title: Mutation in the transcriptional regulator PhoP contributes to avirulence of Mycobacterium tuberculosis H37Ra strain.
abstract: Attenuated strains of mycobacteria can be exploited to determine genes essential for their pathogenesis and persistence. To this goal, we sequenced the genome of H37Ra, an attenuated variant of Mycobacterium tuberculosis H37Rv strain. Comparison with H37Rv revealed three unique coding region polymorphisms. One polymorphism was located in the DNA-binding domain of the transcriptional regulator PhoP, causing the protein's diminished DNA-binding capacity. Temporal gene expression profiles showed that several genes with reduced expression in H37Ra were also repressed in an H37Rv phoP knockout strain. At later time points, genes of the dormancy regulon, typically expressed in a state of nonreplicating persistence, were upregulated in H37Ra. Complementation of H37Ra with H37Rv phoP partially restored its persistence in a murine macrophage infection model. Our approach demonstrates the feasibility of identifying minute but distinct differences between isogenic strains and illustrates the consequences of single point mutations on the survival stratagem of M. tuberculosis.
authors.affiliation: Department of Immunology, Max Planck Institute for Infection Biology, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Jong Seok
authors.initials: JS
authors.lastname: Lee
authors.forename: Roland
authors.initials: R
authors.lastname: Krause
authors.forename: Jörg
authors.initials: J
authors.lastname: Schreiber
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Mollenkopf
authors.forename: Jane
authors.initials: J
authors.lastname: Kowall
authors.forename: Robert
authors.initials: R
authors.lastname: Stein
authors.forename: Bo-Young
authors.initials: BY
authors.lastname: Jeon
authors.forename: Jeong-Yeon
authors.initials: JY
authors.lastname: Kwak
authors.forename: Min-Kyong
authors.initials: MK
authors.lastname: Song
authors.forename: Juan Pablo
authors.initials: JP
authors.lastname: Patron
authors.forename: Sabine
authors.initials: S
authors.lastname: Jorg
authors.forename: Kyoungmin
authors.initials: K
authors.lastname: Roh
authors.forename: Sang-Nae
authors.initials: SN
authors.lastname: Cho
authors.forename: Stefan H E
authors.initials: SH
authors.lastname: Kaufmann
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001426:Bacterial Proteins / Q000737:chemistry / Q000235:genetics*; D002478:Cells, Cultured; D005816:Genetic Complementation Test; D008264:Macrophages / Q000382:microbiology; D051379:Mice; D008969:Molecular Sequence Data; D009169:Mycobacterium tuberculosis / Q000737:chemistry* / Q000472:pathogenicity*; D017354:Point Mutation; D011110:Polymorphism, Genetic; D017434:Protein Structure, Tertiary / Q000235:genetics; D016415:Sequence Alignment; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics*; D014774:Virulence
chemical_list: D001426:Bacterial Proteins; D014157:Transcription Factors; C061064:PhoP protein, Bacteria