Inhibition of primary human T cell proliferation by<i>Helicobacter pylori</i>vacuolating toxin (VacA) is independent of VacA effects on IL-2 secretion

Sundrud, Mark S.; Torres, Victor J.; Unutmaz, Derya; Cover, Timothy L.

doi:10.1073/pnas.0401528101

Cited by 237 publications

(233 citation statements)

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“…VacA causes numerous effects on intoxicated cells (7,10,57), and many VacA-mediated effects are dependent on the capacity of VacA to form membrane channels (11,14,19,(21)(22)(23)(24). Therefore, it is of interest to view the current results in the context of what is known about functional domains of other pore-forming toxins.…”

Section: Discussionmentioning

confidence: 99%

“…Other reported effects of VacA include depolarization of the membrane potential (11)(12)(13), apoptosis (14,15), detachment of epithelial cells from the basement membrane (16), interference with the process of antigen presentation (17), activation of mitogen-activated protein kinases (18,19), and inhibition of activation-induced proliferation of T lymphocytes (19 -21). Many of these effects are dependent on the capacity of VacA to form anion-selective membrane channels (13,15,(21)(22)(23)(24).…”

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confidence: 99%

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Functional Properties of the p33 and p55 Domains of the Helicobacter pylori Vacuolating Cytotoxin

Torres¹,

Ivie²,

McClain

et al. 2005

Journal of Biological Chemistry

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Helicobacter pylori secretes an 88-kDa vacuolating cytotoxin (VacA) that may contribute to the pathogenesis of peptic ulcer disease and gastric cancer. VacA cytotoxic activity requires assembly of VacA monomers into oligomeric structures, formation of anion-selective membrane channels, and entry of VacA into host cells. In this study, we analyzed the functional properties of recombinant VacA fragments corresponding to two putative VacA domains (designated p33 and p55). Immunoprecipitation experiments indicated that these two domains can interact with each other to form protein complexes. In comparison to the individual VacA domains, a mixture of the p33 and p55 proteins exhibited markedly enhanced binding to the plasma membrane of mammalian cells. Furthermore, internalization of the VacA domains was detected when cells were incubated with the p33/p55 mixture but not when the p33 and p55 proteins were tested individually. Incubation of cells with the p33/p55 mixture resulted in cell vacuolation, whereas the individual domains lacked detectable cytotoxic activity. Interestingly, sequential addition of p55 followed by p33 resulted in VacA internalization and cell vacuolation, whereas sequential addition in the reverse order was ineffective. These results indicate that both the p33 and p55 domains contribute to the binding and internalization of VacA and that both domains are required for vacuolating cytotoxic activity. Reconstitution of toxin activity from two separate domains, as described here for VacA, has rarely been described for pore-forming bacterial toxins, which suggests that VacA is a pore-forming toxin with unique structural properties.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Functional Properties of the p33 and p55 Domains of the Helicobacter pylori Vacuolating Cytotoxin

Torres¹,

Ivie²,

McClain

et al. 2005

Journal of Biological Chemistry

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“…Here, we extend these findings and implicate two H. pylori virulence determinants, VacA and GGT, in DC tolerization. Both factors were previously known to share several important properties: They both facilitate murine colonization (16,17), inhibit human T-cell activation (18)(19)(20)25), and induce epithelial cell apoptosis (26,27). The evidence now provided here documents a unique role for VacA and GGT in DC tolerization and links the tolerizing effects of both factors on DCs to persistence: (i) The H. pylori-induced inhibition of DC maturation depends on the (nonredundant) activity of both factors; (ii) the induction of Treg properties in naive T cells by H. pylori-experienced DCs likewise depends on both factors, and strains lacking either VacA or GGT due to targeted gene deletion (iii) fail to colonize mice at wild-type levels, and, in the case of the ΔvacA mutant (iv) induce somewhat stronger Th1 and Th17 responses and gastric pathology and fail to protect against allergen-induced asthma.…”

Section: Discussionmentioning

confidence: 99%

Helicobacter pylori γ-glutamyl transpeptidase and vacuolating cytotoxin promote gastric persistence and immune tolerance

Oertli

Noben

Engler

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

211

190

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Infection with the gastric bacterial pathogen Helicobacter pylori is typically contracted in early childhood and often persists for decades. The immunomodulatory properties of H. pylori that allow it to colonize humans persistently are believed to also account for H. pylori's protective effects against allergic and chronic inflammatory diseases. H. pylori infection efficiently reprograms dendritic cells (DCs) toward a tolerogenic phenotype and induces regulatory T cells (Tregs) with highly suppressive activity in models of allergen-induced asthma. We show here that two H. pylori virulence determinants, the γ-glutamyl transpeptidase GGT and the vacuolating cytotoxin VacA, contribute critically and nonredundantly to H. pylori's tolerizing effects on murine DCs in vitro and in vivo. The tolerancepromoting effects of both factors are independent of their described suppressive activity on T cells. Isogenic H. pylori mutants lacking either GGT or VacA are incapable of preventing LPS-induced DC maturation and fail to drive DC tolerization as assessed by induction of Treg properties in cocultured naive T cells. The Δggt and ΔvacA mutants colonize mice at significantly reduced levels, induce stronger T-helper 1 (Th1) and T-helper 17 (Th17) responses, and/or trigger more severe gastric pathology. Both factors promote the efficient induction of Tregs in vivo, and VacA is required to prevent allergen-induced asthma. The defects of the Δggt mutant in vitro and in vivo are phenocopied by pharmacological inhibition of the transpeptidase activity of GGT in all readouts. In conclusion, our results reveal the molecular players and mechanistic basis for H. pyloriinduced immunomodulation, promoting persistent infection and conferring protection against allergic asthma.bacterial virulence factors | hygiene hypothesis | persistent bacterial infection | human microbiota | persistence strategies T he bacterial pathogen Helicobacter pylori persistently colonizes the gastric mucosa of humans. It is typically acquired in early childhood (1) and, in the absence of antibiotic therapy, may persist for the entire lifespan of the host (2, 3). The extraordinary ability of H. pylori to resist a vigorous adaptive immune response driven in large part by T-helper 1 (Th1) and/or T-helper 17 (Th17)-polarized effector T cells (4, 5) has been attributed to its perfect adaptation to-and manipulation of-the human innate and adaptive immune systems (6). H. pylori has colonized its human host for at least 60,000 y (7) and during this long period of coevolution has evolved elaborate ways to systemically manipulate adaptive immune responses and to promote its persistence through the preferential induction of regulatory T-cell (Treg) over T-effector cell responses. Treg-predominant responses are characteristic of heavily colonized but asymptomatic carriers (4) and of children with particularly mild forms of Helicobacter-associated gastritis (8). Several recent functional studies using experimentally infected animals have implicated Tregs and dendritic cells (...

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“…Firstly, the presence of Hp in the body affects the organism by its molecular factors. The most widely studied are proteins cytotoxin associated gene A (CagA) and vacuolating cytotoxin A (VacA), which have been implicated in perturbing host immunological responses [7,8].…”

Section: Pathogenesis Of Metabolic Changes and Pro-inflammatory Statementioning

confidence: 99%

Untitled

2016

Russ. Open Med. J.

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Abstract:The incidence and prevalence of type 2 diabetes mellitus is considered to be one of the most critical problems in the healthcare system. The pathophysiology of the disease has proven to be complicated and multiple factors are involved in its development. Recently Helicobacter pylori was proposed as a new risk factor for developing type 2 diabetes mellitus as well as other disease. This study is a review of the current data involving Helicobacter pylori association with type 2 diabetes mellitus and its complications.

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Inhibition of primary human T cell proliferation byHelicobacter pylorivacuolating toxin (VacA) is independent of VacA effects on IL-2 secretion

Cited by 237 publications

References 37 publications

Functional Properties of the p33 and p55 Domains of the Helicobacter pylori Vacuolating Cytotoxin

Functional Properties of the p33 and p55 Domains of the Helicobacter pylori Vacuolating Cytotoxin

Helicobacter pylori γ-glutamyl transpeptidase and vacuolating cytotoxin promote gastric persistence and immune tolerance

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