Cmr is a redox-responsive regulator of DosR that contributes to M. tuberculosis virulence

Smith, Laura J., Bochkareva, Aleksandra, Rolfe, Matthew D., Hunt, Debbie M, Kahramanoglou, Christina, Braun, Yvonne, Rodgers, Angela, Blockley, Alix, Coade, Stephen, Lougheed, Kathryn EA, Hafneh, Nor Azian, Glenn, Sarah M, Crack, Jason C, Le Brun, Nick E, Saldanha, José W, Macarov, Vadim, Nobeli, Irene, Arnvig, Kristine, Mukamolova, Galina V, Buxton, Roger S and Green, Jeffrey (2017) Cmr is a redox-responsive regulator of DosR that contributes to M. tuberculosis virulence. Nucleic Acids Research, 45 (11). pp. 6600-6612. ISSN 0305-1048

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Abstract

Mycobacterium tuberculosis (MTb) is the causative agent of pulmonary tuberculosis (TB). MTb colonizes the human lung, often entering a non-replicating state before progressing to life-threatening active infections. Transcriptional reprogramming is essential for TB pathogenesis. In vitro, Cmr (a member of the CRP/FNR super-family of transcription regulators) bound at a single DNA site to act as a dual regulator of cmr transcription and an activator of the divergent rv1676 gene. Transcriptional profiling and DNA-binding assays suggested that Cmr directly represses dosR expression. The DosR regulon is thought to be involved in establishing latent tuberculosis infections in response to hypoxia and nitric oxide. Accordingly, DNA-binding by Cmr was severely impaired by nitrosation. A cmr mutant was better able to survive a nitrosative stress challenge but was attenuated in a mouse aerosol infection model. The complemented mutant exhibited a ∼2-fold increase in cmr expression, which led to increased sensitivity to nitrosative stress. This, and the inability to restore wild-type behaviour in the infection model, suggests that precise regulation of the cmr locus, which is associated with Region of Difference 150 in hypervirulent Beijing strains of Mtb, is important for TB pathogenesis.

Item Type: Article
Faculty \ School: Faculty of Science > School of Chemistry
Depositing User: Pure Connector
Date Deposited: 16 May 2017 05:05
Last Modified: 04 Aug 2020 23:39
URI: https://ueaeprints.uea.ac.uk/id/eprint/63524
DOI: 10.1093/nar/gkx406

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