A Polymorphism in the P2X<sub>7</sub>Gene Increases Susceptibility to Extrapulmonary Tuberculosis

Fernando, Suran L.; Saunders, Bernadette M.; Sluyter, Ronald; Skarratt, Kristen K.; Goldberg, Hazel; Marks, Guy B.; Wiley, James S.; Britton, Warwick J.

doi:10.1164/rccm.200607-970oc

Cited by 196 publications

(172 citation statements)

References 39 publications

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“…Three loss-of function SNPs (T357S, E496A, and I568N) and one gain-of-function SNP (Q460R) are located in the long intracellular domain [54][55][56]58]. These loss-of-function polymorphisms lead not only to reduced P2X 7 pore function but also to impaired ATP-induced mycobacterial killing by macrophages [56,60,61,81,82]. Recent studies have found that the E496A polymorphism does not affect the electrophysiological phenotype of the P2X 7 channel in transfected oocytes and HEK293 cells [83].…”

Section: Discussionmentioning

confidence: 99%

“…Another putative gain-of-function polymorphism described recently, the Q460R substitution, appears to enhance pore activity of the P2X 7 receptor [58]. Increasing evidence from genetic association studies have demonstrated that the polymorphisms of the P2X 7 gene are implicated in various diseases such as chronic lymphocytic leukemia, tuberculosis, bipolar affective disorders, and diabetes [60][61][62][63][64][65][66][67]. It has also been reported that the polymorphisms are related to clinical outcome in allogeneic stem cell transplantation and to fracture risk and the efficacy of hormone replacement therapy [28,68].…”

Section: Introductionmentioning

confidence: 99%

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Identification and characterization of a novel variant of the human P2X7 receptor resulting in gain of function

Sun

Chu

Singh

et al. 2009

Purinergic Signalling

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The P2X 7 receptor exhibits significant allelic polymorphism in humans, with both loss and gain of function variants potentially impacting on a variety of infectious and inflammatory disorders. At least five loss-offunction polymorphisms (G150R, R307Q, T357S, E496A, and I568N) and two gain-of-function polymorphisms (H155Y and Q460R) have been identified and characterized to date. In this study, we used RT-PCR cloning to isolate and characterize P2X 7 cDNA clones from human PBMCs and THP-1 cells. A previously unreported variant with substitutions of V80M and A166G was identified. When expressed in HEK293 cells, this variant exhibited heightened sensitivity to the P2X 7 agonist (BzATP) relative to the most frequent allele, as shown by pore formation measured by fluorescent dye uptake into cells. Mutational analyses showed that A166G alteration was critical for the gain-offunction change, while V80M was not. Full-length variants with multiple previously identified nonsynonymous SNPs (H155Y, H270R, A348T, and E496A) were also identified. Distinct functional phenotypes of the P2X 7 variants or mutants constructed with multiple polymorphisms were observed. Gain-of-function variations (A166G or H155Y) could not rescue the loss-of-function E496A polymorphism. Synergistic effects of the gain-of-function variations were also observed. We also identified the A348T alteration as a weak gain-of-function variant. Thus, these results identify the new gain-of-function variant A166G and demonstrate that multiple-gene polymorphisms contribute to functional phenotypes of the human P2X 7 receptor.Furthermore, the results demonstrate that the C-terminal of the cysteine-rich domain 1 of P2X 7 is critical for regulation of P2X 7 -mediated pore formation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Identification and characterization of a novel variant of the human P2X7 receptor resulting in gain of function

Sun

Chu

Singh

et al. 2009

Purinergic Signalling

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“…Given the ability of various P2Y family receptors to regulate Ca 2+ and lipid signaling, it seems likely that P2X7 and various P2Y receptors act cooperatively to mediate the actions of extracellular ATP on killing of internalized mycobacteria or chlamydia. Such an interaction between P2X7R and another P2 receptor subtype(s) could explain the disparate associations of particular P2X7R polymorphisms with altered progression of tubercular phenotypes within different subgroups of human populations or mouse models [64,[68][69][70][71][72][73][74][75].…”

Section: P2x7r Regulation Of Phagosome Maturation and Microbial Killingmentioning

confidence: 99%

P2X7 receptors regulate multiple types of membrane trafficking responses and non-classical secretion pathways

Dubyak

2009

Purinergic Signalling

105

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Activation of the P2X7 receptor (P2X7R) triggers a remarkably diverse array of membrane trafficking responses in leukocytes and epithelial cells. These responses result in altered profiles of cell surface lipid and protein composition that can modulate the direct interactions of P2X7R-expressing cells with other cell types in the circulation, in blood vessels, at epithelial barriers, or within sites of immune and inflammatory activation. Additionally, these responses can result in the release of bioactive proteins, lipids, and large membrane complexes into extracellular compartments for remote communication between P2X7R-expressing cells and other cells that amplify or modulate inflammation, immunity, and responses to tissue damages. This review will discuss P2X7R-mediated effects on membrane composition and trafficking in the plasma membrane (PM) and intracellular organelles, as well as actions of P2X7R in controlling various modes of nonclassical secretion. It will review P2X7R regulation of: (1) phosphatidylserine distribution in the PM outer leaflet; (2) shedding of PM surface proteins; (3) release of PM-derived microvesicles or microparticles; (4) PM blebbing; (5) cell-cell fusion resulting in formation of multinucleate cells; (6) phagosome maturation and fusion with lysosomes; (7) permeability of endosomes with internalized pathogen-associated molecular patterns; (8) permeability/integrity of mitochondria; (9) exocytosis of secretory lysosomes; and (10) release of exosomes from multivesicular bodies.

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“…9 In patients with extra-pulmonary TB, a failure of some of the immune response genes involved in controlling M. tuberculosis may partially explain the dissemination of M. tuberculosis from the lung to other tissues such as the brain. 10 A number of reports have recently found mutations and polymorphisms in Toll-like receptor (TLR) genes that affect host susceptibility to infectious diseases. 11À14 The TLR family contains 10 human proteins (TLR1-10).…”

Section: Introductionmentioning

confidence: 99%

A polymorphism in human TLR2 is associated with increased susceptibility to tuberculous meningitis

et al. 2007

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Tuberculous meningitis (TBM) results from the haematogenous dissemination of Mycobacterium tuberculosis from the lung to the brain. Dissemination is believed to occur early during infection, before the development of adaptive immunity. Toll-like receptor 2 (TLR2) mediates recognition of M. tuberculosis and initiates the innate immune response to infection. We hypothesized that polymorphisms in the TLR2 gene influence bacterial dissemination and the development of TBM. A casecontrol study was designed to test the hypothesis. Cases of bacteriologically confirmed pulmonary tuberculosis (TB) (n ¼ 183) and TBM (n ¼ 175), and cord blood controls (n ¼ 389) were enrolled in Vietnam. TLR2 genotype 597CC was associated with susceptibility to TB (odds ratio (OR) ¼ 2.22, 95% confidence interval (CI): 1.23À3.99). The association was found with meningeal rather than pulmonary TB (TBM vs control, OR ¼ 3.26, 95% CI: 1.72À6.18), and was strongest when miliary TB was found on chest radiography (controls vs TBM with miliary TB, OR ¼ 5.28, 95% CI: 2.20À12.65). Furthermore, the association increased with the severity of neurologic symptoms (grade I TBM, OR ¼ 1.93, 95% CI: 0.54À6.92; grade II, OR ¼ 3.32, 95% CI: 0.84À13.2; and grade III, OR ¼ 5.70, 95% CI: 1.81À18.0). These results demonstrate a strong association of TLR2 SNP T597C with the development of TBM and miliary TB and indicate that TLR2 influences the dissemination of M. tuberculosis.

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A Polymorphism in the P2X₇Gene Increases Susceptibility to Extrapulmonary Tuberculosis

Abstract: The 1513C allele increases susceptibility to extrapulmonary TB, and this defect is associated with the reduction in the capacity of macrophages to kill M. tuberculosis.

Cited by 196 publications

References 39 publications

Identification and characterization of a novel variant of the human P2X7 receptor resulting in gain of function

Identification and characterization of a novel variant of the human P2X7 receptor resulting in gain of function

P2X7 receptors regulate multiple types of membrane trafficking responses and non-classical secretion pathways

A polymorphism in human TLR2 is associated with increased susceptibility to tuberculous meningitis

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A Polymorphism in the P2X7Gene Increases Susceptibility to Extrapulmonary Tuberculosis

Abstract: The 1513C allele increases susceptibility to extrapulmonary TB, and this defect is associated with the reduction in the capacity of macrophages to kill M. tuberculosis.

Cited by 196 publications

References 39 publications

Identification and characterization of a novel variant of the human P2X7 receptor resulting in gain of function

Identification and characterization of a novel variant of the human P2X7 receptor resulting in gain of function

P2X7 receptors regulate multiple types of membrane trafficking responses and non-classical secretion pathways

A polymorphism in human TLR2 is associated with increased susceptibility to tuberculous meningitis

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Product

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A Polymorphism in the P2X₇Gene Increases Susceptibility to Extrapulmonary Tuberculosis