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PMID: 14715274 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

A two-component signal transduction system with a PAS domain-containing sensor is required for virulence of Mycobacterium tuberculosis in mice.

Biochemical and biophysical research communications ·Vol. 314 ·No. 1 ·2004-01-30 ·Pages 259-67

Rickman L, Saldanha JW, Hunt DM, Hoar DN, Colston MJ, Millar JB, Buxton RS

Abstract

Mycobacterium tuberculosis, the causative organism of tuberculosis, encounters oxidative stress during phagocytosis by the macrophage and following macrophage activation during an acquired immune response, and also from internally generated sources of radical oxygen intermediates through intermediary metabolism. We have identified the SenX3 protein, a sensor in 1 of the 11 complete pairs of two-component signal transduction systems in M. tuberculosis, as a possible orthologue of the Mak2p protein from the fission yeast Schizosaccharomyces pombe that is known to sense peroxide stress. Moreover, the SenX3-RegX3 two-component system was the top scoring hit in a homology search with the Escherichia coli ArcB-ArcA global control system of aerobic genes. Using structural modelling techniques we have determined that SenX3 contains a PAS-like domain found in a variety of prokaryotic and eukaryotic sensors of oxygen and redox. Mutants with knock-outs of senX3 or of the accompanying transcriptional regulator regX3 were constructed and found to have reduced virulence in a mouse model of tuberculosis infection, the mutant bacteria persisting for up to 4 months post-infection; complemented mutants had regained virulence confirming that it was mutations of this two-component system that were responsible for the avirulent phenotype. This work identifies the PAS domain as a possible drug target for tuberculosis and mutations in the senX3-regX signal transduction system as potentially useful components of live vaccine strains.

MeSH Terms
Amino Acid Sequence Animals Bacterial Proteins/chemistry,metabolism Computer Simulation Female Mice Mice, Inbred BALB C Models, Molecular Molecular Sequence Data Mutation Mycobacterium tuberculosis/growth & development,metabolism,pathogenicity Oxidative Stress Phosphotransferases/chemistry,metabolism Protein Structure, Tertiary Recombinant Proteins/chemistry,metabolism Sequence Alignment Signal Transduction/physiology Tuberculosis/microbiology
Chemicals
Bacterial Proteins Recombinant Proteins Phosphotransferases SenX3 protein, Mycobacterium
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Rickman Lisa
Division of Mycobacterial Research, National Institute for Medical Research, London, UK. [email protected]
Saldanha José W
Hunt Debbie M
Hoar Dominic N
Colston M Joseph
Millar Jonathan B A
Buxton Roger S
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Article Info
Journal
Biochemical and biophysical research communications
Abbr.
Biochem Biophys Res Commun
ISSN
0006-291X
DOI
10.1016/j.bbrc.2003.12.082
Email
[email protected]
Published
2004-01-30
Pages
259-67
Language
English
Region
United States
NLM ID
0372516
PMCID
PMC2963928
Subset
IM
Grants
Medical Research Council · MC_U117531948 · United Kingdom
Medical Research Council · MC_U117585867 · United Kingdom
Medical Research Council · U.1175.02.002.00013 (85867) · United Kingdom
External Links
PubMed source DOI: 10.1016/j.bbrc.2003.12.082 PMC Full Text View journal details
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