Helicobacter pylori-Induced TLR9 Activation and Injury Are Associated With the Virulence-Associated Adhesin HopQ.
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ABSTRACT:
SUBMITTER: Dooyema SDR
PROVIDER: S-EPMC8280490 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The human gastric pathogen Helicobacter pylori is a major causative agent of gastritis, peptic ulcer disease, and gastric cancer. As part of its adhesive lifestyle, the bacterium targets members of the carcinoembryonic antigen-related cell adhesion molecule (CEACAM) family by the conserved outer membrane adhesin HopQ. The HopQ-CEACAM1 interaction is associated with inflammatory responses and enables the intracellular delivery and phosphorylation of the CagA oncoprotein via a yet unknown mechanism. Here, we generated crystal structures of HopQ isotypes I and II bound to the N-terminal domain of human CEACAM1 (C1ND) and elucidated the structural basis of H. pylori specificity toward human CEACAM receptors. Both HopQ alleles target the ?-strands G, F, and C of C1ND, which form the trans dimerization interface in homo- and heterophilic CEACAM interactions. Using SAXS, we show that the HopQ ectodomain is sufficient to induce C1ND monomerization and thus providing H. pylori a route to influence CEACAM-mediated cell adherence and signaling events.
| S-EPMC6028033 | biostudies-literature
Project description:Attachment to the host gastric mucosa is a key step in Helicobacter pylori infection. Recently, a novel adhesin, HopQ, was shown to bind distinct host CEACAM proteins-an interaction that was found to be essential for the translocation of CagA, a key virulence factor of H. pylori. The HopQ-CEACAM1 co-crystal structure revealed a binding mode dependent on loops in HopQ that are clasped by disulfide bonds. In this study, we investigated the importance of these cysteine residues for CEACAM1 engagement by H. pylori. We observed a loss of CEACAM1 binding and CagA translocation upon disruption of the disulfide bond in loop CL1 (connecting C103 to C132 in HopQ). Deletion of the Dsb-like oxidoreductase HP0231 did not affect cell surface expression of HopQ or alter the interaction of H. pylori with target cells. Although HP0231 deletion was previously described to impede CagA translocation, our results indicate that this occurs through a HopQ-independent mechanism. Together, our results open up new avenues to therapeutically target the HopQ-CEACAM1 interaction and reduce the burden of pathogenic H. pylori.
| S-EPMC7232459 | biostudies-literature
Project description:Helicobacter pylori is a bacterial pathogen that colonizes the gastric niche of ??50% of the human population worldwide and is known to cause peptic ulceration and gastric cancer. Pathology of infection strongly depends on a cag pathogenicity island (cagPAI)-encoded type IV secretion system (T4SS). Here, we aimed to identify as yet unknown bacterial factors involved in cagPAI effector function and performed a large-scale screen of an H.?pylori transposon mutant library using activation of the pro-inflammatory transcription factor NF-?B in human gastric epithelial cells as a measure of T4SS function. Analysis of ??3000 H.?pylori mutants revealed three non-cagPAI genes that affected NF-?B nuclear translocation. Of these, the outer membrane protein HopQ from H.?pylori strain P12 was essential for CagA translocation and for CagA-mediated host cell responses such as formation of the hummingbird phenotype and cell scattering. Besides that, deletion of hopQ reduced T4SS-dependent activation of NF-?B, induction of MAPK signalling and secretion of interleukin 8 (IL-8) in the host cells, but did not affect motility or the quantity of bacteria attached to host cells. Hence, we identified HopQ as a non-cagPAI-encoded cofactor of T4SS function.
| S-EPMC3797234 | biostudies-literature
Project description:Helicobacter pylori has developed several strategies using its diverse virulence factors to trigger and, at the same time, limit the host's inflammatory responses in order to establish a chronic infection in the human stomach. One of the virulence factors that has recently received more attention is a member of the Helicobacter outer membrane protein family, the adhesin HopQ, which binds to the human Carcinoembryonic Antigen-related Cell Adhesion Molecules (CEACAMs) on the host cell surface. The HopQ-CEACAM interaction facilitates the translocation of the cytotoxin-associated gene A (CagA), an important effector protein of H. pylori, into host cells via the Type IV secretion system (T4SS). Both the T4SS itself and CagA are important virulence factors that are linked to many aberrant host signaling cascades. In the last few years, many studies have emphasized the prerequisite role of the HopQ-CEACAM interaction not only for the adhesion of this pathogen to host cells but also for the regulation of cellular processes. This review summarizes recent findings about the structural characteristics of the HopQ-CEACAM complex and the consequences of this interaction in gastric epithelial cells as well as immune cells. Given that the upregulation of CEACAMs is associated with many H. pylori-induced gastric diseases including gastritis and gastric cancer, these data may enable us to better understand the mechanisms of H. pylori's pathogenicity.
| S-EPMC9986547 | biostudies-literature
Project description:Helicobacter pylori genomes contain about 30 different hop genes, which encode outer membrane proteins. In this study, we analyzed genetic diversity in the H. pylori hopQ (omp27) locus, which corresponds to HP1177 in the genome of H. pylori reference strain 26,695. hopQ and its flanking genes were PCR amplified from multiple H. pylori strains, and the nucleotide sequences were determined. This analysis revealed the existence of two different families of hopQ alleles. Type I hopQ alleles are present in the genomes of two fully sequenced H. pylori strains, whereas the existence of type II hopQ alleles has not previously been recognized. Type I and type II hopQ alleles are 75 to 80% identical in nucleotide sequences and encode predicted outer membrane proteins that are 68 to 72% identical in amino acid sequences. PCR-based methods were developed to enable rapid differentiation between type I and type II hopQ alleles. Type I hopQ alleles were found significantly more commonly in cag(+)/type s1-vacA strains from patients with peptic ulcer disease than in cag-negative/s2-vacA strains from patients without ulcer disease (P < 0.001). Determination of hopQ allelic types provides a new method for classification of H. pylori strains. Further studies in multiple populations of patients are indicated to evaluate the usefulness of this approach for distinguishing potentially ulcerogenic H. pylori strains from less virulent strains.
| S-EPMC154617 | biostudies-literature
Project description:Helicobacter pylori infects half of the world's population, and strains that encode the cag type IV secretion system for injection of the oncoprotein CagA into host gastric epithelial cells are associated with elevated levels of cancer. CagA translocation into host cells is dependent on interactions between the H. pylori adhesin protein HopQ and human CEACAMs. Here, we present high-resolution structures of several HopQ-CEACAM complexes and CEACAMs in their monomeric and dimeric forms establishing that HopQ uses a coupled folding and binding mechanism to engage the canonical CEACAM dimerization interface for CEACAM recognition. By combining mutagenesis with biophysical and functional analyses, we show that the modes of CEACAM recognition by HopQ and CEACAMs themselves are starkly different. Our data describe precise molecular mechanisms by which microbes exploit host CEACAMs for infection and enable future development of novel oncoprotein translocation inhibitors and H. pylori-specific antimicrobial agents.
| S-EPMC6028028 | biostudies-literature
Project description:We previously showed that the colorectal cancer colonizing bacterium Fusobacterium nucleatum protects tumors from immune cell attack via binding of the fusbacterial Fap2 outer-membrane protein to TIGIT, a checkpoint inhibitory receptor expressed on T cells and NK cells. Helicobacter pylori, the causative agent for peptic ulcer disease, is associated with the development of gastric adenocarcinoma and MALT lymphoma. The HopQ outer-membrane adhesin of H. pylori was recently shown to bind carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) including CEACAM1, an inhibitory receptor expressed mainly by activated T and NK cells. Here we investigated the possibility that similar to Fap2, HopQ can also inhibit immune cell activities by interacting with CEACAM1. We used several approaches to confirm that HopQ indeed interacts with CEACAM1, and show that CEACAM1-mediated activation by HopQ, may inhibit NK and T cell functions.
| S-EPMC6422397 | biostudies-literature
Project description:Helicobacter pylori infection is usually acquired in childhood, but little is known about its natural history in asymptomatic children, primarily due to the paucity of non-invasive diagnostic methods. H. pylori strains harboring cagA and specific alleles of hopQ and vacA are associated with increased risk for gastric cancer. Many studies of H. pylori virulence markers in children have the bias that symptomatic subjects are selected for endoscopy, and these children may harbor the most virulent strains. Our aim is to genotype cagA, hopQ, and vacA alleles in stool DNA samples of healthy Colombian children residing in an area with high incidence of gastric cancer, to avoid selection bias resulting from endoscopy.H. pylori status of 86 asymptomatic children was assessed by (13) C-urea breath test (UBT) and PCR. H. pylori 16S rRNA, cagA, hopQ, and vacA genes were amplified from stool DNA samples and sequenced.UBT was positive in 69 (80.2%) of 86 children; in stool DNA analysis, 78.3% were positive by 16S rRNA PCR. cagA, vacA, and hopQ were detected in 66.1%, 84.6%, and 72.3% of stool DNA samples from 16S rRNA-positive children. Of the children's DNA samples, which revealed vacA and hopQ alleles, 91.7% showed vacA s1 and 73.7% showed type I hopQ. Type I hopQ alleles were associated with cagA positivity and vacA s1 genotypes (p < 0.0001).Using stool DNA samples, virulence markers of H. pylori were successfully genotyped in a high percentage of the asymptomatic infected children, revealing a high prevalence of genotypes associated with virulence. Type I hopQ alleles were associated with the presence of cagA and the vacA s1 genotype.
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Project description:Helicobacter pylori adherence in the human gastric mucosa involves specific bacterial adhesins and cognate host receptors. Here, we identify sialyl-dimeric-Lewis x glycosphingolipid as a receptor for H. pylori and show that H. pylori infection induced formation of sialyl-Lewis x antigens in gastric epithelium in humans and in a Rhesus monkey. The corresponding sialic acid-binding adhesin (SabA) was isolated with the "retagging" method, and the underlying sabA gene (JHP662/HP0725) was identified. The ability of many H. pylori strains to adhere to sialylated glycoconjugates expressed during chronic inflammation might thus contribute to virulence and the extraordinary chronicity of H. pylori infection.
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Project description:Expression of the Helicobacter pylori blood group antigen binding adhesin A (BabA) is more common in strains isolated from patients with peptic ulcer disease or gastric cancer, rather than asymptomatic colonization. Here we used mouse models to examine host determinants that affect H. pylori BabA expression. BabA expression was lost by phase variation as frequently in WT mice as in RAG2-/- mice that do not have functional B or T cells, and in MyD88-/-, TLR2-/- and TLR4-/- mice that are defective in toll like receptor signaling. The presence of other bacteria had no effect on BabA expression as shown by infection of germ free mice. Moreover, loss of BabA expression was not dependent on Leb expression or the capacity of BabA to bind Leb. Surprisingly, gender was the host determinant most associated with loss of BabA expression, which was maintained to a greater extent in male mice and was associated with greater bacterial load. These results suggest the possibility that loss of BabA expression is not driven by adaptive immunity or toll-like receptor signaling, and that BabA may have other, unrecognized functions in addition to serving as an adhesin that binds Leb.
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