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1.
Cell Host Microbe ; 21(3): 376-389, 2017 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-28279347

RESUMO

The BabA adhesin mediates high-affinity binding of Helicobacter pylori to the ABO blood group antigen-glycosylated gastric mucosa. Here we show that BabA is acid responsive-binding is reduced at low pH and restored by acid neutralization. Acid responsiveness differs among strains; often correlates with different intragastric regions and evolves during chronic infection and disease progression; and depends on pH sensor sequences in BabA and on pH reversible formation of high-affinity binding BabA multimers. We propose that BabA's extraordinary reversible acid responsiveness enables tight mucosal bacterial adherence while also allowing an effective escape from epithelial cells and mucus that are shed into the acidic bactericidal lumen and that bio-selection and changes in BabA binding properties through mutation and recombination with babA-related genes are selected by differences among individuals and by changes in gastric acidity over time. These processes generate diverse H. pylori subpopulations, in which BabA's adaptive evolution contributes to H. pylori persistence and overt gastric disease.


Assuntos
Adesinas Bacterianas/metabolismo , Aderência Bacteriana , Mucosa Gástrica/microbiologia , Infecções por Helicobacter/microbiologia , Helicobacter pylori/fisiologia , Mucosa Gástrica/patologia , Infecções por Helicobacter/patologia , Concentração de Íons de Hidrogênio
4.
Nat Microbiol ; 2: 16188, 2016 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-27748756

RESUMO

Helicobacter pylori (Hp) strains that carry the cag type IV secretion system (cag-T4SS) to inject the cytotoxin-associated antigen A (CagA) into host cells are associated with peptic ulcer disease and gastric adenocarcinoma. CagA translocation by Hp is mediated by ß1 integrin interaction of the cag-T4SS. However, other cellular receptors or bacterial outer membrane adhesins essential for this process are unknown. Here, we identify the HopQ protein as a genuine Hp adhesin, exploiting defined members of the carcinoembryonic antigen-related cell adhesion molecule family (CEACAMs) as host cell receptors. HopQ binds the amino-terminal IgV-like domain of human CEACAM1, CEACAM3, CEACAM5 or CEACAM6 proteins, thereby enabling translocation of the major pathogenicity factor CagA into host cells. The HopQ-CEACAM interaction is characterized by a remarkably high affinity (KD from 23 to 268 nM), which is independent of CEACAM glycosylation, identifying CEACAMs as bona fide protein receptors for Hp. Our data suggest that the HopQ-CEACAM interaction contributes to gastric colonization or Hp-induced pathologies, although the precise role and functional consequences of this interaction in vivo remain to be determined.


Assuntos
Adesinas Bacterianas/metabolismo , Antígenos de Bactérias/metabolismo , Aderência Bacteriana , Proteínas de Bactérias/metabolismo , Moléculas de Adesão Celular/metabolismo , Helicobacter pylori/fisiologia , Interações Hospedeiro-Patógeno , Transporte Proteico , Linhagem Celular , Humanos , Ligação Proteica
5.
Nat Microbiol ; 2: 16189, 2016 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-27748768

RESUMO

Helicobacter pylori specifically colonizes the human gastric epithelium and is the major causative agent for ulcer disease and gastric cancer development. Here, we identify members of the carcinoembryonic antigen-related cell adhesion molecule (CEACAM) family as receptors of H. pylori and show that HopQ is the surface-exposed adhesin that specifically binds human CEACAM1, CEACAM3, CEACAM5 and CEACAM6. HopQ-CEACAM binding is glycan-independent and targeted to the N-domain. H. pylori binding induces CEACAM1-mediated signalling, and the HopQ-CEACAM1 interaction enables translocation of the virulence factor CagA into host cells and enhances the release of pro-inflammatory mediators such as interleukin-8. Based on the crystal structure of HopQ, we found that a ß-hairpin insertion (HopQ-ID) in HopQ's extracellular 3+4 helix bundle domain is important for CEACAM binding. A peptide derived from this domain competitively inhibits HopQ-mediated activation of the Cag virulence pathway, as genetic or antibody-mediated abrogation of the HopQ function shows. Together, our data suggest the HopQ-CEACAM1 interaction to be a potentially promising novel therapeutic target to combat H. pylori-associated diseases.


Assuntos
Adesinas Bacterianas/metabolismo , Aderência Bacteriana , Moléculas de Adesão Celular/metabolismo , Helicobacter pylori/fisiologia , Helicobacter pylori/patogenicidade , Interações Hospedeiro-Patógeno , Adesinas Bacterianas/química , Antígenos de Bactérias/metabolismo , Proteínas de Bactérias/metabolismo , Linhagem Celular , Cristalografia por Raios X , Humanos , Interleucina-8/metabolismo , Ligação Proteica , Conformação Proteica , Transporte Proteico , Virulência
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