Gaudion, A.E.; (2011) The role of the ECF sigma factor SigG in Mycobacterium tuberculosis. Doctoral thesis , UCL (University College London).

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Abstract

Mycobacterium tuberculosis is the causative agent of Tuberculosis (TB). Two billion people are currently infected with M. tuberculosis bacilli, one in ten of whom will develop active TB in their lifetime. M. tuberculosis is able to survive within macrophages but the exact mechanisms used for intracellular survival are poorly understood. DNA-dependent RNA polymerase is the enzyme responsible for transcription in all living organisms. In bacteria this enzyme recognises different promoters by binding to sigma factors that recognise those promoters. This study focuses on the role and regulation of the M. tuberculosis extracytoplasmic function (ECF) sigma factor, SigG. ECF sigma factors are responsible for upregulating genes necessary for bacterial stress responses. SigG has previously been shown to be upregulated in response to DNA damage and during macrophage infection. It has been demonstrated that sigG is expressed from at least 2 promoters and that only promoter P1 is DNA-damage inducible. sigG is co-transcribed with the two downstream genes Rv0181c and Rv0180c, which were hypothesised to be anti- and anti-anti-sigma factors to SigG. Protein-protein interaction studies showed that SigG and Rv0181c do not interact. Potential anti-sigma factors to SigG were identified, the most promising of which was the thioredoxin family protein Rv1084. Two potential SigG-dependent genes had previously been identified, Rv0887c and Rv0911. It has been demonstrated that SigG is able to bind to the promoter regions of these genes but this interaction was not specific. An M. tuberculosis sigG-Rv0180c deletion strain was constructed and complemented with the whole operon as well as with sigG alone. The phenotype of the mutant strain was examined in vitro as well as in vivo to test the hypothesis that SigG has a role during infection. Use of a phenotype microarray revealed an enhanced susceptibility of the mutant strain to oleic acid and its ester, Tween 80, leading to investigation of the sensitivity of the strains to a range of fatty acids.

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