scholarly journals The IntactdupACluster Is a More Reliable Helicobacter pylori Virulence Marker thandupAAlone

2011 ◽  
Vol 80 (1) ◽  
pp. 381-387 ◽  
Author(s):  
Sung Woo Jung ◽  
Mitsushige Sugimoto ◽  
Seiji Shiota ◽  
David Y. Graham ◽  
Yoshio Yamaoka
Keyword(s):  
Duodenal Ulcer ◽  
Helicobacter Pylori ◽  
Content Type ◽  
Cluster Group ◽  
Type Iv ◽  
Plasticity Region ◽  
The Status ◽  
H Pylori ◽  
Secretory System ◽  
The U.S

ABSTRACTThe duodenal ulcer promoting (dupA) gene, located in the plasticity region ofHelicobacter pylori, is associated with duodenal ulcer development.dupAwas predicted to form a type IV secretory system (T4SS) withvirgenes arounddupA(dupAcluster). We investigated the prevalence ofdupAanddupAclusters and clarified associations between thedupAcluster status and clinical outcomes in the U.S. population. In all, 245H. pyloristrains were examined using PCR to evaluate the status ofdupAand the adjacentvirgenes predicted to form T4SS, in addition to the status ofcagpathogenicity island (PAI). The associations betweendupAcluster status and interleukin-8 (IL-8) and IL-12 production were also examined. The presence ofdupAand all adjacentvirgenes were defined as a completedupAcluster. Many variations related to the status ofdupAanddupAcluster genes were identified. ConcurrentH. pyloriinfection and the presence of a completedupAcluster increases duodenal ulcer risk compared toH. pyloriinfection with incompletedupAcluster or without thedupAgene independent on thecagPAI status (adjusted odds ratio, 2.13; 95% confidence interval, 1.13 to 4.03). Gastric mucosal IL-8 levels were also significantly higher in the completedupAcluster group than in other groups (P= 0.01). In conclusion, although the causal relationship between thedupAcluster and duodenal ulcer development is not proved, the presence of a completedupAcluster but notdupAalone, is associated with duodenal ulcer development.

scholarly journals The Helicobacter pylori Autotransporter ImaA Tempers the Bacterium's Interaction with α5β1 Integrin

2016 ◽  
Vol 85 (1) ◽  
Author(s):  
William E. Sause ◽  
Daniela Keilberg ◽  
Soufiane Aboulhouda ◽  
Karen M. Ottemann
Keyword(s):  
Helicobacter Pylori ◽  
Host Cell ◽  
Type Iv Secretion ◽  
Host Cells ◽  
Wild Type ◽  
Content Type ◽  
Type Iv ◽  
H Pylori ◽  
Α5β1 Integrin ◽  
Cell Interface

ABSTRACT The human pathogen Helicobacter pylori uses the host receptor α5β1 integrin to trigger inflammation in host cells via its cag pathogenicity island (cag PAI) type IV secretion system (T4SS). Here, we report that the H. pylori ImaA protein (HP0289) decreases the action of the cag PAI T4SS via tempering the bacterium's interaction with α5β1 integrin. Previously, imaA-null mutants were found to induce an elevated inflammatory response that was dependent on the cag PAI T4SS; here we extend those findings to show that the elevated response is independent of the CagA effector protein. To understand how ImaA could be affecting cag PAI T4SS activity at the host cell interface, we utilized the Phyre structural threading program and found that ImaA has a region with remote homology to bacterial integrin-binding proteins. This region was required for ImaA function. Unexpectedly, we observed that imaA mutants bound higher levels of α5β1 integrin than wild-type H. pylori, an outcome that required the predicted integrin-binding homology region of ImaA. Lastly, we report that ImaA directly affected the amount of host cell β1 integrin but not other cellular integrins. Our results thus suggest a model in which H. pylori employs ImaA to regulate interactions between integrin and the T4SS and thus alter the host inflammatory strength.

scholarly journals Natural Competence Promotes Helicobacter pylori Chronic Infection

2012 ◽  
Vol 81 (1) ◽  
pp. 209-215 ◽  
Author(s):  
Marion S. Dorer ◽  
Ilana E. Cohen ◽  
Tate H. Sessler ◽  
Jutta Fero ◽  
Nina R. Salama
Keyword(s):  
Helicobacter Pylori ◽  
Chronic Infection ◽  
Acute Infection ◽  
Host Cells ◽  
High Rate ◽  
Natural Competence ◽  
Content Type ◽  
Type Iv ◽  
Competence Factor ◽  
H Pylori

Animal models are important tools for studies of human disease, but developing these models is a particular challenge with regard to organisms with restricted host ranges, such as the human stomach pathogenHelicobacter pylori. In most cases,H. pyloriinfects the stomach for many decades before symptoms appear, distinguishing it from many bacterial pathogens that cause acute infection. To model chronic infection in the mouse, a human clinical isolate was selected for its ability to survive for 2 months in the mouse stomach, and the resulting strain, MSD132, colonized the mouse stomach for at least 28 weeks. During selection, thecagYcomponent of the Cag type IV secretion system was mutated, disrupting a key interaction with host cells. Increases in both bacterial persistence and bacterial burden occurred prior to this mutation, and a mixed population ofcagY+andcagYmutant cells was isolated from a single mouse, suggesting that mutations accumulate during selection and that factors in addition to the Cag apparatus are important for murine adaptation. Diversity in both alleles and genes is common inH. pyloristrains, and natural competence mediates a high rate of interstrain genetic exchange. Mutations of the Com apparatus, a membrane DNA transporter, and DprA, a cytosolic competence factor, resulted in reduced persistence, although initial colonization was normal. Thus, exchange of DNA between genetically heterogeneousH. pyloristrains may improve chronic colonization. The strains and methods described here will be important tools for defining both the spectrum of mutations that promote murine adaptation and the genetic program of chronic infection.

scholarly journals Maintenance of Type IV Secretion Function During Helicobacter pylori Infection in Mice

mBio ◽  
2020 ◽  
Vol 11 (6) ◽  
pp. e03147-20
Author(s):  
Emma C. Skoog ◽  
Miriam E. Martin ◽  
Roberto M. Barrozo ◽  
Lori M. Hansen ◽  
Lucy P. Cai ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Murine Model ◽  
Pathogenicity Island ◽  
Secretion System ◽  
Type Iv Secretion ◽  
Type Iv Secretion System ◽  
Content Type ◽  
Biologically Relevant ◽  
Type Iv ◽  
H Pylori

ABSTRACTThe Helicobacter pylori type IV secretion system (T4SS) encoded on the cag pathogenicity island (cagPAI) secretes the CagA oncoprotein and other effectors into the gastric epithelium. During murine infection, T4SS function is lost in an immune-dependent manner, typically as a result of in-frame recombination in the middle repeat region of cagY, though single nucleotide polymorphisms (SNPs) in cagY or in other essential genes may also occur. Loss of T4SS function also occurs in gerbils, nonhuman primates, and humans, suggesting that it is biologically relevant and not simply an artifact of the murine model. Here, we sought to identify physiologically relevant conditions under which T4SS function is maintained in the murine model. We found that loss of H. pylori T4SS function in mice was blunted by systemic Salmonella coinfection and completely eliminated by dietary iron restriction. Both have epidemiologic parallels in humans, since H. pylori strains from individuals in developing countries, where iron deficiency and systemic infections are common, are also more often cagPAI+ than strains from developed countries. These results have implications for our fundamental understanding of the cagPAI and also provide experimental tools that permit the study of T4SS function in the murine model.IMPORTANCE The type IV secretion system (T4SS) is the major Helicobacter pylori virulence factor, though its function is lost during murine infection. Loss of function also occurs in gerbils and in humans, suggesting that it is biologically relevant, but the conditions under which T4SS regulation occurs are unknown. Here, we found that systemic coinfection with Salmonella and iron deprivation each promote retention of T4SS function. These results improve our understanding of the cag pathogenicity island (cagPAI) and provide experimental tools that permit the study of T4SS function in the murine model.

scholarly journals Genome-wide association study of gastric cancer- and duodenal ulcer-derived Helicobacter pylori strains reveals discriminatory genetic variations and novel oncoprotein candidates

2021 ◽  
Vol 7 (11) ◽  
Author(s):  
Vo Phuoc Tuan ◽  
Koji Yahara ◽  
Ho Dang Quy Dung ◽  
Tran Thanh Binh ◽  
Pham Huu Tung ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Duodenal Ulcer ◽  
Helicobacter Pylori ◽  
Type Species ◽  
Genetic Variations ◽  
Genome Wide Association ◽  
Content Type ◽  
Link Type ◽  
Genome Wide ◽  
H Pylori

Genome-wide association studies (GWASs) can reveal genetic variations associated with a phenotype in the absence of any hypothesis of candidate genes. The problem of false-positive sites linked with the responsible site might be bypassed in bacteria with a high homologous recombination rate, such as Helicobacter pylori , which causes gastric cancer. We conducted a small-sample GWAS (125 gastric cancer cases and 115 controls) followed by prediction of gastric cancer and control (duodenal ulcer) H. pylori strains. We identified 11 single nucleotide polymorphisms (eight amino acid changes) and three DNA motifs that, combined, allowed effective disease discrimination. They were often informative of the underlying molecular mechanisms, such as electric charge alteration at the ligand-binding pocket, alteration in subunit interaction, and mode-switching of DNA methylation. We also identified three novel virulence factors/oncoprotein candidates. These results provide both defined targets for further informatic and experimental analyses to gain insights into gastric cancer pathogenesis and a basis for identifying a set of biomarkers for distinguishing these H. pylori -related diseases.

scholarly journals Genes Required for Assembly of Pili Associated with the Helicobacter pylori cag Type IV Secretion System

2014 ◽  
Vol 82 (8) ◽  
pp. 3457-3470 ◽  
Author(s):  
Elizabeth M. Johnson ◽  
Jennifer A. Gaddy ◽  
Bradley J. Voss ◽  
Ewa E. Hennig ◽  
Timothy L. Cover
Keyword(s):  
Helicobacter Pylori ◽  
Epithelial Cells ◽  
Secretion System ◽  
Type Iv Secretion ◽  
Type Iv Secretion System ◽  
Gastric Epithelial Cells ◽  
Content Type ◽  
Type Iv ◽  
Pilus Biogenesis ◽  
H Pylori

ABSTRACTHelicobacter pyloricauses numerous alterations in gastric epithelial cells through processes that are dependent on activity of thecagtype IV secretion system (T4SS). Filamentous structures termed “pili” have been visualized at the interface betweenH. pyloriand gastric epithelial cells, and previous studies suggested that pilus formation is dependent on the presence of thecagpathogenicity island (PAI). Thus far, there has been relatively little effort to identify specific genes that are required for pilus formation, and the role of pili in T4SS function is unclear. In this study, we selected 7 genes in thecagPAI that are known to be required for T4SS function and investigated whether these genes were required for pilus formation.cagT,cagX,cagV,cagM, andcag3mutants were defective in both T4SS function and pilus formation; complemented mutants regained T4SS function and the capacity for pilus formation.cagYandcagCmutants were defective in T4SS function but retained the capacity for pilus formation. These results define a set ofcagPAI genes that are required for both pilus biogenesis and T4SS function and reveal that these processes can be uncoupled in specific mutant strains.

scholarly journals In Situ Molecular Architecture of the Helicobacter pylori Cag Type IV Secretion System

mBio ◽  
2019 ◽  
Vol 10 (3) ◽  
Author(s):  
Bo Hu ◽  
Pratick Khara ◽  
Liqiang Song ◽  
Aung Soe Lin ◽  
Arwen E. Frick-Cheng ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Legionella Pneumophila ◽  
Type Iv Secretion ◽  
Type Iv Secretion System ◽  
Content Type ◽  
Membrane Complex ◽  
Type Iv ◽  
Increased Risk ◽  
H Pylori

ABSTRACT Helicobacter pylori colonizes about half of humans worldwide, and its presence in the gastric mucosa is associated with an increased risk of gastric adenocarcinoma, gastric lymphoma, and peptic ulcer disease. H. pylori strains carrying the cag pathogenicity island (cagPAI) are associated with increased risk of disease progression. The cagPAI encodes the Cag type IV secretion system (CagT4SS), which delivers the CagA oncoprotein and other effector molecules into human gastric epithelial cells. We visualized structures of native and mutant CagT4SS machines on the H. pylori cell envelope by cryoelectron tomography. Individual H. pylori cells contain multiple CagT4SS nanomachines, each composed of a wheel-shaped outer membrane complex (OMC) with 14-fold symmetry and an inner membrane complex (IMC) with 6-fold symmetry. CagX, CagY, and CagM are required for assembly of the OMC, whereas strains lacking Cag3 and CagT produce outer membrane complexes lacking peripheral components. The IMC, which has never been visualized in detail, is configured as six tiers in cross-section view and three concentric rings surrounding a central channel in end-on view. The IMC contains three T4SS ATPases: (i) VirB4-like CagE, arranged as a hexamer of dimers at the channel entrance; (ii) a hexamer of VirB11-like Cagα, docked at the base of the CagE hexamer; and (iii) VirD4-like Cagβ and other unspecified Cag subunits, associated with the stacked CagE/Cagα complex and forming the outermost rings. The CagT4SS and recently solved Legionella pneumophila Dot/Icm system comprise new structural prototypes for the T4SS superfamily. IMPORTANCE Bacterial type IV secretion systems (T4SSs) have been phylogenetically grouped into two subfamilies. The T4ASSs, represented by the Agrobacterium tumefaciens VirB/VirD4T4SS, include “minimized” machines assembled from 12 VirB- and VirD4-like subunits and compositionally larger systems such as the Helicobacter pylori CagT4SS. T4BSSs encompass systems closely related in subunit composition to the Legionella pneumophila Dot/IcmT4SS. Here, we present structures of native and mutant H. pylori Cag machines determined by in situ cryoelectron tomography. We identify distinct outer and inner membrane complexes and, for the first time, visualize structural contributions of all three “signature” ATPases of T4SSs at the cytoplasmic entrance of the translocation channel. Despite their evolutionary divergence, the CagT4SS aligns structurally much more closely to the Dot/IcmT4SS than an available VirB/VirD4 subcomplex. Our findings highlight the diversity of T4SSs and suggest a structural classification scheme in which T4SSs are grouped as minimized VirB/VirD4-like or larger Cag-like and Dot/Icm-like systems.

scholarly journals In VivoExpression of Helicobacter pylori Virulence Genes in Patients with Gastritis, Ulcer, and Gastric Cancer

2011 ◽  
Vol 80 (2) ◽  
pp. 594-601 ◽  
Author(s):  
Francisco Avilés-Jiménez ◽  
Adriana Reyes-Leon ◽  
Erik Nieto-Patlán ◽  
Lori M. Hansen ◽  
Juan Burgueño ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Helicobacter Pylori ◽  
Environmental Conditions ◽  
Virulence Genes ◽  
Content Type ◽  
Ulcer Disease ◽  
Type Iv ◽  
H Pylori

ABSTRACTThe best-studiedHelicobacter pylorivirulence factor associated with development of peptic ulcer disease or gastric cancer (GC) rather than asymptomatic nonatrophic gastritis (NAG) is thecagpathogenicity island (cagPAI), which encodes a type IV secretion system (T4SS) that injects the CagA oncoprotein into host epithelial cells. Here we used real-time reverse transcription-PCR (RT-PCR) to measure thein vivoexpression of genes on thecagPAI and of other virulence genes in patients with NAG, duodenal ulcer (DU), or GC.In vivoexpression ofH. pylorivirulence genes was greater overall in gastric biopsy specimens of patients with GC than in those of patients with NAG or DU. However, sincein vitroexpression ofcagAwas not greater inH. pyloristrains from patients with GC than in those from patients with NAG or DU, increased expression in GCin vivois likely a result of environmental conditions in the gastric mucosa, though it may in turn cause more severe pathology. Increased expression of virulence genes in GC may represent a stress response to elevated pH or other environmental conditions in the stomach of patients with GC, which may be less hospitable toH. pyloricolonization than the acidic environment in patients with NAG or DU.

scholarly journals Roles of the plasticity regions of Helicobacter pylori in gastroduodenal pathogenesis

2008 ◽  
Vol 57 (5) ◽  
pp. 545-553 ◽  
Author(s):  
Yoshio Yamaoka
Keyword(s):  
Helicobacter Pylori ◽  
Virulence Genes ◽  
Type Iv Secretion ◽  
Phase Variable ◽  
Duodenal Ulcers ◽  
Gastric Cancers ◽  
Type Iv ◽  
Plasticity Region ◽  
Increased Risk ◽  
H Pylori

Putative virulence genes of Helicobacter pylori are generally classified into three categories: strain-specific genes, phase-variable genes and genes with variable structures/genotypes. Among these, there has recently been considerable interest in strain-specific genes found outside of the cag pathogenicity island, especially genes in the plasticity regions. Nearly half of the strain-specific genes of H. pylori are located in the plasticity regions in strains 26695 and J99. Strain HPAG1, however, seems to lack a typical plasticity region; instead it has 43 HPAG1-specific genes which are either undetectable or incompletely represented in the genomes of strains 26695 and J99. Recent studies showed that certain genes or combination of genes in this region may play important roles in the pathogenesis of H. pylori-associated gastroduodenal diseases. Most previous studies have focused on the plasticity region in strain J99 (jhp0914–jhp0961) and the jhp0947 gene and the duodenal ulcer promoting (dupA) gene are good candidate markers for gastroduodenal diseases although there are some paradoxical findings. The jhp0947 gene is reported to be associated with an increased risk of both duodenal ulcers and gastric cancers, whereas the dupA gene, which encompasses jhp0917 and jhp0918, is reported to be associated with an increased risk of duodenal ulcers and protection against gastric cancers. In addition, recent studies showed that approximately 10–30 % of clinical isolates possess a 16.3 kb type IV secretion apparatus (tfs3) in the plasticity region. Studies on the plasticity region have only just begun, and further investigation is necessary to elucidate the roles of genes in this region in gastroduodenal pathogenesis.

scholarly journals Identification of Pathogenicity Island Genes Associated with Loss of Type IV Secretion Function during Murine Infection with Helicobacter pylori

2020 ◽  
Vol 88 (6) ◽  
Author(s):  
Lori M. Hansen ◽  
Dylan J. Dekalb ◽  
Lucy P. Cai ◽  
Jay V. Solnick
Keyword(s):  
Helicobacter Pylori ◽  
Single Molecule ◽  
Pathogenicity Island ◽  
Type Iv Secretion ◽  
Common Mechanism ◽  
Loss Of Function ◽  
Genetic Changes ◽  
Content Type ◽  
Type Iv ◽  
H Pylori

ABSTRACT Chronic Helicobacter pylori colonization in animal models often leads to downregulation of the type IV secretion system (T4SS), typically by recombination in cagY, which is an essential T4SS gene. However, 17 other cag pathogenicity island (cagPAI) genes, as well as some non-cagPAI genes, are also essential for T4SS function. To get a more complete picture of how H. pylori regulates the T4SS during animal colonization, we examined cagY in 534 mouse-passaged isolates that lost T4SS function, defined as a normalized interleukin-8 (IL-8) value of <0.3 relative to the input H. pylori strain PMSS1. In order to analyze the genetic changes in the strains with unchanged cagY, we sequenced the entire pathogenicity island of 60 such isolates using single-molecule, real-time (SMRT) sequencing technology (PacBio, Menlo Park, CA), and we compared the results to the PMSS1 wild type (WT). Of the 534 strains, 271 (51%) showed evidence of recombination in cagY, but we also found indels or nonsynonymous changes in 13 other essential cagPAI genes implicated in H. pylori T4SS function, most commonly cag5, cag10, and cagA. While cagY recombination is the most common mechanism by which H. pylori downregulates T4SS function during murine infection, loss of function is also associated with changes in other essential cagPAI genes.

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