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; Sang Nae Cho; Stefan H.E. Kaufmann

doi:10.1016/j.chom.2008.01.002

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, Sang Nae Cho, Stefan H.E. Kaufmann

Department of Microbiology

Research output: Contribution to journal › Article › peer-review

136 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 language	English
Pages (from-to)	97-103
Number of pages	7
Journal	Cell Host and Microbe
Volume	3
Issue number	2
DOIs	https://doi.org/10.1016/j.chom.2008.01.002
Publication status	Published - 2008 Feb 14

Bibliographical note

Funding Information:
This work received financial support from the European Union Framework Program 6 Project “Design and Testing of Vaccine Candidates Against Tuberculosis (TBVAC),” the Bundesministerium für Bildung und Forschung Kompetenz Netzwerk “PathoGenoMikPlus,” the National Genome Research Network 2 (Germany) to S.H.E.K., and the Korea Health 21 R&D Project, Ministry of Health and Welfare, Republic of Korea (01-PJ10-PG6-01GM03-002) to S.-N.C. We thank Carlos Martin for providing the PhoP complementation plasmid and for discussing results and Stewart T. Cole for providing the H37Rv strain. Thanks also to Mary Louise Grossman for editorial help and Marc Jacobsen, Vladimir Yeremeev, and Arunava Dasgupta for helpful discussions.

All Science Journal Classification (ASJC) codes

Parasitology
Microbiology
Virology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.chom.2008.01.002

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Lee, J. S., Krause, R., Schreiber, J., Mollenkopf, H. J., Kowall, J., Stein, R., Jeon, B. Y., Kwak, J. Y., Song, M. K., Patron, J. P., Jorg, S., Roh, K., Cho, S. N., & 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

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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.",

author = "Lee, {Jong Seok} and Roland Krause and J{\"o}rg Schreiber and Mollenkopf, {Hans Joachim} and Jane Kowall and Robert Stein and Jeon, {Bo Young} and Kwak, {Jeong Yeon} and Song, {Min Kyong} and Patron, {Juan Pablo} and Sabine Jorg and Kyoungmin Roh and Cho, {Sang Nae} and Kaufmann, {Stefan H.E.}",

note = "Funding Information: This work received financial support from the European Union Framework Program 6 Project “Design and Testing of Vaccine Candidates Against Tuberculosis (TBVAC),” the Bundesministerium f{\"u}r Bildung und Forschung Kompetenz Netzwerk “PathoGenoMikPlus,” the National Genome Research Network 2 (Germany) to S.H.E.K., and the Korea Health 21 R&D Project, Ministry of Health and Welfare, Republic of Korea (01-PJ10-PG6-01GM03-002) to S.-N.C. We thank Carlos Martin for providing the PhoP complementation plasmid and for discussing results and Stewart T. Cole for providing the H37Rv strain. Thanks also to Mary Louise Grossman for editorial help and Marc Jacobsen, Vladimir Yeremeev, and Arunava Dasgupta for helpful discussions. ",

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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, SN & 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

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T1 - Mutation in the Transcriptional Regulator PhoP Contributes to Avirulence of Mycobacterium tuberculosis H37Ra Strain

AU - Lee, Jong Seok

AU - Krause, Roland

AU - Schreiber, Jörg

AU - Mollenkopf, Hans Joachim

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, Sang Nae

AU - Kaufmann, Stefan H.E.

N1 - Funding Information: This work received financial support from the European Union Framework Program 6 Project “Design and Testing of Vaccine Candidates Against Tuberculosis (TBVAC),” the Bundesministerium für Bildung und Forschung Kompetenz Netzwerk “PathoGenoMikPlus,” the National Genome Research Network 2 (Germany) to S.H.E.K., and the Korea Health 21 R&D Project, Ministry of Health and Welfare, Republic of Korea (01-PJ10-PG6-01GM03-002) to S.-N.C. We thank Carlos Martin for providing the PhoP complementation plasmid and for discussing results and Stewart T. Cole for providing the H37Rv strain. Thanks also to Mary Louise Grossman for editorial help and Marc Jacobsen, Vladimir Yeremeev, and Arunava Dasgupta for helpful discussions.

PY - 2008/2/14

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

Abstract

Bibliographical note

All Science Journal Classification (ASJC) codes

UN SDGs

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