title: Mycobacterium tuberculosis requires phosphate-responsive gene regulation to resist host immunity.
abstract: Mycobacterium tuberculosis persists in the tissues of mammalian hosts despite inducing a robust immune response dominated by the macrophage-activating cytokine gamma interferon (IFN-γ). We identified the M. tuberculosis phosphate-specific transport (Pst) system component PstA1 as a factor required to resist IFN-γ-dependent immunity. A ΔpstA1 mutant was fully virulent in IFN-γ(-/-) mice but attenuated in wild-type (WT) mice and mice lacking specific IFN-γ-inducible immune mechanisms: nitric oxide synthase (NOS2), phagosome-associated p47 GTPase (Irgm1), or phagocyte oxidase (phox). These phenotypes suggest that ΔpstA1 bacteria are sensitized to an IFN-γ-dependent immune mechanism(s) other than NOS2, Irgm1, or phox. In other species, the Pst system has a secondary role as a negative regulator of phosphate starvation-responsive gene expression through an interaction with a two-component signal transduction system. In M. tuberculosis, we found that ΔpstA1 bacteria exhibited dysregulated gene expression during growth in phosphate-rich medium that was mediated by the two-component sensor kinase/response regulator system SenX3-RegX3. Remarkably, deletion of the regX3 gene suppressed the replication and virulence defects of ΔpstA1 bacteria in NOS2(-/-) mice, suggesting that M. tuberculosis requires the Pst system to negatively regulate activity of RegX3 in response to available phosphate in vivo. We therefore speculate that inorganic phosphate is readily available during replication in the lung and is an important signal controlling M. tuberculosis gene expression via the Pst-SenX3-RegX3 signal transduction system. Inability to sense this environmental signal, due to Pst deficiency, results in dysregulation of gene expression and sensitization of the bacteria to the host immune response.
authors.affiliation: School of Life Sciences, Swiss Federal Institute of Technology, Lausanne, Switzerland. tischler@umn.edu
authors.forename: Anna D
authors.initials: AD
authors.lastname: Tischler
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Leistikow
authors.forename: Meghan A
authors.initials: MA
authors.lastname: Kirksey
authors.forename: Martin I
authors.initials: MI
authors.lastname: Voskuil
authors.forename: John D
authors.initials: JD
authors.lastname: McKinney
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D005260:Female; D019204:GTP-Binding Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015870:Gene Expression / Q000235:genetics / Q000276:immunology; D015964:Gene Expression Regulation, Bacterial; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009169:Mycobacterium tuberculosis / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D010088:Oxidoreductases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D010586:Phagocytes / Q000276:immunology / Q000378:metabolism; D010710:Phosphates / Q000276:immunology* / Q000378:metabolism; D010770:Phosphotransferases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D014376:Tuberculosis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D014774:Virulence
chemical_list: D018528:ATP-Binding Cassette Transporters; D001426:Bacterial Proteins; C096000:Ifi1 protein, mouse; D010710:Phosphates; C110608:RegX3 protein, Mycobacterium; C078408:phosphate-specific transport protein A, bacteria; D007371:Interferon-gamma; D010088:Oxidoreductases; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D010770:Phosphotransferases; C110607:SenX3 protein, Mycobacterium; D019204:GTP-Binding Proteins