Selective Inhibition of Ii-dependent Antigen Presentation by <i>Helicobacter pylori</i> Toxin VacA

Molinari, Maurizio; Salio, Mariolina; Galli, Carmela; Norais, Nathalie; Rappuoli, Rino; Lanzavecchia, Antonio; Montecucco, Cesare

doi:10.1084/jem.187.1.135

Cited by 259 publications

(177 citation statements)

References 30 publications

(44 reference statements)

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“…It has been shown that VacA toxin released by H. pylori strains harboring a pathogenicity island 32 inhibits antigen processing in APCs but not the exocytosis of perforin-containing granules of natural killer cells. 33 It is possible that, in some H. pylori-infected individuals, other bacterial components affect the development or expression of regulatory cytotoxic mechanisms on B-cell proliferation by gastric T cells, allowing exhaustive and unbalanced B-cell help and lymphomagenesis.…”

Section: Discussionmentioning

confidence: 99%

Impaired T-cell regulation of B-cell growth in Helicobacter pylori–related gastric low-grade MALT lymphoma

D’Elios¹,

Amedei²,

Manghetti³

et al. 1999

Gastroenterology

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Section: Discussionmentioning

confidence: 99%

Impaired T-cell regulation of B-cell growth in Helicobacter pylori–related gastric low-grade MALT lymphoma

D’Elios¹,

Amedei²,

Manghetti³

et al. 1999

Gastroenterology

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“…Likewise, Helicobacter pylori blocks proper acidification by inhibiting fusion of its compartment with late lysosomal compartments. This obstruction interferes with antigen presentation, presumably because efficient antigen processing cannot take place in the absence of functional proteases (35). We propose that each pathogen, by virtue of its unique surface architecture, may be delivered to a cellular compartment with distinct processing proteases and with different routes of access to the class II MHC molecules themselves.…”

Section: Discussionmentioning

confidence: 99%

Recruitment of CD63 toCryptococcus neoformansphagosomes requires acidification

Artavanis‐Tsakonas

Love

Ploegh

et al. 2006

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

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The subcellular localization of the cluster of differentiation 63 (CD63) tetraspanin and its interaction with the class II MHC antigen presentation pathway were examined in the context of phagocytosis by live cell imaging, by using monomeric red fluorescent protein-tagged mouse CD63 expressed in primary bone marrow-derived cell cultures. Upon phagocytosis of Cryptococcus neoformans and polystyrene beads, CD63 was recruited selectively to C. neoformans-containing phagosomes in a MyD88-independent acidification-dependent manner. Bead-containing phagosomes, within a C. neoformans-containing cell, acidified to a lesser extent and failed to recruit CD63 to a level detectable by microscopy. CD63 recruitment to yeast phagosomes occurred independently of class II MHC and LAMP-1. These observations indicate that the composition of distinct phagosomal compartments within the same cell is determined by phagosomal cargo and may affect the outcome of antigen processing and presentation.dendritic cells ͉ live cell imaging ͉ lysosome ͉ phagocytosis ͉ yeast P rofessional antigen-presenting cells (APCs) acquire microbial pathogens by phagocytosis and process them for presentationbyclassIIMHCmolecules.Internalizationofparticulate matter can be mediated through a number of receptors, including Fc receptors, complement receptors, integrins, and scavenger receptors. Each mode of entry is associated with specific morphological changes, all of which ultimately result in formation of the phagosome (reviewed in ref. 1). Phagosome maturation is complex and not completely understood. Once formed, the phagosome undergoes a series of fusion and fission events that sequentially incorporate elements of early endosomes, late endosomes, and lysosomes; these events result in dynamic delivery and removal of material (reviewed in ref. 2).Several pathogens successfully evade immune attack by exploiting the phagosomal environment to render it favorable for replication and survival. Examples include Leishmania donovani (3), Salmonella typhimurium (4), Mycobacterium tuberculosis (5), and Cryptococcus neoformans (6). Furthermore, internalization of different pathogenic organisms may yield functionally distinct phagosomes. Whatever the routes involved in pathogen entry and subsequent phagosome maturation, current models would benefit from a more accurate description of phagocytosis in living cells through use of suitably tagged endosomal proteins, such as the class II MHC products that ultimately present pathogen-derived peptides (7).Here we investigate the cluster of differentiation 63 (CD63) tetraspanin within the endosomal pathway by tagging it with monomeric red fluorescent protein (mRFP1) and using live cell imaging to observe its behavior in primary mouse APCs. CD63, also known as LAMP-3, was characterized originally as a platelet activation marker (8) and has been used as a marker of late endosomes and lysosomes (9). More recently, the focus has shifted to its interaction with class II MHC and its role in antigen presentation. In professional APC...

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“…A second possibility is that VacA possesses an important biological function other than inducing vacuolation, which is not blocked by the s2 extension. For example, it may perform other functions ascribed to VacA such as increasing epithelial permeability, stimulating epithelial cell apoptosis (52), inhibiting antigen presentation (53), or binding to cytoskeletal proteins (54).…”

Section: Discussionmentioning

confidence: 99%

Determinants of Non-toxicity in the Gastric Pathogen Helicobacter pylori

Letley

Rhead

Twells

et al. 2003

Journal of Biological Chemistry

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The Helicobacter pylori vacuolating cytotoxin gene, vacA, is naturally polymorphic, the two most diverse regions being the signal region (which can be type s1 or s2) and the mid region (m1 or m2). Previous work has shown which features of vacA make peptic ulcer and gastric cancer-associated type s1/m1 and s1/m2 strains toxic. vacA s2/m2 strains are associated with lower peptic ulcer and gastric cancer risk and are non-toxic. We now define the features of vacA that determine the nontoxicity of these strains. To do this, we deleted parts of vacA and constructed isogenic hybrid strains in which regions of vacA were exchanged between toxigenic and non-toxigenic strains. We showed that a naturally occurring 12-amino acid hydrophilic N-terminal extension found on s2 VacA blocks vacuolating activity as its removal (to make the strain s1-like) confers activity. The mid region of s2/m2 vacA does not cause the non-vacuolating phenotype, but if VacA is unblocked, it confers cell line specificity of vacuolation as in natural s1/m2 strains. Chromosomal replacement of vacA in a nontoxigenic strain with vacA from a toxigenic strain confers full vacuolating activity proving that this activity is entirely controlled by elements within vacA. This work defines why H. pylori strains with different vacA allelic structures have differing toxicity and provides a rational basis for vacA typing schemes.

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Selective Inhibition of Ii-dependent Antigen Presentation by Helicobacter pylori Toxin VacA

Cited by 259 publications

References 30 publications

Impaired T-cell regulation of B-cell growth in Helicobacter pylori–related gastric low-grade MALT lymphoma

Impaired T-cell regulation of B-cell growth in Helicobacter pylori–related gastric low-grade MALT lymphoma

Recruitment of CD63 toCryptococcus neoformansphagosomes requires acidification

Determinants of Non-toxicity in the Gastric Pathogen Helicobacter pylori

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