Mutation in the transcriptional regulator PhoP contributes to avirulence of Mycobacterium tuberculosis H37Ra strain.
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.
Lee
Jong Seok
JS
Department of Immunology, Max Planck Institute for Infection Biology, Charitéplatz 1, 10117 Berlin, Germany.
Krause
Roland
R
Schreiber
Jörg
J
Mollenkopf
Hans-Joachim
HJ
Kowall
Jane
J
Stein
Robert
R
Jeon
Bo-Young
BY
Kwak
Jeong-Yeon
JY
Song
Min-Kyong
MK
Patron
Juan Pablo
JP
Jorg
Sabine
S
Roh
Kyoungmin
K
Cho
Sang-Nae
SN
Kaufmann
Stefan H E
SH
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
D001426:Bacterial Proteins; D014157:Transcription Factors; C061064:PhoP protein, Bacteria