Mutation in the Transcriptional Regulator PhoP Contributes to Avirulence of Mycobacterium tuberculosis H37Ra Strain

Jong Seok Lee, Roland Krause, Jörg Schreiber, Hans Joachim Mollenkopf, Jane Kowall, Robert Stein, Bo Young Jeon, Jeong Yeon Kwak, Min Kyong Song, Juan Pablo Patron, Sabine Jorg, Kyoungmin Roh, Sangnae Cho, Stefan H.E. Kaufmann

Research output: Contribution to journalArticle

116 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)97-103
Number of pages7
JournalCell Host and Microbe
Volume3
Issue number2
DOIs
Publication statusPublished - 2008 Feb 14

Fingerprint

Mycobacterium tuberculosis
Regulon
Mutation
Essential Genes
DNA-Binding Proteins
Mycobacterium
Transcriptome
Point Mutation
Genes
Macrophages
Genome
DNA
Infection

All Science Journal Classification (ASJC) codes

  • Parasitology
  • Microbiology
  • Virology

Cite this

Lee, J. S., Krause, R., Schreiber, J., Mollenkopf, H. J., Kowall, J., Stein, R., ... Kaufmann, S. H. E. (2008). Mutation in the Transcriptional Regulator PhoP Contributes to Avirulence of Mycobacterium tuberculosis H37Ra Strain. Cell Host and Microbe, 3(2), 97-103. https://doi.org/10.1016/j.chom.2008.01.002
Lee, Jong Seok ; Krause, Roland ; Schreiber, Jörg ; Mollenkopf, Hans Joachim ; Kowall, Jane ; Stein, Robert ; Jeon, Bo Young ; Kwak, Jeong Yeon ; Song, Min Kyong ; Patron, Juan Pablo ; Jorg, Sabine ; Roh, Kyoungmin ; Cho, Sangnae ; Kaufmann, Stefan H.E. / Mutation in the Transcriptional Regulator PhoP Contributes to Avirulence of Mycobacterium tuberculosis H37Ra Strain. In: Cell Host and Microbe. 2008 ; Vol. 3, No. 2. pp. 97-103.
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Lee, JS, Krause, R, Schreiber, J, Mollenkopf, HJ, Kowall, J, Stein, R, Jeon, BY, Kwak, JY, Song, MK, Patron, JP, Jorg, S, Roh, K, Cho, S & Kaufmann, SHE 2008, 'Mutation in the Transcriptional Regulator PhoP Contributes to Avirulence of Mycobacterium tuberculosis H37Ra Strain', Cell Host and Microbe, vol. 3, no. 2, pp. 97-103. https://doi.org/10.1016/j.chom.2008.01.002

Mutation in the Transcriptional Regulator PhoP Contributes to Avirulence of Mycobacterium tuberculosis H37Ra Strain. / Lee, Jong Seok; Krause, Roland; Schreiber, Jörg; Mollenkopf, Hans Joachim; Kowall, Jane; Stein, Robert; Jeon, Bo Young; Kwak, Jeong Yeon; Song, Min Kyong; Patron, Juan Pablo; Jorg, Sabine; Roh, Kyoungmin; Cho, Sangnae; Kaufmann, Stefan H.E.

In: Cell Host and Microbe, Vol. 3, No. 2, 14.02.2008, p. 97-103.

Research output: Contribution to journalArticle

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AU - Kowall, Jane

AU - Stein, Robert

AU - Jeon, Bo Young

AU - Kwak, Jeong Yeon

AU - Song, Min Kyong

AU - Patron, Juan Pablo

AU - Jorg, Sabine

AU - Roh, Kyoungmin

AU - Cho, Sangnae

AU - Kaufmann, Stefan H.E.

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N2 - 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.

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