title: Role of the dosR-dosS two-component regulatory system in Mycobacterium tuberculosis virulence in three animal models.
abstract: The Mycobacterium tuberculosis dosR gene (Rv3133c) is part of an operon, Rv3134c-Rv3132c, and encodes a response regulator that has been shown to be upregulated by hypoxia and other in vitro stress conditions and may be important for bacterial survival within granulomatous lesions found in tuberculosis. DosR is activated in response to hypoxia and nitric oxide by DosS (Rv3132c) or DosT (Rv2027c). We compared the virulence levels of an M. tuberculosis dosR-dosS deletion mutant (DeltadosR-dosS [DeltadosR-S]), a dosR-complemented strain, and wild-type H37Rv in rabbits, guinea pigs, and mice infected by the aerosol route and in a mouse hollow-fiber model that may mimic in vivo granulomatous conditions. In the mouse and the guinea pig models, the DeltadosR-S mutant exhibited a growth defect. In the rabbit, the DeltadosR-S mutant did not replicate more than the wild type. In the hollow-fiber model, the mutant phenotype was not different from that of the wild-type strain. Our analyses reveal that the dosR and dosS genes are required for full virulence and that there may be differences in the patterns of attenuation of this mutant between the animal models studied.
authors.affiliation: Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA. pconvers@jhsph.edu
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Converse
authors.forename: Petros C
authors.initials: PC
authors.lastname: Karakousis
authors.forename: Lee G
authors.initials: LG
authors.lastname: Klinkenberg
authors.forename: Anup K
authors.initials: AK
authors.lastname: Kesavan
authors.forename: Lan H
authors.initials: LH
authors.lastname: Ly
authors.forename: Shannon Sedberry
authors.initials: SS
authors.lastname: Allen
authors.forename: Jacques H
authors.initials: JH
authors.lastname: Grosset
authors.forename: Sanjay K
authors.initials: SK
authors.lastname: Jain
authors.forename: Gyanu
authors.initials: G
authors.lastname: Lamichhane
authors.forename: Yukari C
authors.initials: YC
authors.lastname: Manabe
authors.forename: David N
authors.initials: DN
authors.lastname: McMurray
authors.forename: Eric L
authors.initials: EL
authors.lastname: Nuermberger
authors.forename: William R
authors.initials: WR
authors.lastname: Bishai
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics*; D004195:Disease Models, Animal; D015964:Gene Expression Regulation, Bacterial; D006168:Guinea Pigs; D008168:Lung / Q000382:microbiology / Q000473:pathology; D051379:Mice; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000235:genetics* / Q000472:pathogenicity*; D009876:Operon / Q000235:genetics; D006656:Protamine Kinase / Q000235:genetics*; D011817:Rabbits; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000382:microbiology / Q000473:pathology; D014376:Tuberculosis / Q000235:genetics* / Q000473:pathology; D014774:Virulence
chemical_list: D001426:Bacterial Proteins; C506260:DevS protein, Mycobacterium tuberculosis; D006656:Protamine Kinase