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Mycobacterium tuberculosis Requires Phosphate-Responsive Gene Regulation to Resist Host Immunity

ABSTRACT: Mycobacterium tuberculosis persists in the lungs of mammalian hosts despite inducing an immune response dominated by the macrophage-activating cytokine interferon-gamma (IFN-gamma). We identified the M. tuberculosis phosphate uptake system component PstA1 as a factor required to resist IFN-gamma dependent immunity. A ∆pstA1 mutant was fully virulent in IFN-gamma-/- mice but was attenuated in mice lacking the IFN-gamma-inducible nitric oxide synthase (NOS2). This phenotype suggests that ∆pstA1 bacteria are hypersensitive to an IFN-gamma-dependent immune mechanism(s) other than NOS2. In other species, the Pst system participates in phosphate-responsive gene regulation by interacting with a two-component signal transduction system. We identified genes that exhibited dysregulated expression in the ∆pstA1 mutant and showed that aberrant gene expression was dependent on the two-component system response regulator RegX3. Deletion of regX3 suppressed the replication and virulence defects of ∆pstA1 bacteria in NOS2-/- mice, suggesting that the ∆pstA1 mutant is attenuated, in part, due to aberrant RegX3-dependent gene expression. Our data imply that phosphate is an important signal controlling M. tuberculosis gene expression during replication in the lung. Aerobically growing logarithmic phase Wt or pstA1/regX3/pstA1regX3 mutant strains were grown in phosphate replete media and analyzed after several hours. Experiments were repeated in triplicate (pstA1 mutant) or quadruplicate (regX3/pstA1regX3 mutant).

ORGANISM(S): Mycobacterium tuberculosis str. Erdman = ATCC 35801

SUBMITTER: Martin Voskuil

PROVIDER: E-GEOD-36998 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Mycobacterium tuberculosis Requires Phosphate-Responsive Gene Regulation to Resist Host Immunity

Project description:Mycobacterium tuberculosis persists in the lungs of mammalian hosts despite inducing an immune response dominated by the macrophage-activating cytokine interferon-gamma (IFN-gamma). We identified the M. tuberculosis phosphate uptake system component PstA1 as a factor required to resist IFN-gamma dependent immunity. A ∆pstA1 mutant was fully virulent in IFN-gamma-/- mice but was attenuated in mice lacking the IFN-gamma-inducible nitric oxide synthase (NOS2). This phenotype suggests that ∆pstA1 bacteria are hypersensitive to an IFN-gamma-dependent immune mechanism(s) other than NOS2. In other species, the Pst system participates in phosphate-responsive gene regulation by interacting with a two-component signal transduction system. We identified genes that exhibited dysregulated expression in the ∆pstA1 mutant and showed that aberrant gene expression was dependent on the two-component system response regulator RegX3. Deletion of regX3 suppressed the replication and virulence defects of ∆pstA1 bacteria in NOS2-/- mice, suggesting that the ∆pstA1 mutant is attenuated, in part, due to aberrant RegX3-dependent gene expression. Our data imply that phosphate is an important signal controlling M. tuberculosis gene expression during replication in the lung.

2013-01-01 | GSE36998 | GEO

Mycobacterium tuberculosis Phosphate Uptake System Component PstA2 is Not Required for Gene Regulation or Virulence

Project description:The Mycobacterium tuberculosis genome encodes two complete high-affinity Pst phosphate-specific transporters. We previously demonstrated that a membrane-spanning component of one Pst system, PstA1, was essential both for M. tuberculosis virulence and for regulation of gene expression in response to external phosphate availability. To determine if the alternative Pst system is similarly required for virulence or gene regulation, we constructed a deletion of pstA2. Transcriptome analysis revealed that PstA2 is not required for regulation of gene expression in phosphate-replete growth conditions. PstA2 was also dispensable for replication and virulence of M. tuberculosis in a mouse aerosol infection model. However, a âpstA1âpstA2 double mutant was attenuated in mice lacking the cytokine interferon-gamma, suggesting that M. tuberculosis requires high-affinity phosphate transport to survive phosphate limitation encountered in the host. Surprisingly, âpstA2 bacteria were more resistant to acid stress in vitro. This phenotype is intrinsic to the alternative Pst transporter since a âpstS1 mutant exhibited similar acid resistance. Our data indicate that the two M. tuberculosis Pst transporters have distinct physiological functions, with the PstA1 transporter being specifically involved in phosphate sensing and gene regulation while the PstA2 transporter influences survival in acidic conditions. Aerobically growing logarithmic phase Wt or pstA2 mutant or pstA1A2 double mutant strains were grown in phosphate replete media and analyzed after several hours. Experiments were repeated in triplicate.

2016-06-29 | E-GEOD-83812 | biostudies-arrayexpress

Mycobacterium tuberculosis Phosphate Uptake System Component PstA2 is Not Required for Gene Regulation or Virulence

Project description:The Mycobacterium tuberculosis genome encodes two complete high-affinity Pst phosphate-specific transporters. We previously demonstrated that a membrane-spanning component of one Pst system, PstA1, was essential both for M. tuberculosis virulence and for regulation of gene expression in response to external phosphate availability. To determine if the alternative Pst system is similarly required for virulence or gene regulation, we constructed a deletion of pstA2. Transcriptome analysis revealed that PstA2 is not required for regulation of gene expression in phosphate-replete growth conditions. PstA2 was also dispensable for replication and virulence of M. tuberculosis in a mouse aerosol infection model. However, a ∆pstA1∆pstA2 double mutant was attenuated in mice lacking the cytokine interferon-gamma, suggesting that M. tuberculosis requires high-affinity phosphate transport to survive phosphate limitation encountered in the host. Surprisingly, ∆pstA2 bacteria were more resistant to acid stress in vitro. This phenotype is intrinsic to the alternative Pst transporter since a ∆pstS1 mutant exhibited similar acid resistance. Our data indicate that the two M. tuberculosis Pst transporters have distinct physiological functions, with the PstA1 transporter being specifically involved in phosphate sensing and gene regulation while the PstA2 transporter influences survival in acidic conditions.

2016-06-29 | GSE83812 | GEO

Towards understanding the biological function of the unusual chaperonin GroEL1 of Mycobacterium tuberculosis

Project description:Expression data from wild type (H37Rv) and GroEL1(H37RvΔgroEL1::Hyg) mutant strains under a range of environmental stresses The 60 kDa heat shock proteins, also known as GroELs are components of the essential protein folding machinery of the cell, but are also dominant antigens in many infectious diseases. Although generally essential for cellular survival, in some organisms such as Mycobacterium tuberculosis, one or more paralogous GroELs are known to be dispensable. In M. tuberculosis, groEL2 is essential for cell survival, but the biological role of the non-essential GroEL1 is still elusive. To understand the relevance of GroEL1 in M. tuberculosis physiology, detailed transcriptomic analyses for the wild type H37Rv and groEL1 knockout (groEL1 KO) were performed under in vitro stress conditions: stationary phase, cold shock, low aeration, mild cold shock and low pH. Additionally, the survival of the groEL1 KO was assessed in macrophages at multiplicity of infection (MOI) of 1:1 and 1:5. We observed that survival under low aeration was significantly compromised in the groEL1 KO. Further, the gene expression analyses under low aeration showed change in expression of several key virulence factors like two component system PhoP/R and MprA/B, sigma factors sigG, M and H and adversely affected known hypoxia response regulators Rv0081, Rv0023 and DosR. Our work is therefore suggestive of an important role of GroEL1 for survival under low aeration by affecting the expression of genes known for hypoxia response. Expression data from wild type and GroEL1 mutant strains in response to 8 environmental stresses plus log phase growth, with at least three biological replicates of each.

2015-05-14 | E-GEOD-68856 | biostudies-arrayexpress

Mycobacterium tuberculosis produces D-serine under hypoxia to limit CD8+ T cell-dependent immunity in mice

Project description:Interferon (IFN)-γ-producing CD8+ T cells are involved in control of Mycobacterium tuberculosis (Mtb) infection, in part by promoting antimicrobial activities of macrophages. Whether Mtb counters these responses, particularly during the hypoxic conditions that arise within granulomas during infection, remains unknown. Using metabolomic, proteomic and genetic approaches, here we show that Mtb induces Rv0884c (SerC), a Mtb phosphoserine aminotransferase, to produce D-serine. This activity increased Mtb pathogenesis in mice but did not directly affect intramacrophage Mtb survival. Instead, D-serine inhibited IFN-γ production by CD8+ T cells, which indirectly reduced the ability of macrophages to restrict Mtb upon coculture. Mechanistically, D-serine interacted with WDR24, a subunit of GATOR2, and inhibited mTORC1 activation in T cells. This decreased T-bet transcription factor expression by CD8+ T cells and reduced IFN-γ production. Our findings suggest a mechanism of mycobacterial metabolic adaptation to hypoxia which leads to amino acid-dependent suppression of adaptive anti-TB immunity.

2024-08-10 | PXD050258 | Pride

Mycofactocin is critical for Mycobacterium tuberculosis adaptation into microaerophilic conditions

Project description:Mycofactocin is a new class of peptide-derived redox cofactor whose structural elucidation and functional characterization have recently received enormous focus. Among the six-gene cluster, mftD mediates a probable penultimate step in mycofactocin biosynthesis. MftD is a putative lactate dehydrogenase predicted critical for Mycobacterium tuberculosis survival under oxygen-limited conditions. In this study, mftD transcripts levels were found significantly increased in M. tuberculosis cells adapted to 0.01% oxygen. mftD deletion mutant of M. tuberculosis exhibited survival deficit in in vitro hypoxia and wayne models. However, mftD functions was found dispensable for M. tuberculosis L-Lactate metabolism. Rather surprisingly, the growth fitness of mftD mutant was increased in glucose under aerobic conditions. While the cause of this in vitro phenotype remains unestablished, the levels of NAD(P)H and glucose-6-phosphate dehydrogenase activity was found decreased in ΔmftD when compared to its parental strain. Increased growth fitness did not have any major impact on bacterial cell shape and size except the formation of extracellular fibril-like structures in subpopulations of ΔmftD. Cell-surface proteins analysis showed that genetic deficiency of mycofactocin likely to predispose accumulation of cofactor-free protein aggregates resembling destabilization of the flavoproteome upon riboflavin deprivation. Nevertheless, like in vitro findings, disruption of mftD increased the fitness of M. tuberculosis in C57BL/6J mice at early phase and resulted in growth stasis in a Nos2-/- hypoxia mouse model. Collectively these results establish the relevance of MftD in M. tuberculosis growth, redox and cofactor homeostasis, and pathogenesis.

2021-07-05 | PXD023045 | Pride

Development of gene expression signatures for latent and clinical tuberculosis (TB)

Project description:For further identify the differentiation between latent and clinical tuberculosis (TB), we employed whole genome microarray expression profiling to study genes with significant expression change in peripheral CD4+T cells between healthy control, latent tuberculosis (LTB) and clinical tuberculosis (TB). Our experiment included 4 groups: healthy donor (HD), latent TB1 (LTB1) with low IFN-gamma release level, latent TB2 (LTB2) with high IFN-gamma release level, and tuberculosis (TB) with high IFN-gamma release level. Human peripheral blood mononuclear cells were collected, from which CD4+T cells were isolated. Total RNA of each individuals of each group was extracted from peripheral CD4+T cells. One μg of RNA mixture, pooled equivalently by each individual total RNA of each group, was administrated microarray test. Compared with HD, through analyzing enriched-Gene Ontology (GO) terms and KEGG pathways of each group, we found peripheral CD4+T cells might had different ability for mycobacterium tuberculosis infection in LTB1, LTB2 and TB. Finally we detected that TNFSF13/APRIL and TNFSF13B/BAFF was significant up-regulation in both CD4+T cells and serum of TB by real time PCR and ELISA, respectively.

2012-08-07 | GSE27882 | GEO

Mycobacterium tuberculosis str. Erdman = ATCC 35801

Project description:Mycobacterium tuberculosis Phosphate Uptake System Component PstA2 is Not Required for Gene Regulation or Virulence

| PRJNA327079 | ENA

Development of gene expression signatures for latent and clinical tuberculosis (TB)

Project description:For further identify the differentiation between latent and clinical tuberculosis (TB), we employed whole genome microarray expression profiling to study genes with significant expression change in peripheral CD4+T cells between healthy control, latent tuberculosis (LTB) and clinical tuberculosis (TB). Our experiment included 4 groups: healthy donor (HD), latent TB1 (LTB1) with low IFN-gamma release level, latent TB2 (LTB2) with high IFN-gamma release level, and tuberculosis (TB) with high IFN-gamma release level. Human peripheral blood mononuclear cells were collected, from which CD4+T cells were isolated. Total RNA of each individuals of each group was extracted from peripheral CD4+T cells. One ?g of RNA mixture, pooled equivalently by each individual total RNA of each group, was administrated microarray test. Compared with HD, through analyzing enriched-Gene Ontology (GO) terms and KEGG pathways of each group, we found peripheral CD4+T cells might had different ability for mycobacterium tuberculosis infection in LTB1, LTB2 and TB. Finally we detected that TNFSF13/APRIL and TNFSF13B/BAFF was significant up-regulation in both CD4+T cells and serum of TB by real time PCR and ELISA, respectively. Peripheral CD4+ T cells were purified by positive selection using magnetic beads (BD IMagTM anti-human CD4 Particles-DM, BD Biosciences). Total RNA was extracted from CD4+ T cells (CD4-RNA) of LTB1, LTB2 and TB patients and healthy controls by RNeasy Mini Kit (QIAGEN).Then, RNA quality was checked and mixed with an equal quantity of each individual. The number of included-individuals in each group was 11 for HD, 11 for LTB1, 12 for LTB2 and 11 for TB.

2012-08-06 | E-GEOD-27882 | biostudies-arrayexpress

Conserved and cell type-specific transcriptional responses to IFN-γ in the ventral midbrain

Project description:Dysregulated inflammation within the central nervous system (CNS) contributes to neuropathology in infectious, autoimmune, and neurodegenerative disease. With the exception of microglia, major histocompatibility complex (MHC) proteins are virtually undetectable in the mature, healthy central nervous system (CNS). Neurons have generally been considered incapable of antigen presentation, and although interferon gamma (IFN-γ) can elicit neuronal MHC class I (MHC-I) expression and antigen presentation in vitro, it remains unclear whether similar responses occur in vivo. Here we directly injected IFN-γ into the ventral midbrain of mature mice and analyzed gene expression profiles of specific CNS cell types. We find that IFN-γ induces cellular proliferation and expression of MHC-II and associated genes only in microglia. However, IFN-γ upregulated MHC-I and associated mRNAs in ventral midbrain microglia, astrocytes, oligodendrocytes, and GABAergic, glutamatergic, and dopaminergic neurons. The core set of IFN-γ-induced genes and their response kinetics were conserved across neurons and glia, with a lower amplitude of expression in neurons. A diverse repertoire of genes was upregulated in glia, particularly microglia, while no neuron-specific responses to IFN-γ were observed. Using mutant mice to selectively delete the IFN-γ-binding domain of IFNGR1 in dopaminergic neurons, we demonstrate that dopaminergic neurons respond directly to IFN-γ. Our results suggest that most neurons are capable of responding directly to IFN-γ and upregulating MHC-I and related genes in vivo, but their expression amplitude and repertoire is limited compared to oligodendrocytes, astrocytes, and microglia.

2022-12-10 | GSE218132 | GEO

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