DosS Is Required for the Complete Virulence of Mycobacterium tuberculosis in Mice with Classical Granulomatous Lesions
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE64045 | GEO | 2014/12/11
SECONDARY ACCESSION(S): PRJNA269958
REPOSITORIES: GEO
Similar Datasets
Project description:Here we are including replicate mouse microarray data from Kramnik mice infected over the course of different time points with M. tuberculosis H37Rv and its isogenic mutants in dosR, dosS and dosT genes. Mice from day 1 infection universally served as controls and RNA derived from these was always labeled with Cy3. RNA derived from mice at 4, 8 and 16 weeks was labeled with Cy5
2014-12-11 | E-GEOD-64045 | biostudies-arrayexpress
Project description:Mycobacterium tuberculosis (Mtb) must counter hypoxia within granulomas to persist. DosR, in concert with sensor kinases DosS and DosT, regulates the response to hypoxia. Yet Mtb lacking functional DosR colonize the lungs of C57Bl/6 mice, presumably owing to the lack of organized lesions with sufficient hypoxia in that model. We compared the phenotype of the ?-dosR, ?-dosS, and ?-dosT mutants to Mtb using C3HeB/FeJ mice, an alternate mouse model where lesions develop hypoxia. C3HeB/FeJ mice were infected via aerosol. The progression of infection was analyzed by tissue bacterial burden and histopathology. A measure of the comparative global immune responses was also analyzed. Although ?-dosR and ?-dosT grew comparably to wild-type Mtb, ?-dosS exhibited a significant defect in bacterial burden and pathology in vivo, accompanied by ablated proinflammatory response. ?-dosS retained the ability to induce DosR. The ?-dosS mutant was also attenuated in murine macrophages ex vivo, with evidence of reduced expression of the proinflammatory signature. Our results show that DosS, but not DosR and DosT, is required by Mtb to survive in C3HeB/FeJ mice. The attenuation of ?-dosS is not due to its inability to induce the DosR regulon, nor is it a result of the accumulation of hypoxia. That the in vivo growth restriction of ?-dosS could be mimicked ex vivo suggested sensitivity to macrophage oxidative burst. Anoxic caseous centers within tuberculosis lesions eventually progress to cavities. Our results provide greater insight into the molecular mechanisms of Mtb persistence within host lungs.
| S-EPMC4491129 | biostudies-literature
Project description:In Mycobacterium tuberculosis, the sensor kinases DosT and DosS activate the transcriptional regulator DosR, resulting in the induction of the DosR regulon, important for anaerobic survival and perhaps latent infection. The individual and collective roles of these sensors has been postulated biochemically, but their roles have remained unclear in vivo. This work demonstrates distinct and additive roles for each sensor during anaerobic dormancy. Both sensors are necessary for wild type levels of DosR regulon induction, and concomitantly, full induction of the regulon is required for wild type anaerobic survival. In the anaerobic model, DosT plays an early role, responding to hypoxia. DosT then induces the regulon and with it DosS, which sustains and further induces the regulon. DosT then loses its functionality as oxygen becomes limited, and DosS alone maintains induction of the genes from that point forward. Thus, M. tuberculosis has evolved a system whereby it responds to hypoxic conditions in a stepwise fashion as it enters an anaerobic state. Various DosS and DosT mutant strains were analyzed against wild type (reference strain H37Rv, identical conditions as mutant) under various conditions: day 6 in an anaerobic dormancy model, 4 or 24 hours in a GasPak model, or log phase with the addition of a nitric oxide donor. Experiments were repeated in triplicate or quadruplicate.
2009-06-26 | E-GEOD-16811 | biostudies-arrayexpress
Project description:The DosR regulon in Mycobacterium tuberculosis is involved in respiration-limiting conditions and its induction is controlled by two histidine kinases, DosS and DosT. Recent experimental evidence indicates DosS senses either molecular oxygen or a redox change. This report demonstrates that DosS responds to a reduced electron transport system (ETS), although this does not rule out a role for oxygen in silencing signaling. Under aerobic conditions induction of the DosR regulon by DosS but not DosT was observed after the addition of ascorbate, a powerful cytochrome c reductant, demonstrating DosS responds to a redox signal even in the presence of high oxygen tension. During hypoxic conditions regulon induction was attenuated by treatment with compounds that occluded electron flow into the menaquinone pool or decreased the size of the menaquinone pool itself. Increased regulon expression during hypoxia was observed when exogenous menaquinone was added, demonstrating the menaquinone pool is a limiting factor in regulon induction. Taken together these data indicate that a reduced menaquinone pool directly or indirectly triggers induction of the DosR regulon via DosS. Biochemical analysis of menaquinones upon entry into hypoxic/anaerobic conditions demonstrated the disappearance of the unsaturated species and low-level maintenance of the mono-saturated menaquinone. Relative to the unsaturated form, an analog of the saturated form is better able to induce signaling via DosS, rescue inhibition of menaquinone synthesis, and is less toxic. The menaquinone pool is central to the ETS and therefore provides a mechanistic link between the respiratory state of the bacilli and DosS signaling.
2010-05-22 | GSE21963 | GEO
Project description:In Mycobacterium tuberculosis, the sensor kinases DosT and DosS activate the transcriptional regulator DosR, resulting in the induction of the DosR regulon, important for anaerobic survival and perhaps latent infection. The individual and collective roles of these sensors has been postulated biochemically, but their roles have remained unclear in vivo. This work demonstrates distinct and additive roles for each sensor during anaerobic dormancy. Both sensors are necessary for wild type levels of DosR regulon induction, and concomitantly, full induction of the regulon is required for wild type anaerobic survival. In the anaerobic model, DosT plays an early role, responding to hypoxia. DosT then induces the regulon and with it DosS, which sustains and further induces the regulon. DosT then loses its functionality as oxygen becomes limited, and DosS alone maintains induction of the genes from that point forward. Thus, M. tuberculosis has evolved a system whereby it responds to hypoxic conditions in a stepwise fashion as it enters an anaerobic state.
2009-06-26 | GSE16811 | GEO
Project description:The DosR regulon in Mycobacterium tuberculosis is involved in respiration-limiting conditions and its induction is controlled by two histidine kinases, DosS and DosT. Recent experimental evidence indicates DosS senses either molecular oxygen or a redox change. This report demonstrates that DosS responds to a reduced electron transport system (ETS), although this does not rule out a role for oxygen in silencing signaling. Under aerobic conditions induction of the DosR regulon by DosS but not DosT was observed after the addition of ascorbate, a powerful cytochrome c reductant, demonstrating DosS responds to a redox signal even in the presence of high oxygen tension. During hypoxic conditions regulon induction was attenuated by treatment with compounds that occluded electron flow into the menaquinone pool or decreased the size of the menaquinone pool itself. Increased regulon expression during hypoxia was observed when exogenous menaquinone was added, demonstrating the menaquinone pool is a limiting factor in regulon induction. Taken together these data indicate that a reduced menaquinone pool directly or indirectly triggers induction of the DosR regulon via DosS. Biochemical analysis of menaquinones upon entry into hypoxic/anaerobic conditions demonstrated the disappearance of the unsaturated species and low-level maintenance of the mono-saturated menaquinone. Relative to the unsaturated form, an analog of the saturated form is better able to induce signaling via DosS, rescue inhibition of menaquinone synthesis, and is less toxic. The menaquinone pool is central to the ETS and therefore provides a mechanistic link between the respiratory state of the bacilli and DosS signaling. Aerobically growing logarithmic phase DosS and DosT mutant strains were analyzed after treatment with the cytochrome c reductant ascorbate to examine the effect on DosR signaling caused by reducing the electron transport system. Experiments were repeated in triplicate (dosT mutant) or duplicate (dosS mutant).
2010-05-22 | E-GEOD-21963 | biostudies-arrayexpress
Project description:Transcriptional profiling of M. tuberculosis dosR and dosS mutants and wild type growing in log phase treated with carbon monoxide or nitric oxide versus untreated controls Keywords: Genetic modification
2008-05-29 | GSE11096 | GEO
Project description:Transcriptional profiling of M. tuberculosis dosR and dosS mutants and wild type growing in log phase treated with carbon monoxide or nitric oxide versus untreated controls Keywords: Genetic modification Two condition experiment, DETANO treated cells at 100 uM or CO treated cells at 20000 ppm versus untreated controls for various M. tuberculosis mutants. Biological replicates: 2 replicates per dose, 1 array per replicate
2008-05-28 | E-GEOD-11096 | biostudies-arrayexpress
Project description:Mycobacterium tuberculosis Sensor Kinase DosS Modulates the Autophagosome in a DosR-independent Manner
| PRJNA487069 | ENA
Project description:Mycobacterium tuberculosis Sensor Kinase DosS Modulates the Autophagosome in a DosR-independent Manner [I]
| PRJNA487072 | ENA