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

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journal contribution
posted on 01.11.2017, 09:54 by Laura J. Smith, Aleksandra Bochkareva, Matthew D. Rolfe, Debbie M. Hunt, Christina Kahramanoglou, Yvonne Braun, Angela Rodgers, Alix Blockley, Stephen Coade, Kathryn E. A. Lougheed, Nor Azian Hafneh, Sarah M. Glenn, Jason C. Crack, Nick E. Le Brun, José W. Saldanha, Vadim Makarov, Irene Nobeli, Kristine Arnvig, Galina V Mukamolova, Roger S. Buxton, Jeffrey Green
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. Acmr 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.

Funding

Biotechnology and Biological Sciences Research Council UK [BB/K000071/1, BB/L008114/1 to J.G., BB/K000330/1 to G.V.M., BB/L007673/1 to N.L.B. and J.C.]; Medical Research Council [U117585867 to R.S.B.]; Wellcome Trust [078731/Z/05/Z to J.G. and R.S.B.]; NAH is sponsored by Government of Brunei Darussalam. Funding for open access charge: RCUK.

History

Citation

Nucleic Acids Research, 2017, 45 (11), pp. 6600-6612

Author affiliation

/Organisation/COLLEGE OF LIFE SCIENCES/School of Medicine/Department of Infection, Immunity and Inflammation

Version

VoR (Version of Record)

Published in

Nucleic Acids Research

Publisher

Oxford University Press (OUP)

issn

0305-1048

eissn

1362-4962

Acceptance date

28/04/2017

Copyright date

2017

Available date

01/11/2017

Publisher version

https://academic.oup.com/nar/article-lookup/doi/10.1093/nar/gkx406

Notes

Supplementary Data are available at NAR Online.

Language

en

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