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The Mycobacterium tuberculosis PhoPR two‐component system regulates genes essential for virulence and complex lipid biosynthesis
Author(s) -
Walters Shaun B.,
Dubnau Eugenie,
Kolesnikova Irina,
Laval Francoise,
Daffe Mamadou,
Smith Issar
Publication year - 2006
Publication title -
molecular microbiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.857
H-Index - 247
eISSN - 1365-2958
pISSN - 0950-382X
DOI - 10.1111/j.1365-2958.2006.05102.x
Subject(s) - biology , virulence , mutant , gene , mycobacterium tuberculosis , microbiology and biotechnology , response regulator , signal transduction , genetics , transcription (linguistics) , sigma factor , cell envelope , gene expression , promoter , tuberculosis , escherichia coli , medicine , linguistics , philosophy , pathology
Summary Two‐component signal transduction systems (2‐CS) play an important role in bacterial pathogenesis. In the work presented here, we have studied the effects of a mutation in the Mycobacterium tuberculosis ( Mtb ) PhoPR 2‐CS on the pathogenicity, physiology and global gene expression of this bacterial pathogen. Disruption of PhoPR causes a marked attenuation of growth in macrophages and mice and prevents growth in low‐Mg 2+ media. The inability to grow in THP‐1 macrophages can be partially overcome by the addition of excess Mg 2+ during infection. Global transcription assays demonstrate PhoP is a positive transcriptional regulator of several genes, but do not support the hypothesis that the Mtb PhoPR system is sensing Mg 2+ starvation, as is the case with the Salmonella typhimurium PhoPQ 2‐CS. The genes that were positively regulated include those found in the pks2 and the msl3 gene clusters that encode enzymes for the biosynthesis of sulphatides and diacyltrehalose and polyacyltrehalose respectively. Complementary biochemical studies, in agreement with recent results from another group, indicate that these complex lipids are also absent from the phoP mutant, and the lack of these components in its cell envelope may indirectly cause the mutant's high‐Mg 2+ growth requirement. The experiments reported here provide functional evidence for the PhoPR 2‐CS involvement in Mtb pathogenesis, and they suggest that a major reason for the attenuation observed in the phoP mutant is the absence of certain complex lipids that are known to be important for virulence.