Individual RD1 -region genes are required for export of ESAT-6/CFP-10 and for virulence of Mycobacterium tuberculosis

Kristi M. Guinn; Mark J. Hickey; Sanjeev K. Mathur; Kelly L. Zakel; Jeff E. Grotzke; David M. Lewinsohn; Sherilyn Smith; David R. Sherman

doi:10.1046/j.1365-2958.2003.03844.x

Individual RD1 -region genes are required for export of ESAT-6/CFP-10 and for virulence of Mycobacterium tuberculosis

Kristi M. Guinn, Mark J. Hickey, Sanjeev K. Mathur, Kelly L. Zakel, Jeff E. Grotzke, David M. Lewinsohn, Sherilyn Smith, David R. Sherman

Pulmonary and Critical Care Medicine

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

423 Scopus citations

Abstract

The RD1 genomic region is present in virulent strains of Mycobacterium tuberculosis (MTB), missing from the vaccine strain M. bovis BCG, and its importance to virulence has been established experimentally. Based on in silico analysis, it has been suggested that RD1 may encode a novel secretion system, but the mechanism by which this region affects virulence is unknown. Here we examined mutants disrupted in five individual RD1 genes. Both in vitro and in vivo, each mutant displayed an attenuated phenotype very similar to a mutant missing the entire RD1 region. Genetic complementation of individual genes restored virulence. Attenuated mutants could multiply within THP-1 cells, but they were unable to spread to uninfected macrophages. We also examined export of two immunodominant RD1 proteins, CFP-10 and ESAT-6. Export of these proteins was greatly reduced or abolished in each attenuated mutant. Again, genetic complementation restored a wild-type phenotype. Our results indicate that RD1 genes work together to form a single virulence determinant, and argue that RD1 encodes a novel specialized secretion system that Is required for pathogenesis of MTB.

Original language	English (US)
Pages (from-to)	359-370
Number of pages	12
Journal	Molecular Microbiology
Volume	51
Issue number	2
DOIs	https://doi.org/10.1046/j.1365-2958.2003.03844.x
State	Published - Jan 2004

ASJC Scopus subject areas

Microbiology
Molecular Biology

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10.1046/j.1365-2958.2003.03844.x

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title = "Individual RD1 -region genes are required for export of ESAT-6/CFP-10 and for virulence of Mycobacterium tuberculosis",

abstract = "The RD1 genomic region is present in virulent strains of Mycobacterium tuberculosis (MTB), missing from the vaccine strain M. bovis BCG, and its importance to virulence has been established experimentally. Based on in silico analysis, it has been suggested that RD1 may encode a novel secretion system, but the mechanism by which this region affects virulence is unknown. Here we examined mutants disrupted in five individual RD1 genes. Both in vitro and in vivo, each mutant displayed an attenuated phenotype very similar to a mutant missing the entire RD1 region. Genetic complementation of individual genes restored virulence. Attenuated mutants could multiply within THP-1 cells, but they were unable to spread to uninfected macrophages. We also examined export of two immunodominant RD1 proteins, CFP-10 and ESAT-6. Export of these proteins was greatly reduced or abolished in each attenuated mutant. Again, genetic complementation restored a wild-type phenotype. Our results indicate that RD1 genes work together to form a single virulence determinant, and argue that RD1 encodes a novel specialized secretion system that Is required for pathogenesis of MTB.",

author = "Guinn, {Kristi M.} and Hickey, {Mark J.} and Mathur, {Sanjeev K.} and Zakel, {Kelly L.} and Grotzke, {Jeff E.} and Lewinsohn, {David M.} and Sherilyn Smith and Sherman, {David R.}",

year = "2004",

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doi = "10.1046/j.1365-2958.2003.03844.x",

language = "English (US)",

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AU - Guinn, Kristi M.

AU - Hickey, Mark J.

AU - Mathur, Sanjeev K.

AU - Zakel, Kelly L.

AU - Grotzke, Jeff E.

AU - Lewinsohn, David M.

AU - Smith, Sherilyn

AU - Sherman, David R.

PY - 2004/1

Y1 - 2004/1

N2 - The RD1 genomic region is present in virulent strains of Mycobacterium tuberculosis (MTB), missing from the vaccine strain M. bovis BCG, and its importance to virulence has been established experimentally. Based on in silico analysis, it has been suggested that RD1 may encode a novel secretion system, but the mechanism by which this region affects virulence is unknown. Here we examined mutants disrupted in five individual RD1 genes. Both in vitro and in vivo, each mutant displayed an attenuated phenotype very similar to a mutant missing the entire RD1 region. Genetic complementation of individual genes restored virulence. Attenuated mutants could multiply within THP-1 cells, but they were unable to spread to uninfected macrophages. We also examined export of two immunodominant RD1 proteins, CFP-10 and ESAT-6. Export of these proteins was greatly reduced or abolished in each attenuated mutant. Again, genetic complementation restored a wild-type phenotype. Our results indicate that RD1 genes work together to form a single virulence determinant, and argue that RD1 encodes a novel specialized secretion system that Is required for pathogenesis of MTB.

AB - The RD1 genomic region is present in virulent strains of Mycobacterium tuberculosis (MTB), missing from the vaccine strain M. bovis BCG, and its importance to virulence has been established experimentally. Based on in silico analysis, it has been suggested that RD1 may encode a novel secretion system, but the mechanism by which this region affects virulence is unknown. Here we examined mutants disrupted in five individual RD1 genes. Both in vitro and in vivo, each mutant displayed an attenuated phenotype very similar to a mutant missing the entire RD1 region. Genetic complementation of individual genes restored virulence. Attenuated mutants could multiply within THP-1 cells, but they were unable to spread to uninfected macrophages. We also examined export of two immunodominant RD1 proteins, CFP-10 and ESAT-6. Export of these proteins was greatly reduced or abolished in each attenuated mutant. Again, genetic complementation restored a wild-type phenotype. Our results indicate that RD1 genes work together to form a single virulence determinant, and argue that RD1 encodes a novel specialized secretion system that Is required for pathogenesis of MTB.

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Individual RD1 -region genes are required for export of ESAT-6/CFP-10 and for virulence of Mycobacterium tuberculosis

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