Direct binding of gangliosides to Helicobacter pylori vacuolating cytotoxin (VacA) neutralizes its toxin activity

Wada, Akihiro; Hasegawa, Makoto; Wong, Pooi-Fong; Shirai, Emi; Shirai, Nobuyuki; Tan, Li-Jing; Llanes, Rafael; Hojo, Hironobu; Yamasaki, Eiki; Ichinose, Akitoyo; Ichinose, Yoshio; Senba, Masachika

doi:10.1093/glycob/cwq014

Cited by 21 publications

(7 citation statements)

References 37 publications

(30 reference statements)

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“…2C) [45]. Although GM3 ganglioside is not involved in H. pylori binding [46,47], it was demonstrated that GM3 has a good neutralizing capacity against the H. pylori vacuolating toxin VacA, preventing its entrance into the gastric cells [48]. Hence, the induction of ST3GAL5 may reflect a host response to decrease the epithelial damage associated with the infection.…”

Section: Discussionmentioning

confidence: 99%

Helicobacter pylori chronic infection and mucosal inflammation switches the human gastric glycosylation pathways

Magalhães

Marcos-Pinto

Nairn

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Helicobacter pylori exploits host glycoconjugates to colonize the gastric niche. Infection can persist for decades promoting chronic inflammation, and in a subset of individuals lesions can silently progress to cancer. This study shows that H. pylori chronic infection and gastric tissue inflammation result in a remodeling of the gastric glycophenotype with increased expression of sialyl-Lewis a/x antigens due to transcriptional up-regulation of the B3GNT5, B3GALT5, and FUT3 genes. We observed that H. pylori infected individuals present a marked gastric local proinflammatory signature with significantly higher TNF-α levels and demonstrated that TNF-induced activation of the NF-kappaB pathway results in B3GNT5 transcriptional up-regulation. Furthermore, we show that this gastric glycosylation shift, characterized by increased sialylation patterns, favors SabA-mediated H. pylori attachment to human inflamed gastric mucosa. This study provides novel clinically relevant insights into the regulatory mechanisms underlying H. pylori modulation of host glycosylation machinery, and phenotypic alterations crucial for life-long infection. Moreover, the biosynthetic pathways here identified as responsible for gastric mucosa increased sialylation, in response to H. pylori infection, can be exploited as drug targets for hindering bacteria adhesion and counteract the infection chronicity.

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Section: Discussionmentioning

confidence: 99%

Helicobacter pylori chronic infection and mucosal inflammation switches the human gastric glycosylation pathways

Magalhães

Marcos-Pinto

Nairn

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…Pull-down assay by using GM1-Sepharose for the toxins were performed as previously described [23]. Briefly, lyso-GM1 was coupled using NHS-activated Sepharose 4 Fast Flow (GE Healthcare, England) in 0.2 M NaHCO 3 and 0.5 M NaCl (pH 8.3) at room temperature for 4 h with rotation.…”

Section: Pull-down Assay By Gm1-sepharosementioning

confidence: 99%

Vibiro vulnificus hemolysin associates with gangliosides

et al. 2020

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Background: Vibrio vulnificus hemolysin (VVH) is a pore-forming toxin secreted by Vibrio vulnificus. Cellular cholesterol was believed to be the receptor for VVH, because cholesterol could bind to VVH and preincubation with cholesterol inhibited cytotoxicity. It has been reported that specific glycans such as N-acetyl-D-galactosamine and N-acetyl-D-lactosamine bind to VVH, however, it has not been known whether these glycans could inhibit the cytotoxicity of VVH without oligomer formation. Thus, to date, binding mechanisms of VVH to cellular membrane, including specific receptors have not been elucidated. Results: We show here that VVH associates with ganglioside GM1a, Fucosyl-GM1, GD1a, GT1c, and GD1b by glycan array. Among them, GM1a could pulldown VVH. Moreover, the GD1a inhibited the cytotoxicity of VVH without the formation of oligomers. Conclusion: This is the first report of a molecule able to inhibit the binding of VVH to target cells without oligomerization of VVH.

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“…VacA and CagA are major H. pylori -secreted proteins that lack known homologs in other bacterial species (Jones et al, 2010 ). VacA exists in all H. pylori strains and encodes vacuolating cell toxins that dysregulate gene expression and other cellular processes (Wada et al, 2010 ; Palframan et al, 2012 ). Additionally, VacA causes the apoptosis of gastric epithelial cells through targeting mitochondria and inhibits the proliferation of T cells (Sundrud et al, 2004 ; Jain et al, 2011 ).…”

Section: Pathogenic Mechanisms Of H Pylorimentioning

confidence: 99%

Transforming growth factor-β: an important mediator in Helicobacter pylori-associated pathogenesis

Xie

Lü

2015

Front. Cell. Infect. Microbiol.

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Helicobacter pylori (H.pylori) is a Gram-negative, microaerophilic, helical bacillus that specifically colonizes the gastric mucosa. The interaction of virulence factors, host genetic factors, and environmental factors contributes to the pathogenesis of H. pylori-associated conditions, such as atrophic gastritis and intestinal metaplasia. Infection with H. pylori has recently been recognized as the strongest risk factor for gastric cancer. As a pleiotropic cytokine, transforming growth factor (TGF)-β regulates various biological processes, including cell cycle, proliferation, apoptosis, and metastasis. Recent studies have shed new light on the involvement of TGF-β signaling in the pathogenesis of H. pylori infection. This review focuses on the potential etiological roles of TGF-β in H. pylori-mediated gastric pathogenesis.

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Direct binding of gangliosides to Helicobacter pylori vacuolating cytotoxin (VacA) neutralizes its toxin activity

Cited by 21 publications

References 37 publications

Helicobacter pylori chronic infection and mucosal inflammation switches the human gastric glycosylation pathways

Helicobacter pylori chronic infection and mucosal inflammation switches the human gastric glycosylation pathways

Vibiro vulnificus hemolysin associates with gangliosides

Transforming growth factor-β: an important mediator in Helicobacter pylori-associated pathogenesis

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