Modulation of Mycobacterium tuberculosis proliferation by MtrA, an essential two-component response regulator

Marek Fol, Ashwini Chauhan, Naveen K. Nair, Erin Maloney, Meredith Moomey, Chinnaswamy Jagannath, Murty V.V.S. Madiraju, Malini Rajagopalan

Research output: Contribution to journalArticlepeer-review

118 Scopus citations

Abstract

Paired two-component regulatory systems consisting of a sensor kinase and a response regulator are the major means by which bacteria sense and respond to different stimuli. The role of essential response regulator, MtrA, in Mycobacterium tuberculosis proliferation is unknown. We showed that elevating the intracellular levels of MtrA prevented M. tuberculosis from multiplying in macrophages, mice lungs and spleens, but did not affect its growth in broth. Intracellular trafficking analysis revealed that a vast majority of MtrA overproducing merodiploids were associated with lysosomal associated membrane protein (LAMP-1) positive vacuoles, indicating that intracellular growth attenuation is, in part, due to an impaired ability to block phagosome-lysosome fusion. A merodiploid strain producing elevated levels of phosphorylation- defective MtrA (MtrAD53N) was partially replicative in macrophages, but was attenuated in mice. Quantitative real-time PCR analyses revealed that expression of dnaA, an essential replication gene, was sharply upregulated during intramacrophage growth in the MtrA overproducer in a phosphorylation- dependent manner. Chromatin immunoprecipitation using anti-MtrA antibodies provided direct evidence that MtrA regulator binds to dnaA promoter in vivo indicating that dnaA promoter is a MtrA target. Simultaneous overexpression of mtrA regulator and its cognate mtrB kinase neither inhibited growth nor sharply increased the expression levels of dnaA in macrophages. We propose that proliferation of M. tuberculosis in vivo depends, in part, on the optimal ratio of phosphorylated to non-phosphorylated MtrA response regulator.

Original languageEnglish (US)
Pages (from-to)643-657
Number of pages15
JournalMolecular Microbiology
Volume60
Issue number3
DOIs
StatePublished - May 2006

ASJC Scopus subject areas

  • Microbiology
  • Molecular Biology

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