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A Novel Gene Regulates Vesiculogenesis and Immunomodulation in Mycobacterium tuberculosis

ABSTRACT: After co-evolving with humans, its only major host, Mycobacterium tuberculosis (Mtb) restrains immune responses well enough to escape eradication, yet elicits enough immunopathology to ensure its transmission. Here, we provide evidence that this balance is regulated in part by a previously uncharacterized, cytosolic, membrane-associated protein with a novel structural fold, encoded by the Mtb gene rv0431. The protein acts by regulating the quantity and quality of Mtb-derived membrane vesicles bearing TLR2 ligands, including the lipoproteins LpqH and SodC. We propose that rv0431 be named virR (vesiculogenesis and immune response regulator). To our knowledge, VirR is the first bacterial protein identified to regulate vesiculogenesis.

ORGANISM(S): Mus musculus

PROVIDER: GSE50050 | GEO | 2013/12/03

SECONDARY ACCESSION(S): PRJNA215865

REPOSITORIES: GEO

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A Novel Gene Regulates Vesiculogenesis and Immunomodulation in Mycobacterium tuberculosis

Project description:After co-evolving with humans, its only major host, Mycobacterium tuberculosis (Mtb) restrains immune responses well enough to escape eradication, yet elicits enough immunopathology to ensure its transmission. Here, we provide evidence that this balance is regulated in part by a previously uncharacterized, cytosolic, membrane-associated protein with a novel structural fold, encoded by the Mtb gene rv0431. The protein acts by regulating the quantity and quality of Mtb-derived membrane vesicles bearing TLR2 ligands, including the lipoproteins LpqH and SodC. We propose that rv0431 be named virR (vesiculogenesis and immune response regulator). To our knowledge, VirR is the first bacterial protein identified to regulate vesiculogenesis. Transcriptome sequencing of mouse macrophages uninfected, infected with WT Mtb, or infected with rv0431 mutant Mtb.

2013-12-03 | E-GEOD-50050 | biostudies-arrayexpress

Dynamin-like proteins are essential for vesicle biogenesis in Mycobacterium tuberculosis.

Project description:Mycobacterium tuberculosis (Mtb) secretes pathogenicity factors and immunologically active molecules via membrane vesicles. However, nothing is known about the mechanisms involved in mycobacterial vesicle biogenesis. This study investigates molecular determinants of membrane vesicle production in Mtb by analyzing Mtb cells under conditions of high vesicle production: iron limitation and VirR restriction. Ultrastructural analysis showed extensive cell envelope restructuring in association with vesicle release that correlated with downregulation of cell surface lipid biosynthesis and peptidoglycan alterations. Comparative transcriptomics showed common upregulation of the iniBAC operon in association with high vesicle production in Mtb cells. Vesicle production analysis demonstrated that the dynamin-like proteins (DLPs) encoded by this operon, IniA and IniC, are necessary for release of EV by Mtb in culture and in infected macrophages. Isoniazid, a first-line antibiotic, used in tuberculosis treatment, was found to stimulate vesicle release in a DLP-dependent manner. Our results provide a new understanding of the function of mycobacterial DLPs and mechanistic insights into vesicle biogenesis. The findings will enable further understanding of the relevance of Mtb-derived extracellular vesicles in the pathogenesis of tuberculosis and may open new avenues for therapeutic research.

2023-06-22 | GSE143996 | GEO

Essential role of Helicobacter pylori apolipoprotein N-acyltransferase (Lnt) in stomach colonization

Project description:Deleting lnt changes the number of acyl chains on lipoproteins and the number of acyl chains on lipoproteins impacts the innate immune response through TLR2 signaling. We treated primary human gastric epithelial cells with a purified lipoprotein from wild-type or lnt mutant H. pylori and performed RNAseq. Differential gene expression analysis indicated lipoprotein from the lnt mutant induced a more robust TLR2 response.

2023-10-17 | GSE241938 | GEO

Toll-like receptor 2 activation depends on lipopeptide shedding by bacterial surfactants

Project description:Sepsis caused by Gram-positive bacterial pathogens is a major fatal disease but its molecular basis remains elusive. Toll-like receptor 2 (TLR2) has been implicated in the orchestration of inflammation and sepsis but its role appears to vary for different pathogen species and clones. Accordingly, Staphylococcus aureus clinical isolates differ substantially in their capacity to activate TLR2. Here we show that strong TLR2 stimulation depends on high-level production of phenol-soluble modulin (PSM) peptides in response to the global virulence activator Agr. PSMs are required for mobilizing lipoproteins, the TLR2 agonists, from the staphylococcal cytoplasmic membrane. Notably, the course of sepsis caused by PSM-deficient S. aureus is similar in wild-type and TLR2-deficient mice, but TLR2 is required for protection of mice against PSM-producing S. aureus. Thus, a crucial role of TLR2 depends on agonist release by bacterial surfactants. Modulation of this process may lead to new therapeutic strategies against Gram-positive infections.

2016-06-08 | PXD004283 | Pride

Tuberculosis resistance protein TOLLIP controls immune pathology by resolving the integrated stress response in alveolar macrophages

Project description:A functional polymorphism responsible for TOLLIP deficiency is associated with increased tuberculosis risk. However, TOLLIP’s role in TB pathogenesis is unknown. Tollip-/- mice developed severe Mycobacterium tuberculosis (Mtb) disease, characterized by macrophage and T cell inflammation from multiple cell populations alongside foam cell formation and lipid accumulation. Tollip-/- alveolar macrophages (AM) selectively accumulated lipid and underwent necrosis in an autonomous manner. Transcriptional and protein analysis analysis of Mtb-infected, Tollip-/- AM demonstrated increased EIF2 signaling, a key regulator of the integrated stress response (ISR) to variable environmental conditions. The ISR, inflammation, and lipid accumulation were linked, as incubation of the Mtb lipid mycolic acid with Mtb-infected Tollip-/- AM led to ISR activation and Mtb replication. Correspondingly, ISRIB, a small-molecule ISR inhibitor, selectively reduced Mtb intracellular carriage in AM and improved Mtb control, overcoming the inflammatory phenotypeinflammation. Targeting the ISR broadly improves Mtb control and immunopathology, offering a promising target for host-directed tuberculosis therapy.

2023-09-27 | GSE243818 | GEO

A Ferritin Mutant Induces Protective Immunity against Virulent Mycobacterium tuberculosis Infection

Project description:Iron plays a critical role in the pathogenesis of many organisms including Mtb. It is the preferred redox cofactor in many basic cellular processes but due to its insolubility and potential toxicity under physiological conditions is a limiting nutrient in the host environment. Previously, we demonstrated that Mtb requires the iron storage protein ferritin (BfrB), for adaptation to both low and sufficient concentrations of environmental iron. We also showed that absence of bfrB compromises the ability of Mtb to overcome iron deficiency and prevent excess iron toxicity. In this study, we tested whether vaccination with ?bfrB could elicit host protective immune response against virulent Mtb infection. The results show that immunization of mice with the ?bfrB stimulates protective immunity associated with reduced immunopathology and better containment of the infection compared to vaccination with BCG. Genome-wide transcriptome analysis showed a distinct expression pattern of significantly differentially expressed genes (SDEG) between the ?bfrB and BCG-vaccinated, Mtb-infected mice lungs. Our network/pathway analysis of SDEG revealed significant inhibition of inflammatory response genes and activation of fibrosis genes in the ?bfrB, compared to BCG vaccinated, Mtb-infected mice lungs. The results provide a frame work for the study of mechanisms of protection relevant for the design of new and improved preventive strategies for TB. Female C57BL/6 mice were vaccinated subcutaneously with ?bfrB or BCG . At 8 weeks post-vaccination, mice were aerosol infected with Mtb H37Rv. At 4 weeks post infection, mice were sacrificed and lungs were removed. Lung total RNA from vaccinated and Mtb-infected mice was extracted, purified and were processed separately for microarray analysis.

2014-09-01 | E-GEOD-58810 | biostudies-arrayexpress

Obesity Potentiates TH2 Immunopathology Via Dysregulation of PPARg

Project description:Clinically, obesity is strongly associated with severe TH2 immunopathology, though the physiological, cellular, and molecular underpinnings of this association remain obscure. We demonstrate that obese mice are susceptible to severe atopic dermatitis (AD), a major manifestation of TH2 immunopathology and disease burden in humans. Mechanistically, we show that dysregulation of the nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPARg) in T cells is a causal link between obesity and the increased TH2 immunopathology. We find that PPARg directly controls a cellular metabolic transcriptional program that restrains nuclear gene expression of the chief TH2 effector cytokines interleukin-4 (IL-4) and interleukin-13 (IL-13). Accordingly, thiazolidinediones (TZDs), potent PPARg agonists, robustly protect obese mice from TH2 immunopathology. Collectively, these findings establish PPARg as a molecular link between obesity and TH2 immune homeostasis and identify TZDs as novel therapeutic candidates for TH2 immunopathology.

2022-03-29 | GSE189216 | GEO

Analysis of Listeria monocytogenes VirR regulon

Project description:by comparing WT strain vs a delta-VirR strain, we complete the analysis of VirR regulon, and we show that virR induces the expression of a small RNA

2022-01-23 | GSE103751 | GEO

Pam3Cys-treated HUVEC before and after TLR2 knockdown

Project description:The vascular endothelium is integrally involved in the host response to infection and in organ failure during acute inflammatory disorders such as sepsis. Gram-negative and gram-positive bacterial lipoproteins circulate in sepsis and can directly activate the endothelium by binding to endothelial cell (EC) Toll-like receptor 2 (TLR2). In this report, we perform the most comprehensive analysis to date of the immune-related genes regulated after activation of endothelial TLR2 by bacterial di- and triacylated lipopeptides. We found that TLR2 activation specifically induces the expression of IL6, IL8, CSF2, CSF3, ICAM1 and SELE by human umbilical vein ECs and human lung microvascular ECs. These proteins participate in neutrophil recruitment, adherence and activation at sites of inflammation. Significantly, our studies demonstrate that bacterial lipopeptides activate human EC exclusively through TLR2, that TLR2-mediated EC responses are specifically geared towards recruitment, activation, and survival of neutrophils and not mononuclear leukocytes, and that ECs do not require priming by other inflammatory stimuli to respond to bacterial lipopeptides. This study suggests that endothelial TLR2 may be an important regulator of neutrophil trafficking to sites of infection in general, and that direct activation of lung endothelial TLR2 may contribute to acute lung injury during sepsis.

2011-06-23 | GSE30117 | GEO

Type I IFNs exacerbate tuberculosis pathogenesis by inhibiting migration of antigen specific T cells

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

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