C-Myc inhibits macrophage antimycobacterial response in Mycobacterium tuberculosis infection
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE298739 | GEO | 2025/08/28
REPOSITORIES: GEO
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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
Project description:Tuberculosis, a chronic granulomatous disease caused by Mycobacterium tuberculosis (Mtb), often becomes exacerbated upon co-infection with other pathogens, yet the underlying immunological mechanisms remain insufficiently understood. Here, mice were initially infected with the hypervirulent Mtb strain K, and later with lymphocytic choriomeningitis virus to investigate the mechanism of severe pulmonary pathology. Virus infection significantly reduced Mtb-specific IFN-g, increased bacterial loads, and aggravated lung inflammation in the lung of Mtb-infected mice, which did not occur in pre-existence of Th1 response by Bacillus Calmette-Guerin vaccination prior to the co-infection. Blockade of type I IFN receptor signaling reinvigorated Mtb-specific IFN-γ response and ameliorated pathogenesis by upregulating pulmonary CXCL9/10 production. Our results demonstrate that virus-induced type I IFN triggers severe immunopathology by deteriorating migration of Mtb-specific IFN-γ-producing T cells, suggesting the balance between type I and type II IFNs determines either control of Mtb or exacerbation of pathology in the lung upon viral infection
2021-02-27 | GSE167650 | GEO
Project description:A craniotomy is a neurosurgical procedure performed to access the intracranial space. In 3-5% of cases, infection can develop, most commonly caused by Staphylococcus aureus biofilm formation on the surface of the skull. Medical management of this infection is difficult, as biofilm properties confer immune- and antimicrobial recalcitrance to the infection and necessitate additional surgical procedures. Still, treatment failure rates can be appreciably high. These factors, in conjunction with rapidly expanding rates of antibacterial resistance, necessitate the development of alternative treatment strategies targeting and reversing the dysfunctional immune response that develops during biofilm infection. Our recent work has identified Th1 and Th17 CD4+ T cells as potent regulators of innate immune antimicrobial capacity during craniotomy infection, where enhanced signatures of IFN-γ production and signaling were observed at the site of infection. Here, we follow up on these findings to determine the specific role of IFN-γ in programing the immune response to biofilm infection using global and cell-type-restricted IFN-γR deficient mice. We show exaggerated bacterial outgrowth in the absence of IFN-γR, despite few changes in immune cell recruitment relative to WT mice. Single-cell transcriptomic analysis identified candidate explanations for this phenotype as alterations in cell death pathways, innate immune cell activation, MHC-II expression, and CD4+ T cell skewing in IFN-γR KO mice. While PMN pyroptosis in vitro and macrophage/microglia MHC-II levels in vivo displayed sensitivity to IFN-γ signaling, granulocyte- and macrophage/microglia-specific conditional IFN-γR KO experiments isolated these factors from observed increases in bacterial burden. Instead, we uncovered evidence of a decreased Th1/Th17 ratio which was corroborated by elevated IL-17 levels during IFN-γR deficiency and correlated with dysfunctional cellular communication with the innate immune system. Further, Th17 cells were less effective than Th1 cells in stimulating macrophage and microglia bacterial killing. In sum, this work identifies Th1 cells as uniquely protective during craniotomy infection, where they likely enhance macrophage and microglial antibacterial abilities in an IFN-γ-independent manner. Therefore, augmentation of CD4+ T cell differentiation towards a Th1 bias may represent a novel therapeutic strategy for treating craniotomy infection in the future.
2025-02-26 | GSE282637 | GEO
Project description:A growing body of evidence suggests that inflammatory cytokines have a dualistic role in immunity. In this study, we sought to determine the direct effects IFN-gamma on the differentiation and maturation of human peripheral blood monocyte-derived dendritic cells (moDC). Here, we report that following differentiation of human peripheral-blood monocytes into moDCs with granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-4, interferon-gamma (IFN-gamma) induces moDC maturation and up-regulates the co-stimulatory markers CD80, CD86, CD95, and MHC Class I, enabling moDCs to effectively generate antigen-specific CD4+ and CD8+ T cell responses for multiple viral and tumor antigens. Interestingly, early exposure of monocytes to high concentrations of IFN-gamma promotes monocyte differentiation into macrophages, despite the presence of GM-CSF and IL-4. However, under low concentrations of IFN-gamma, monocytes continue to differentiate into dendritic cells possessing a unique gene-expression profile, resulting in impairments in subsequent maturation by IFN-gamma and an inability to generate effective antigen-specific CD4+ and CD8+ T cell responses compared to standard moDCs. Monocytes differentiated in the presence of low levels of IFN-gamma downregulate IFN-gamma receptor expression, impairing their response to an inflammatory rechallenge. These findings demonstrate the ability of IFN-gamma to impart differential programs on human moDCs which shape the antigen-specific T cell responses they induce. Timing and intensity of exposure to IFN-gamma can thus determine whether moDCs are tolerogenic or immunostimulating. Human monocyte-derived dendritic cells from 4 healthy donors were differentiated with either GM-CSF and IL-4 (n=4) or GM-CSF, IL-4, and IFN-gamma (n=4). These samples were subsequently hybridized to arrays as 4 biological repeats for each of the two treatment conditions.
2014-06-01 | E-GEOD-47621 | biostudies-arrayexpress
Project description:A growing body of evidence suggests that inflammatory cytokines have a dualistic role in immunity. In this study, we sought to determine the direct effects IFN-gamma on the differentiation and maturation of human peripheral blood monocyte-derived dendritic cells (moDC). Here, we report that following differentiation of human peripheral-blood monocytes into moDCs with granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-4, interferon-gamma (IFN-gamma) induces moDC maturation and up-regulates the co-stimulatory markers CD80, CD86, CD95, and MHC Class I, enabling moDCs to effectively generate antigen-specific CD4+ and CD8+ T cell responses for multiple viral and tumor antigens. Interestingly, early exposure of monocytes to high concentrations of IFN-gamma promotes monocyte differentiation into macrophages, despite the presence of GM-CSF and IL-4. However, under low concentrations of IFN-gamma, monocytes continue to differentiate into dendritic cells possessing a unique gene-expression profile, resulting in impairments in subsequent maturation by IFN-gamma and an inability to generate effective antigen-specific CD4+ and CD8+ T cell responses compared to standard moDCs. Monocytes differentiated in the presence of low levels of IFN-gamma downregulate IFN-gamma receptor expression, impairing their response to an inflammatory rechallenge. These findings demonstrate the ability of IFN-gamma to impart differential programs on human moDCs which shape the antigen-specific T cell responses they induce. Timing and intensity of exposure to IFN-gamma can thus determine whether moDCs are tolerogenic or immunostimulating.
2014-06-01 | GSE47621 | GEO
Project description:c-Myc inhibits macrophage antimycobacterial response in Mycobacterium tuberculosis infection
| PRJNA1271040 | ENA
Project description:Mycobacterium tuberculosis (Mtb) primarily resides in the lung but it can also persist in extrapulmonary sites. Macrophages are considered the prime cellular habitat in all tissues. Here we demonstrate that Mtb resides inside adipocytes of fat tissue where it expresses stress-related genes. In addition, Mtb infection induces changes in adipose tissue biology depending on the route of administration and stage of infection. At day 14 post-systemic Mtb infection, F4/80+ (inducible nitric oxide synthase-positive) iNOS+ cells (M1 macrophages) as well as CD3, CD4 and CD8 T cells were present, and by day 28, B220+ cells had arrived in adipose tissue. In contrast, mice infected via aerosol only showed infiltration of F4/80+ cells that do not express iNOS or arginase 1 (Arg1) and CD3, CD4 and CD8 T cells. Gene expression analysis of adipose tissue of aerosol Mtb-infected mice provided evidence for upregulated expression of genes associated with T cells and NK cells at 28 days post-infection. Moreover, IFN-gamma-producing NK cells and Mtb-specific CD8 T cells were found in perigonadal fat, specifically CD8+CD44-CD69+ and CD8+CD44-CD103+ subpopulations. Gene expression analysis of selected NK cells and Mtb-specific CD8 T cells in perigonadal fat of infected mice revealed that they produced IFN-gamma and transcribed the lectin-like receptor Klrg1 whereas CD27 and CD62L transcript levels were downregulated consistent with an effector phenotype. Sorted NK cells expressed higher levels of Klrg1 upon infection, as well. Our results reveal the ability of Mtb to persist in adipose tissue in a stressed state, and that NK cells and Mtb-specific CD8 T cells infiltrate infected adipose tissue where they produce IFN- and assume an effector phenotype. We conclude that Mtb exploits adipose tissue as niche, to which CD8 T cells and NK cells are attracted.
2017-10-12 | GSE83554 | GEO
Project description:Our previous work identified that type I IFNs mediate macrophage death after infection of Mycobacterium tuberculosis (Mtb) through a novel mechanism.Type I IFN signaling relies on its several hundred ISGs to execute various functions. In order to delineate the downstream mechanism of type I IFN-mediating cell death, we adopted RNA-seq experiments to identify which gene(s) are differentially expressed in WT or Ifnar1-/- bone marrow-derived macrophages (BMDMs). In the meantime, we're also interested in how genetic background affects transcriptomics in BMDMs infected with Mtb. Thus a transcriptomics analysis of C57BL/6, 129S2 and 129X1 infected with Mtb were also conducted.
2025-02-13 | GSE289356 | GEO
Project description:Macrophages are major effector cells and antigen presenting cells of the innate immune system and classical activation of macrophage function requires interferon–γ (IFN-γ) pretreatment (priming) and TLR stimuli, which promotes inflammatory responses though high levels of pro-inflammatory cytokines and lower level of the anti-inflammatory cytokines, resulting in microbicidal and tumoricidal effect. However, the underlying molecular mechanism of IFN-γ priming remains elusive. In this study, we explored the effect of IFN-γ on macrophages at miRNA level and discovered that miR-3473b, which was down-regulated after IFN-γ priming, could attenuate the priming effect of IFN-γ. Molecular study revealed that miR-3473b promoted Akt/GSK3 signaling and IL-10 production through directly targeting PTEN to suppress inflammatory response and tumor-suppressing capability of macrophages. In summary, our data demonstrate that IFN-γ beef up macrophage inflammatory response and tumor suppressing capacity by limiting miR-3473b-mediated PTEN suppression. Our work identified an IFN-γ/miR-3473b/Akt axis in the regulation of macrophage function and activation. the assay was performed with 5 μg total RNA samples from both normal BMM (labeled by Cy3) and BMM primed by IFN-γ (100U/ml) for 4 h(labeled by Cy5), normal BMM serves as control.
2014-10-01 | E-GEOD-50569 | biostudies-arrayexpress
Project description:Although lung myeloid cells provide an intracellular niche for Mycobacterium tuberculosis (Mtb), CD4+ T cells limit Mtb growth in these cells to protect the host. Here, we show that monocyte-derived macrophages (MDMs), instead of phenotypically similar dendritic cells, are preferentially infected with Mtb in murine lungs. Mtb-specific CD4+ T cells recruited monocyte precursors of MDMs into the lungs via interferon-γ (IFN-γ). Although the CD4+ T cells increased the number of Mtb-infectable cells in the lungs, they then attenuated Mtb growth by engaging in MHC class II (MHCII)-mediated cognate interactions with monocyte-derived cells to promote their disinfection. Specifically, cognate CD4+ T cell help via MHCII enhanced MDM expression of glycolytic genes independently of IFN-γ. These results indicate that CD4+ T cells recruit infectable MDMs to the lungs and trigger glycolysis-dependent bacterial control within them by engaging MHCII-bound Mtb peptides on their surfaces.
2025-01-27 | GSE287753 | GEO