating that the mutant was hampered with respect to adaptation to the early macrophage environment. This important role of mptD was supported in mouse infection experiments where MAPΔmptD was significantly attenuated after peritoneal challenge. Metabolic profiling was performed to determine the cause for the reduced virulence and identified profound metabolic disorders especially in the lipid metabolism of MAPΔmptD. Overall our data revealed the mptD gene to be an important factor for the metabolic adaptation of MAP required for persistence in the host.
authors.affiliation: Department of Infectious Diseases, Institute for Microbiology, University of Veterinary Medicine Hannover Hannover, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Meißner
authors.affiliation: Department of Infectious Diseases, Institute for Microbiology, University of Veterinary Medicine Hannover Hannover, Germany.
authors.forename: Elke
authors.initials: E
authors.lastname: Eckelt
authors.affiliation: Department of Infectious Diseases, Institute for Microbiology, University of Veterinary Medicine Hannover Hannover, Germany.
authors.forename: Tina
authors.initials: T
authors.lastname: Basler
authors.affiliation: Department of Infectious Diseases, Institute for Microbiology, University of Veterinary Medicine Hannover Hannover, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Meens
authors.affiliation: Department of Infectious Diseases, Institute for Microbiology, University of Veterinary Medicine Hannover Hannover, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Heinzmann
authors.affiliation: Helmholtz Centre for Infection Research, Molecular Immunology Braunschweig, Germany.
authors.forename: Abdulhadi
authors.initials: A
authors.lastname: Suwandi
authors.affiliation: Departamento de Imunologia, Instituto de Microbiologia Paulo Góes, Universidade Federal do Rio de Janeiro (UFRJ) Rio de Janeiro, Brazil ; Division of Structural Biochemistry, Research Center Borstel, Leibniz-Center for Medicine and Biosciences Borstel, Germany.
authors.forename: Walter M R
authors.initials: WM
authors.lastname: Oelemann
authors.affiliation: Metabolomic Discoveries GmbH Potsdam-Golm, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Trenkamp
authors.affiliation: Division of Structural Biochemistry, Research Center Borstel, Leibniz-Center for Medicine and Biosciences Borstel, Germany.
authors.forename: Otto
authors.initials: O
authors.lastname: Holst
authors.affiliation: Helmholtz Centre for Infection Research, Molecular Immunology Braunschweig, Germany.
authors.forename: Siegfried
authors.initials: S
authors.lastname: Weiss
authors.affiliation: Bioinformatics, Leibniz Institute DSMZ-German Collection of Microorganisms and Cell Cultures Braunschweig, Germany ; German Centre of Infection Research, Partner Site Hannover-Braunschweig Braunschweig, Germany.
authors.forename: Boyke
authors.initials: B
authors.lastname: Bunk
authors.affiliation: Bioinformatics, Leibniz Institute DSMZ-German Collection of Microorganisms and Cell Cultures Braunschweig, Germany ; German Centre of Infection Research, Partner Site Hannover-Braunschweig Braunschweig, Germany.
authors.forename: Cathrin
authors.initials: C
authors.lastname: Spröer
authors.affiliation: Department of Infectious Diseases, Institute for Microbiology, University of Veterinary Medicine Hannover Hannover, Germany.
authors.forename: Gerald-F
authors.initials: GF
authors.lastname: Gerlach
authors.affiliation: Department of Infectious Diseases, Institute for Microbiology, University of Veterinary Medicine Hannover Hannover, Germany.
authors.forename: Ralph
authors.initials: R
authors.lastname: Goethe
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D023061:Gene Order; D005798:Genes, Bacterial; D006706:Homeostasis; D050356:Lipid Metabolism; D008264:Macrophages / Q000382:microbiology; D055442:Metabolome; D055432:Metabolomics / Q000379:methods; D051379:Mice; D050296:Microbial Viability; D009154:Mutation; D016927:Mycobacterium avium subsp. paratuberculosis / Q000235:genetics* / Q000378:metabolism* / Q000472:pathogenicity; D010283:Paratuberculosis / Q000382:microbiology*
keywords: Mycobacterium infections; lipids; macrophages; metabolism; survival