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Inactivation of the Mycobacterium tuberculosis Nramp orthologue (mntH) does not affect virulence in a mouse model of
P Domenech1, A S Pym, M Cellier
1Unité de Génétique Moléculaire Bactérienne, Institut Pasteur, 28 rue du Docteur Roux, 75724 Paris Cedex 15, France.
Abstract:
Mycobacterium tuberculosis is an intracellular pathogen which can survive and multiply within the phagosomal compartment of the macrophage, and in doing so has to withstand the various macrophage defense mechanisms, which include limitation of iron and other metals. Analysis of the complete genome sequence of M. tuberculosis revealed an extensive array of cation transporters, including mntH, an orthologue of the eukaryotic Nramp (natural resistance-associated macrophage protein) gene, that encodes a proton-dependent divalent metal transporter. To assess the effect of this transporter on intracellular survival and pathogenesis, an mntH knock-out mutant of M. tuberculosis H37Rv was created and assayed in bone marrow-derived macrophages and in a murine model of tuberculosis. In neither of these systems was any loss of fitness associated with inactivation of mntH, demonstrating that Nramp orthologues are not important determinants of mycobacterial virulence.
Insights
The mntH gene in Mycobacterium tuberculosis, which transports divalent metals, is not essential for bacterial survival within macrophages or for causing tuberculosis in mice. This suggests Nramp orthologues do not significantly impact mycobacterial virulence.
Area of Science:
- Microbiology
- Pathogenesis
- Molecular Biology
Background:
- Mycobacterium tuberculosis (M. tuberculosis) is an intracellular pathogen surviving within macrophages.
- Macrophages employ metal limitation as a defense mechanism against M. tuberculosis.
- M. tuberculosis possesses cation transporters, including the mntH gene, an Nramp orthologue.
Purpose of the Study:
- To investigate the role of the mntH gene in M. tuberculosis virulence.
- To determine the importance of the proton-dependent divalent metal transporter in intracellular survival and pathogenesis.
Main Methods:
- Creation of an mntH knock-out mutant of M. tuberculosis H37Rv.
- Assaying the mutant's fitness in bone marrow-derived macrophages.
- Evaluating the mutant's virulence in a murine model of tuberculosis.
Main Results:
- Inactivation of the mntH gene did not result in a loss of fitness in macrophages.
- The mntH knock-out mutant showed no diminished virulence in the murine tuberculosis model.
- Nramp orthologues were found not to be critical for mycobacterial virulence.
Conclusions:
- The mntH transporter is not essential for M. tuberculosis survival or pathogenesis.
- Mycobacterial Nramp orthologues play a minor role in virulence, despite the host's metal limitation strategies.