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Tamrakar A, Singh R, Kumar A, Makde RD, Ashish, Kodgire P. Biophysical characterization of the homodimers of HomA and HomB, outer membrane proteins of Helicobacter pylori. Sci Rep 2021; 11:24471. [PMID: 34963695 PMCID: PMC8714817 DOI: 10.1038/s41598-021-04039-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Accepted: 11/24/2021] [Indexed: 12/16/2022] Open
Abstract
Helicobacter pylori is a Gram-negative bacterium that causes chronic inflammations in the stomach area and is involved in ulcers, which can develop into gastric malignancies. H. pylori attaches and colonizes to the human epithelium using some of their outer membrane proteins (OMPs). HomB and HomA are the most studied OMPs from H. pylori as they play a crucial role in adherence, hyper biofilm formation, antibiotic resistance and are also associated with severe gastric malignancies. The role of HomA and HomB in pathogenesis concerning their structure and function has not been evaluated yet. In the present study, we explored the structural aspect of HomA and HomB proteins using various computational, biophysical and small-angle X-ray scattering (SAXS) techniques. Interestingly, the in-silico analysis revealed that HomA/B consists of 8 discontinuous N and C terminal β-strands forming a small β-barrel, along with a large surface-exposed globular domain. Further, biophysical experiments suggested that HomA and HomB are dimeric and most likely the cysteine residues present on surface-exposed loops participate in protein-protein interactions. Our study provides essential structural information of unexplored proteins of the Hom family that can help in a better understanding of H. pylori pathogenesis.
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Affiliation(s)
- Anubhav Tamrakar
- Discipline of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Indore, Madhya Pradesh, 453 552, India
| | - Rahul Singh
- High Pressure and Synchrotron Radiation Physics Division, Bhabha Atomic Research Center, Trombay, Mumbai, India
| | - Amit Kumar
- Discipline of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Indore, Madhya Pradesh, 453 552, India
| | - Ravindra D Makde
- High Pressure and Synchrotron Radiation Physics Division, Bhabha Atomic Research Center, Trombay, Mumbai, India
| | - Ashish
- Protein Science and Engineering Division, CSIR-Institute of Microbial Technology, Chandigarh, India
| | - Prashant Kodgire
- Discipline of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Indore, Madhya Pradesh, 453 552, India.
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Characterization of East-Asian Helicobacter pylori encoding Western EPIYA-ABC CagA. J Microbiol 2021; 60:207-214. [PMID: 34757586 DOI: 10.1007/s12275-022-1483-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 10/20/2021] [Accepted: 10/21/2021] [Indexed: 12/24/2022]
Abstract
The polymorphic bacterial oncoprotein, CagA shows geography-dependent variation in the C-terminal Glu-Pro-Ile-Tyr-Ala (EPIYA) motifs; East-Asian H. pylori isolates carry the ABD type while Western isolates carry the ABC type. In Western isolates, the EPIYA-C motif is sometimes found in multi-copy and this genotype is associated with disease severity. Interestingly, a small number of East-Asian H. pylori isolates have been found to carry Western ABC-type CagA. To gain a better understanding of these unusual isolates, the genomes of four Korean H. pylori clinical isolates carrying ABC-type CagA were sequenced via third generation (Pac-Bio SMRT) sequencing technology. The obtained data were utilized for phylogenetic analysis as well as comparison of additional virulence factors that are known to show geographic-dependent polymorphisms. Three of four isolates indeed belonged to the hpEastAsia group and showed typical East-Asian polymorphism in virulence factors such as homA/B/C, babA/B/C, and oipA. One isolate grouped to HpAfrica and showed typical Western polymorphism of virulence factors such as cagA, homA/B/C, and oipA. To understand the occurrence of the multi-copy EPIYA-C motif genotype in an East-Asian H. pylori background, the Korean clinical isolate, K154 was analyzed; this strain belonged to hpEastAsia but encoded CagA EPIYA-ABCCCC. Based on DNA sequence homology within the CagA multimerization (CM) sequence that flanked the EPIYA-C motifs, we predicted that the number of C motifs might change via homologous recombination. To test this hypothesis, K154 was cultured for one generation and 287 single colonies were analyzed for the number of EPIYA-C motifs using PCR-based screening and DNA sequencing verification. Three out of 284 (1%) single colony isolates showed changes in the number of EPIYA-C motifs in vitro; one isolate increased to five EPIYA-C motifs, one decreased to three EPIYA-C motifs, and one completely deleted the EPIYA-C motifs. The capacity for dynamic changes in the number of EPIYA-C repeats of CagA may play a role in generating important intraspecies diversity in East-Asian H. pylori.
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Kim A, Lai J, Merrell DS, Kim JH, Su H, Cha JH. Geographic diversity in Helicobacter pylori oipA genotype between Korean and United States isolates. J Microbiol 2021; 59:1125-1132. [PMID: 34718962 DOI: 10.1007/s12275-021-1450-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 09/15/2021] [Accepted: 09/23/2021] [Indexed: 12/30/2022]
Abstract
Helicobacter pylori outer membrane inflammatory protein A (OipA) was originally named for its role in inducing inflammation in the host, as evidenced by high mucosal IL-8 levels. Expression of OipA is regulated by phase variation of a CT dinucleotide-repeat located in the 5' region of the gene. However, little is known about OipA geographic diversity across isolates. To address this gap, we conducted a large-scale molecular epidemiologic analysis using H. pylori clinical isolates obtained from two geographically distinct populations: Korea and the United States (US). Most Korean isolates (98.7%) possessed two copies of oipA located at two specific loci (A and B) while all US isolates contained only one copy of oipA at locus A. Furthermore, most Korean oipA (94.8%) possessed three or less CT repeats while most US oipA (96.6%) contained five or more CT repeats. Among the two copies, all Korean H. pylori possessed at least one oipA 'on' phase variant while the single copy of oipA in US isolates showed 56.2% 'on' and 43.8% 'off.' Thus, host differences seem to have driven geographic diversification of H. pylori across these populations such that OipA expression in US isolates is still regulated by phase variation with 5 or more CT repeats, while Korean isolates always express OipA; duplication of the oipA combined with a reduction of CT repeats to three or less ensures continued expression. En masse, these findings suggest that diversity in the oipA gene copy number, CT repeats, and phase variation among H. pylori from different populations may confer a benefit in adaptation to particular host populations.
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Affiliation(s)
- Aeryun Kim
- Department of Oral Biology, Oral Science Research Center, Department of Applied Life Science, The Graduate School, BK21 FOUR Project, Yonsei University College of Dentistry, Seoul, 03722, Republic of Korea.,Department of Dental Hygiene, Gangdong University, Eumseong, 27600, Republic of Korea
| | - Jing Lai
- Department of Oral Biology, Oral Science Research Center, Department of Applied Life Science, The Graduate School, BK21 FOUR Project, Yonsei University College of Dentistry, Seoul, 03722, Republic of Korea
| | - D Scott Merrell
- Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, Maryland, 20814, USA
| | - Ji-Hye Kim
- Department of Dental Hygiene, Baekseok University, Cheonan, 31065, Republic of Korea.
| | - Hanfu Su
- Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510182, P. R. China.
| | - Jeong-Heon Cha
- Department of Oral Biology, Oral Science Research Center, Department of Applied Life Science, The Graduate School, BK21 FOUR Project, Yonsei University College of Dentistry, Seoul, 03722, Republic of Korea. .,Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510182, P. R. China.
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CagL polymorphisms between East Asian and Western Helicobacter pylori are associated with different abilities to induce IL-8 secretion. J Microbiol 2021; 59:763-770. [PMID: 34061339 DOI: 10.1007/s12275-021-1136-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 05/06/2021] [Accepted: 05/07/2021] [Indexed: 12/17/2022]
Abstract
Helicobacter pylori colonizes human gastric mucosa. Its infection is associated with gastric diseases including gastric cancer. CagA is one of the most important toxins produced by H. pylori. It is related to gastric cancer which can be injected into host cells via a type IV secretion system (T4SS). CagL is a structural component of T4SS apparatus, which triggers host cell signaling pathway. It has been reported that CagL polymorphisms may influence the severity of disease development. To explore the contribution of CagL polymorphisms between East Asian and Western H. pylori in pathogenesis, cagL gene in G27 H. pylori was swapped by K74 cagL which is identical to East Asian CagL consensus sequence and by Western 26695 H. pylori, resulting in G27 ΔcagL/cagLK74 and G27 ΔcagL/cagL26695, respectively. Intriguingly, G27 ΔcagL/cagLK74 showed significantly less ability of IL-8 induction than G27 ΔcagL/cagL26695 while displayed similar abilities of CagA phosphorylation, and cell elongation. Taken together, this study suggests that the CagL polymorphism may influence IL-8 induction, and K74 CagL has less ability to induce IL-8 secretion than G27 or 26695 CagL. Further research should address how the different capabilities of IL-8 induction between intraspecies-CagL are associated with the large differences of the incidence of gastric cancer between East Asian and Western countries.
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Keikha M, Karbalaei M. Correlation between the geographical origin of Helicobacter pylori homB-positive strains and their clinical outcomes: a systematic review and meta-analysis. BMC Gastroenterol 2021; 21:181. [PMID: 33879080 PMCID: PMC8056685 DOI: 10.1186/s12876-021-01764-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Accepted: 04/09/2021] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND In general, all virulence factors of Helicobacter pylori (H. pylori) are involved in its infections. However, recent studies have shown that the homB gene is one of the virulence genes that affects the severity of the clinical results of this bacterium. METHODS The main purpose of this study was to investigate the relationship between the presence of homB gene in H. pylori and the progression of its infection to peptic ulcer and gastric cancer. In the present study, we conducted a systematic search to collect all articles related to the effect of homB-positive strains on clinical outcomes. Finally, 12 eligible studies according to our criteria were included in this meta-analysis and the effect of homB gene on gastric ulcer and gastric cancer diseases was evaluated by summary odds ratio (OR). RESULTS Current results showed that the homB-positive strains significantly increase the risk of peptic ulcer (OR 1.36; 1.07-1.72 with 95% CIs), especially in western countries (OR 1.61; 1.20-2.14 with 95% CIs). Moreover, we observed a positive association between the homB gene and risk of gastric cancer (OR 2.16; 1.37-3.40 with 95% CIs). In addition, based on subgroup analysis, it was found that the presence of this gene in H. pylori strains increases the risk of gastric cancer in the Asian population (OR 3.71; 1.85-7.45 with 95% CIs). CONCLUSIONS Overall, in the present study we found that homB gene is responsible for the progressing of primary infection to severe complications, in particular peptic ulcer in western countries and gastric cancer in Asian countries.
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Affiliation(s)
- Masoud Keikha
- Department of Microbiology and Virology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohsen Karbalaei
- Department of Microbiology and Virology, School of Medicine, Jiroft University of Medical Sciences, Jiroft, Iran.
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Palrasu M, Zaika E, El-Rifai W, Que J, Zaika AI. Role of Bacterial and Viral Pathogens in Gastric Carcinogenesis. Cancers (Basel) 2021; 13:1878. [PMID: 33919876 PMCID: PMC8070847 DOI: 10.3390/cancers13081878] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 04/02/2021] [Accepted: 04/11/2021] [Indexed: 01/10/2023] Open
Abstract
Gastric cancer (GC) is one of the deadliest malignancies worldwide. In contrast to many other tumor types, gastric carcinogenesis is tightly linked to infectious events. Infections with Helicobacter pylori (H. pylori) bacterium and Epstein-Barr virus (EBV) are the two most investigated risk factors for GC. These pathogens infect more than half of the world's population. Fortunately, only a small fraction of infected individuals develops GC, suggesting high complexity of tumorigenic processes in the human stomach. Recent studies suggest that the multifaceted interplay between microbial, environmental, and host genetic factors underlies gastric tumorigenesis. Many aspects of these interactions still remain unclear. In this review, we update on recent discoveries, focusing on the roles of various gastric pathogens and gastric microbiome in tumorigenesis.
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Affiliation(s)
- Manikandan Palrasu
- Department of Surgery, University of Miami, Miami, FL 33136, USA; (M.P.); (E.Z.); (W.E.-R.)
| | - Elena Zaika
- Department of Surgery, University of Miami, Miami, FL 33136, USA; (M.P.); (E.Z.); (W.E.-R.)
| | - Wael El-Rifai
- Department of Surgery, University of Miami, Miami, FL 33136, USA; (M.P.); (E.Z.); (W.E.-R.)
- Department of Veterans Affairs, Miami VA Healthcare System, Miami, FL 33136, USA
| | - Jianwen Que
- Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA;
| | - Alexander I. Zaika
- Department of Surgery, University of Miami, Miami, FL 33136, USA; (M.P.); (E.Z.); (W.E.-R.)
- Department of Veterans Affairs, Miami VA Healthcare System, Miami, FL 33136, USA
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Xu C, Soyfoo DM, Wu Y, Xu S. Virulence of Helicobacter pylori outer membrane proteins: an updated review. Eur J Clin Microbiol Infect Dis 2020; 39:1821-1830. [PMID: 32557327 PMCID: PMC7299134 DOI: 10.1007/s10096-020-03948-y] [Citation(s) in RCA: 62] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Accepted: 06/09/2020] [Indexed: 02/07/2023]
Abstract
Helicobacter pylori (H. pylori) infection is associated with some gastric diseases, such as gastritis, peptic ulcer, and gastric cancer. CagA and VacA are known virulence factors of H. pylori, which play a vital role in severe clinical outcomes. Additionally, the expression of outer membrane proteins (OMPs) helps H. pylori attach to gastric epithelial cells at the primary stage and increases the virulence of H. pylori. In this review, we have summarized the paralogs of H. pylori OMPs, their genomic loci, and the different receptors of OMPs identified so far. We focused on five OMPs, BabA (HopS), SabA (HopP), OipA (HopH), HopQ, and HopZ, and one family of OMPs: Hom. We highlight the coexpression of OMPs with other virulence factors and their relationship with clinical outcomes. In conclusion, OMPs are closely related to the pathogenic processes of adhesion, colonization, persistent infection, and severe clinical consequences. They are potential targets for the prevention and treatment of H. pylori–related diseases.
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Affiliation(s)
- Chenjing Xu
- Sir Run Run Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
| | | | - Yao Wu
- Sir Run Run Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Shunfu Xu
- Sir Run Run Hospital, Nanjing Medical University, Nanjing, Jiangsu, China. .,Jiangsu Province Hospital, Nanjing Medical University, Nanjing, Jiangsu, China.
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Šterbenc A, Jarc E, Poljak M, Homan M. Helicobacter pylori virulence genes. World J Gastroenterol 2019; 25:4870-4884. [PMID: 31543679 PMCID: PMC6737321 DOI: 10.3748/wjg.v25.i33.4870] [Citation(s) in RCA: 91] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2019] [Revised: 07/29/2019] [Accepted: 08/07/2019] [Indexed: 02/06/2023] Open
Abstract
Helicobacter pylori (H. pylori) is one of the most important human pathogens, infecting approximately half of the global population. Despite its high prevalence, only a subset of H. pylori infected individuals develop serious gastroduodenal pathology. The pathogenesis of H. pylori infection and disease outcome is thus thought to be mediated by an intricate interplay between host, environmental and bacterial virulence factors. H. pylori has adapted to the harsh milieu of the human stomach through possession of various virulence genes that enable survival of the bacteria in the acidic environment, movement towards the gastric epithelium, and attachment to gastric epithelial cells. These virulence factors enable successful colonization of the gastric mucosa and sustain persistent H. pylori infection, causing chronic inflammation and tissue damage, which may eventually lead to the development of peptic ulcers and gastric cancer. Numerous studies have focused on the prevalence and role of putative H. pylori virulence genes in disease pathogenesis. While several virulence factors with various functions have been identified, disease associations appear to be less evident, especially among different study populations. This review presents key findings on the most important H. pylori virulence genes, including several bacterial adhesins and toxins, in children and adults, and focuses on their prevalence, clinical significance and potential relationships.
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Affiliation(s)
- Anja Šterbenc
- Institute of Microbiology and Immunology, Faculty of Medicine, University of Ljubljana, Ljubljana 1000, Slovenia
| | - Erika Jarc
- Institute of Microbiology and Immunology, Faculty of Medicine, University of Ljubljana, Ljubljana 1000, Slovenia
| | - Mario Poljak
- Institute of Microbiology and Immunology, Faculty of Medicine, University of Ljubljana, Ljubljana 1000, Slovenia
| | - Matjaž Homan
- Department of Gastroenterology, Hepatology and Nutrition, University Children’s Hospital, Faculty of Medicine, University of Ljubljana, Ljubljana 1000, Slovenia
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The Prevalence of Helicobacter Pylori babA, homB, aspA, and sabA Genes and Its Relationship with Clinical Outcomes in Turkey. Can J Gastroenterol Hepatol 2019; 2019:1271872. [PMID: 31312620 PMCID: PMC6595381 DOI: 10.1155/2019/1271872] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Accepted: 05/23/2019] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND AND AIMS The cag A and vac A genes of Helicobacter pylori (H. pylori) are closely associated with the pathogenicity of bacteria. However, the significance of H. pylori babA, homB, aspA, and sabA genes is not clear in phenotypic characteristics of virulence. This study aimed to investigate the frequency and importance of these genes in patients with H. pylori positive peptic ulcer (PU). MATERIALS AND METHODS Patients with a PU or nonulcer dyspepsia (NUD) based on the upper gastrointestinal (UGI) endoscopy findings were included in the study. Biopsy samples from antrum and corpus were cultured into Columbia agar. H pylori were characterized by urease, catalase, oxidase test, and gram staining. Genomic DNA was extracted and stored. The babA, homB, aspA, and sabA genes were determined by using polymerase chain reaction analysis. RESULTS A total 214 patients were included (99 PU and 115 NUD) and H. pylori could be isolated in 82 patients (36 PU and 46 NUD). The frequency of the babA (25% vs. 15.2%, p=0.25), homB (2.7% vs. 4.3%, p=1), aspA (69.4% vs. 73.9%, p=0.2), and sabA (2.7% vs. 10.8%, p=0.88) genotypes was not different between PU and NUD patients. There were some correlations between the presences of these genes. CONCLUSION This study managed to determine babA, homB, aspA, and sabA genes of H. pylori by PCR. However, the frequency of these factors was not different in patients with PU and NUD. There is no role of babA, homB, aspA, and sabA genes for the development of peptic ulcer in Turkish population.
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Differential Helicobacter pylori Plasticity in the Gastric Niche of Subjects at Increased Gastric Cancer Risk. Pathogens 2019; 8:pathogens8020065. [PMID: 31109082 PMCID: PMC6630233 DOI: 10.3390/pathogens8020065] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2019] [Revised: 05/09/2019] [Accepted: 05/15/2019] [Indexed: 02/07/2023] Open
Abstract
Helicobacter pylori (H. pylori) represents an independent risk factor for Gastric Cancer (GC). First Degree Relatives (FDR) of GC subjects and Autoimmune Gastritis (AG) patients are both at increased risk for GC. H. pylori genetic heterogeneity within the gastric niche of FDR and AG individuals has been little explored. To understand whether they exploit an increased H. pylori stability and virulence, 14 AG, 25 FDR, 39 GC and 13 dyspeptic patients (D) were investigated by a cultural PCR-based approach characterizing single colonies-forming-units. We chose three loci within the Cytotoxin-associated gene-A Pathogenicity Island (CagPAI) (cagA,cagE,virB11), vacA, homA and homB as markers of virulence with reported association to GC. Inflammatory/precancerous lesions were staged according to Sydney System. When compared to D, FDR, similarly to GC patients, were associated to higher atrophy (OR = 6.29; 95% CI:1.23-31.96 in FDR; OR = 7.50; 95% CI:1.67-33.72 in GC) and a lower frequency of mixed infections (OR = 0.16; 95% CI:0.03-0.81 in FDR; OR = 0.10; 95% CI:0.02-0.48 in GC). FDR presented also an increased neutrophil infiltration (OR = 7.19; 95% CI:1.16-44.65). Both FDR and GC carried a higher proportion of CagPAI+vacAs1i1mx+homB+ profiles (OR = 2.71; 95% CI: 1.66-4.41 and OR = 3.43; 95% CI: 2.16-5.44, respectively). Conversely, AG patients presented a lower frequency of subtypes carrying a stable CagPAI and vacAs1i1mx. These results underline different H. pylori plasticity in FDR and AG individuals, and thus, a different host-bacterium interaction capacity that should be considered in the context of eradication therapies.
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Whitmire JM, Merrell DS. Helicobacter pylori Genetic Polymorphisms in Gastric Disease Development. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1149:173-194. [DOI: 10.1007/5584_2019_365] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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12
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Šterbenc A, Poljak M, Zidar N, Luzar B, Homan M. Prevalence of the Helicobacter pylori homA and homB genes and their correlation with histological parameters in children. Microb Pathog 2018; 125:26-32. [PMID: 30195645 DOI: 10.1016/j.micpath.2018.09.005] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2018] [Revised: 09/03/2018] [Accepted: 09/05/2018] [Indexed: 12/16/2022]
Abstract
The significance of Helicobacter pylori (H. pylori) virulence genes such as cagA and vacA has been extensively studied in children; however, data regarding the significance of homA and homB genes are scarce. The aim of our study was to evaluate the prevalence and clinical relevance of these genes in Slovenian children. All children diagnosed with H. pylori infection between 1993 and 2013 were included in the study (n = 343). DNA was extracted from biopsy specimens previously used for the rapid urease test. Five histological parameters were evaluated and the presence of the vacA, cagA, iceA, babA2, and homA and homB genes was determined by PCR amplification. The homA and homB genes were detected in 174/285 (61.1%) and 116/285 (40.7%) strains, respectively. The presence of the homA gene was significantly associated with the absence of the homB gene (P < 0.001); however, no associations were found between the presence of either the homA or homB genes and any of the other investigated virulence genes. Similarly, there were no correlations between the presence of the homA and homB genes and any of the histological parameters. In contrast, genotype profiles vacA s1m1/cagA+/babA2+/homB+, vacA s1m2/cagA+/babA2+/homA+, vacA s1m1/cagA+/babA2+/homA+, vacA s1m1/cagA+/babA2-/homA+, vacA s1m2/cagA-/babA2-/homA+, and vacA s2m2/cagA-/babA2-/homB+ were associated with a higher degree of gastric mucosal damage. Thus, although the homA and homB genes did not represent important individual virulence markers in this population, they may act synergistically with other H. pylori virulence genes, causing severe gastritis in children.
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Affiliation(s)
- Anja Šterbenc
- Institute of Microbiology and Immunology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Mario Poljak
- Institute of Microbiology and Immunology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Nina Zidar
- Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Boštjan Luzar
- Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Matjaž Homan
- Department of Gastroenterology, Hepatology, and Nutrition, University Children's Hospital, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
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Servetas SL, Doster RS, Kim A, Windham IH, Cha JH, Gaddy JA, Merrell DS. ArsRS-Dependent Regulation of homB Contributes to Helicobacter pylori Biofilm Formation. Front Microbiol 2018; 9:1497. [PMID: 30116222 PMCID: PMC6083042 DOI: 10.3389/fmicb.2018.01497] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2018] [Accepted: 06/18/2018] [Indexed: 12/14/2022] Open
Abstract
One elusive area in the Helicobacter pylori field is an understanding of why some infections result in gastric cancer, yet others persist asymptomatically for the life-span of the individual. Even before the genomic era, the high level of intraspecies diversity of H. pylori was well recognized and became an intriguing area of investigation with respect to disease progression. Of interest in this regard is the unique repertoire of over 60 outer membrane proteins (OMPs), several of which have been associated with disease outcome. Of these OMPs, the association between HomB and disease outcome varies based on the population being studied. While the molecular roles for some of the disease-associated OMPs have been evaluated, little is known about the role that HomB plays in the H. pylori lifecycle. Thus, herein we investigated homB expression, regulation, and contribution to biofilm formation. We found that in H. pylori strain G27, homB was expressed at a relatively low level until stationary phase. Furthermore, homB expression was suppressed at low pH in an ArsRS-dependent manner; mutation of arsRS resulted in increased homB transcript at all tested time-points. ArsRS regulation of homB appeared to be direct as purified ArsR was able to specifically bind to the homB promoter. This regulation, combined with our previous finding that ArsRS mutations lead to enhanced biofilm formation, led us to test the hypothesis that homB contributes to biofilm formation by H. pylori. Indeed, subsequent biofilm analysis using a crystal-violet quantification assay and scanning electron microscopy (SEM) revealed that loss of homB from hyper-biofilm forming strains resulted in reversion to a biofilm phenotype that mimicked wild-type. Furthermore, expression of homB in trans from a promoter that negated ArsRS regulation led to enhanced biofilm formation even in strains in which the chromosomal copy of homB had been deleted. Thus, homB is necessary for hyper-biofilm formation of ArsRS mutant strains and aberrant regulation of this gene is sufficient to induce a hyper-biofilm phenotype. In summary, these data suggest that the ArsRS-dependent regulation of OMPs such as HomB may be one mechanism by which ArsRS dictates biofilm development in a pH responsive manner.
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Affiliation(s)
- Stephanie L Servetas
- Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, MD, United States
| | - Ryan S Doster
- Department of Medicine, Vanderbilt University, Nashville, TN, United States
| | - Aeryun Kim
- BK21 Plus Project, Department of Oral Biology, Oral Science Research Center, Yonsei University College of Dentistry, Seoul, South Korea
| | - Ian H Windham
- Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, MD, United States
| | - Jeong-Heon Cha
- BK21 Plus Project, Department of Oral Biology, Oral Science Research Center, Yonsei University College of Dentistry, Seoul, South Korea.,Department of Applied Life Science, The Graduate School, Yonsei University, Seoul, South Korea.,Microbiology and Molecular Biology Laboratory, Key Laboratory of Oral Medicine, Guangzhou Institute of Oral Disease, Stomatology Hospital of Guangzhou Medical University, Guangzhou, China
| | - Jennifer A Gaddy
- Department of Medicine, Vanderbilt University, Nashville, TN, United States.,Tennessee Valley Healthcare Systems, Department of Veterans Affairs, Nashville, TN, United States
| | - D Scott Merrell
- Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, MD, United States
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Servetas SL, Kim A, Su H, Cha JH, Merrell DS. Comparative analysis of the Hom family of outer membrane proteins in isolates from two geographically distinct regions: The United States and South Korea. Helicobacter 2018; 23:e12461. [PMID: 29315985 DOI: 10.1111/hel.12461] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Helicobacter pylori encodes numerous outer membrane proteins (OMPs), but only a few have been characterized in depth. Deletion, duplication, and allelic variation of many of the H. pylori OMPs have been reported, which suggests that these proteins may play key roles in host adaptation. Herein, we characterize the variation observed within the Hom family of OMPs in H. pylori obtained from two geographically distinct populations. MATERIALS AND METHODS PCR genotyping of the hom genes was carried out using clinical isolates from South Korea and the United States. A combination of statistical, phylogenetic, and protein modeling analyses was conducted to further characterize the hom variants. RESULTS Variations in the closely related hom genes, homA and homB, occur in regions that are predicted to encode environmentally exposed loops. A similar phenomenon is true for homCS as compared to homCL . Conversely, little variation was observed in homD. Certain variants of the Hom family of proteins were more prominent in isolates from the Korean population as compared to isolates from the United States. CONCLUSION En masse, our data show that the homA, homB, and homC profiles vary based upon the geographic origin of the strain; however, the fourth member of the hom family, homD, is more highly conserved. Additionally, protein topology modeling showed that many of the less well-conserved regions between homA and homB and between homCS and homCL corresponded to predicted environmentally exposed loops, suggesting that the divergence of the Hom family may be due to host adaptation/pressure.
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Affiliation(s)
- Stephanie L Servetas
- Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
| | - Aeryun Kim
- Department of Oral Biology, Oral Science Research Center, BK21 Plus Project, Yonsei University College of Dentistry, Seoul, Korea.,Department of Applied Life Science, The Graduate School, Yonsei University, Seoul, Korea
| | - Hanfu Su
- Department of Oral Biology, Oral Science Research Center, BK21 Plus Project, Yonsei University College of Dentistry, Seoul, Korea.,Department of Applied Life Science, The Graduate School, Yonsei University, Seoul, Korea.,Microbiology and Molecular Biology Laboratory, Key Laboratory of Oral Medicine, Guangzhou Institute of Oral Disease, Stomatology Hospital of Guangzhou Medical University, Guangzhou, China
| | - Jeong-Heon Cha
- Department of Oral Biology, Oral Science Research Center, BK21 Plus Project, Yonsei University College of Dentistry, Seoul, Korea.,Department of Applied Life Science, The Graduate School, Yonsei University, Seoul, Korea.,Microbiology and Molecular Biology Laboratory, Key Laboratory of Oral Medicine, Guangzhou Institute of Oral Disease, Stomatology Hospital of Guangzhou Medical University, Guangzhou, China
| | - D Scott Merrell
- Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
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Fernández de Larrea-Baz N, Pérez-Gómez B, Michel A, Romero B, Lope V, Pawlita M, Fernández-Villa T, Moreno V, Martín V, Willhauck-Fleckenstein M, López-Abente G, Castilla J, Fernández-Tardón G, Dierssen-Sotos T, Santibáñez M, Peiró R, Jiménez-Moleón JJ, Navarro C, Castaño-Vinyals G, Kogevinas M, Pollán M, de Sanjosé S, Del Campo R, Waterboer T, Aragonés N. Helicobacter pylori serological biomarkers of gastric cancer risk in the MCC-Spain case-control Study. Cancer Epidemiol 2017; 50:76-84. [PMID: 28888185 DOI: 10.1016/j.canep.2017.08.002] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2017] [Revised: 07/10/2017] [Accepted: 08/04/2017] [Indexed: 02/08/2023]
Abstract
BACKGROUND Helicobacter pylori infection is one of the main risk factors for non-cardia gastric cancer. However, only a minority of infected persons develop the disease. This study aims at identifying H. pylori related serological biomarkers of risk for gastric cancer. METHODS Incident gastric cancer cases and population controls (age, sex and region frequency-matched) from the MCC-Spain multicase-control Study were included. Seroreactivities against 16H. pylori proteins were determined using multiplex serology. Infection was defined as seropositivity against≥4 proteins. Relation of serological results to non-cardia and cardia gastric cancer was assessed using multivariable mixed logistic regression and principal components analysis. RESULTS Seroprevalence was 88% among 2071 controls, 95% among 202 non-cardia gastric cancer cases (OR=1.9 (95% CI: 1.0-3.6)) and 85% among 62 cardia cancer cases (OR=0.5 (95% CI: 0.3-1.1)). In infected subjects, seropositivity for UreA, HP231, NapA and Cagδ was associated with lower non-cardia gastric cancer risk, while seropositivity for CagA and VacA was associated with higher risk. Seropositivity for CagA and seronegativity for Cagδ maintained the association after additional adjustment by serostatus of significant proteins. We identified two antibody reactivity patterns: the "virulent-pattern", related to a threefold higher risk of non-cardia gastric cancer and the "non-virulent pattern", related to a 60% decreased risk (4th vs. first quartile). CONCLUSIONS In our population, people seropositive for H. pylori were characterized by two patterns of antibody reactivity against H. pylori proteins: 1) Combined high seroreactivity against several proteins, associated with a lower non-cardia gastric cancer risk, and 2) High seroreactivity against CagA and VacA, associated with an increased risk.
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Affiliation(s)
- Nerea Fernández de Larrea-Baz
- Environmental and Cancer Epidemiology Area, National Center of Epidemiology, Carlos III Health Institute (ISCIII), Avda. Monforte de Lemos 5, 28029, Madrid, Spain; Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP)-CIBER of Epidemiology and Public Health (CIBERESP), Avda. Monforte de Lemos, 3-5, Pabellón 11, Planta 0, 28029, Madrid, Spain.
| | - Beatriz Pérez-Gómez
- Environmental and Cancer Epidemiology Area, National Center of Epidemiology, Carlos III Health Institute (ISCIII), Avda. Monforte de Lemos 5, 28029, Madrid, Spain; Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP)-CIBER of Epidemiology and Public Health (CIBERESP), Avda. Monforte de Lemos, 3-5, Pabellón 11, Planta 0, 28029, Madrid, Spain
| | - Angelika Michel
- Division of Molecular Diagnostics of Oncogenic Infections, Infection, Inflammation and Cancer Program, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany
| | - Beatriz Romero
- Department of Microbiology, Hospital Universitario Ramón y Cajal and Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS)-Ramón y Cajal Health Research Institute (IRYCIS), Ctra. de Colmenar Viejo km. 9,100, 28034, Madrid, Spain
| | - Virginia Lope
- Environmental and Cancer Epidemiology Area, National Center of Epidemiology, Carlos III Health Institute (ISCIII), Avda. Monforte de Lemos 5, 28029, Madrid, Spain; Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP)-CIBER of Epidemiology and Public Health (CIBERESP), Avda. Monforte de Lemos, 3-5, Pabellón 11, Planta 0, 28029, Madrid, Spain
| | - Michael Pawlita
- Division of Molecular Diagnostics of Oncogenic Infections, Infection, Inflammation and Cancer Program, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany
| | - Tania Fernández-Villa
- The Research Group in Gene - Environment and Health Interactions (GIIGAS), University of León, Spain; Department of Biomedical Sciences, Area of Preventive Medicine and Public Health, University of León, Campus de Vegazana s/n, 24071, León, Spain
| | - Victor Moreno
- Cancer Prevention and Control Program, Catalan Institute of Oncology, Avinguda de la Granvia de l'Hospitalet 199-203, 08908, Hospitalet de Llobregat, Barcelona, Spain; Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Gran Via de les Corts Catalanes, 585, 08007, Barcelona, Spain; Colorectal Cancer Group, Bellvitge Biomedical Research Institute (IDIBELL), Gran Via de l'Hospitalet, 199, 08908, Hospitalet de Llobregat, Barcelona, Spain; Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP)-CIBER of Epidemiology and Public Health (CIBERESP), Avda. Monforte de Lemos, 3-5, Pabellón 11, Planta 0, 28029, Madrid, Spain
| | - Vicente Martín
- The Research Group in Gene - Environment and Health Interactions (GIIGAS), University of León, Spain; Department of Biomedical Sciences, Area of Preventive Medicine and Public Health, University of León, Campus de Vegazana s/n, 24071, León, Spain; Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP)-CIBER of Epidemiology and Public Health (CIBERESP), Avda. Monforte de Lemos, 3-5, Pabellón 11, Planta 0, 28029, Madrid, Spain
| | - Martina Willhauck-Fleckenstein
- Division of Molecular Diagnostics of Oncogenic Infections, Infection, Inflammation and Cancer Program, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany
| | - Gonzalo López-Abente
- Environmental and Cancer Epidemiology Area, National Center of Epidemiology, Carlos III Health Institute (ISCIII), Avda. Monforte de Lemos 5, 28029, Madrid, Spain; Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP)-CIBER of Epidemiology and Public Health (CIBERESP), Avda. Monforte de Lemos, 3-5, Pabellón 11, Planta 0, 28029, Madrid, Spain
| | - Jesús Castilla
- Instituto de Salud Pública de Navarra, IdiSNA-Navarra Institute for Health Research, C/Leyre, 15, 31003, Pamplona, Spain; Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP)-CIBER of Epidemiology and Public Health (CIBERESP), Avda. Monforte de Lemos, 3-5, Pabellón 11, Planta 0, 28029, Madrid, Spain
| | - Guillermo Fernández-Tardón
- University Institute of Oncology (IUOPA), University of Oviedo, Fernando Bongera. Building "Santiago Gascón", 1 st Floor, Campus of "El Cristo" B, 33006, Oviedo, Asturias, Spain; Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP)-CIBER of Epidemiology and Public Health (CIBERESP), Avda. Monforte de Lemos, 3-5, Pabellón 11, Planta 0, 28029, Madrid, Spain
| | - Trinidad Dierssen-Sotos
- University of Cantabria - IDIVAL-Instituto de Investigación Marqués de Valdecilla-Marqués de Valdecilla Research Institute (IDIVAL), C/Cardenal Herrera Oria, s/n, 39011, Santander, Spain; Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP)-CIBER of Epidemiology and Public Health (CIBERESP), Avda. Monforte de Lemos, 3-5, Pabellón 11, Planta 0, 28029, Madrid, Spain
| | - Miguel Santibáñez
- University of Cantabria - IDIVAL-Instituto de Investigación Marqués de Valdecilla-Marqués de Valdecilla Research Institute (IDIVAL), C/Cardenal Herrera Oria, s/n, 39011, Santander, Spain; Centro de Investigación en Recursos Naturales, Salud, y Medio Ambiente (RENSMA), University of Huelva, Campus de El Carmen, 21007, Huelva, Spain
| | - Rosana Peiró
- Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana FISABIO-Salud Pública - Foundation for the Promotion of Health and Biomedical Research of Valencia Region (FISABIO), Avda. de Catalunya, 21, 46020, Valencia, Spain; Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP)-CIBER of Epidemiology and Public Health (CIBERESP), Avda. Monforte de Lemos, 3-5, Pabellón 11, Planta 0, 28029, Madrid, Spain
| | - José Juan Jiménez-Moleón
- Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA)-Granada Health Research Institute (ibs.GRANADA), 18012, Granada, Spain; Department of Preventive Medicine and Public Health, University of Granada, Avda. de la Investigación, 11, Building A, 8th Floor, 18016, Granada, Spain; Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP)-CIBER of Epidemiology and Public Health (CIBERESP), Avda. Monforte de Lemos, 3-5, Pabellón 11, Planta 0, 28029, Madrid, Spain
| | - Carmen Navarro
- Department of Epidemiology, Murcia Regional Health Council, IMIB-Arrixaca, Ronda de Levante, 11, 2ª planta, 30008, Murcia, Spain; Department of Health and Social Sciences, University of Murcia, Avda. Teniente Flomesta, 5, 30003, Murcia, Spain; Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP)-CIBER of Epidemiology and Public Health (CIBERESP), Avda. Monforte de Lemos, 3-5, Pabellón 11, Planta 0, 28029, Madrid, Spain
| | - Gemma Castaño-Vinyals
- ISGlobal, Centre for Research in Environmental Epidemiology (CREAL), Doctor Aiguader, 88, 08003, Barcelona, Spain; IMIM (Hospital del Mar Medical Research Institute), Dr. Aiguader, 88, 08003, Barcelona, Spain; Pompeu Fabra University (UPF), Plaça de la Mercè, 10-12, 08002, Barcelona, Spain; Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP)-CIBER of Epidemiology and Public Health (CIBERESP), Avda. Monforte de Lemos, 3-5, Pabellón 11, Planta 0, 28029, Madrid, Spain
| | - Manolis Kogevinas
- ISGlobal, Centre for Research in Environmental Epidemiology (CREAL), Doctor Aiguader, 88, 08003, Barcelona, Spain; IMIM (Hospital del Mar Medical Research Institute), Dr. Aiguader, 88, 08003, Barcelona, Spain; Pompeu Fabra University (UPF), Plaça de la Mercè, 10-12, 08002, Barcelona, Spain; Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP)-CIBER of Epidemiology and Public Health (CIBERESP), Avda. Monforte de Lemos, 3-5, Pabellón 11, Planta 0, 28029, Madrid, Spain
| | - Marina Pollán
- Environmental and Cancer Epidemiology Area, National Center of Epidemiology, Carlos III Health Institute (ISCIII), Avda. Monforte de Lemos 5, 28029, Madrid, Spain; Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP)-CIBER of Epidemiology and Public Health (CIBERESP), Avda. Monforte de Lemos, 3-5, Pabellón 11, Planta 0, 28029, Madrid, Spain
| | - Silvia de Sanjosé
- Cancer Epidemiology Research Program, Catalan Institute of Oncology-IDIBELL, Avinguda de la Granvia de l'Hospitalet 199-203, 08908, l'Hospitalet de Llobregat, Spain; Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP)-CIBER of Epidemiology and Public Health (CIBERESP), Avda. Monforte de Lemos, 3-5, Pabellón 11, Planta 0, 28029, Madrid, Spain
| | - Rosa Del Campo
- Department of Microbiology, Hospital Universitario Ramón y Cajal and Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS)-Ramón y Cajal Health Research Institute (IRYCIS), Ctra. de Colmenar Viejo km. 9,100, 28034, Madrid, Spain; Red Española de Investigación en Patología Infecciosa (REIPI)-Spanish Network for Research in Infectious Diseases (REIPI), Spain
| | - Tim Waterboer
- Division of Molecular Diagnostics of Oncogenic Infections, Infection, Inflammation and Cancer Program, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany
| | - Nuria Aragonés
- Environmental and Cancer Epidemiology Area, National Center of Epidemiology, Carlos III Health Institute (ISCIII), Avda. Monforte de Lemos 5, 28029, Madrid, Spain; Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP)-CIBER of Epidemiology and Public Health (CIBERESP), Avda. Monforte de Lemos, 3-5, Pabellón 11, Planta 0, 28029, Madrid, Spain
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Dynamic Expansion and Contraction of cagA Copy Number in Helicobacter pylori Impact Development of Gastric Disease. mBio 2017; 8:mBio.01779-16. [PMID: 28223454 PMCID: PMC5358911 DOI: 10.1128/mbio.01779-16] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Infection with Helicobacter pylori is a major risk factor for development of gastric disease, including gastric cancer. Patients infected with H. pylori strains that express CagA are at even greater risk of gastric carcinoma. Given the importance of CagA, this report describes a new molecular mechanism by which the cagA copy number dynamically expands and contracts in H. pylori. Analysis of strain PMSS1 revealed a heterogeneous population in terms of numbers of cagA copies; strains carried from zero to four copies of cagA that were arranged as direct repeats within the chromosome. Each of the multiple copies of cagA was expressed and encoded functional CagA; strains with more cagA repeats exhibited higher levels of CagA expression and increased levels of delivery and phosphorylation of CagA within host cells. This concomitantly resulted in more virulent phenotypes as measured by cell elongation and interleukin-8 (IL-8) induction. Sequence analysis of the repeat region revealed three cagA homologous areas (CHAs) within the cagA repeats. Of these, CHA-ud flanked each of the cagA copies and is likely important for the dynamic variation of cagA copy numbers. Analysis of a large panel of clinical isolates showed that 7.5% of H. pylori strains isolated in the United States harbored multiple cagA repeats, while none of the tested Korean isolates carried more than one copy of cagA. Finally, H. pylori strains carrying multiple cagA copies were differentially associated with gastric disease. Thus, the dynamic expansion and contraction of cagA copy numbers may serve as a novel mechanism by which H. pylori modulates gastric disease development. Severity of H. pylori-associated disease is directly associated with carriage of the CagA toxin. Though the sequences of the CagA protein can differ across strains, previous analyses showed that virtually all H. pylori strains carry one or no copies of cagA. This study showed that H. pylori can carry multiple tandem copies of cagA that can change dynamically. Isolates harboring more cagA copies produced more CagA, thus enhancing toxicity to host cells. Analysis of 314 H. pylori clinical strains isolated from patients in South Korea and the United States showed that 7.5% of clinical strains in the United States carried multiple cagA copies whereas none of the South Korean strains did. This study demonstrated a novel molecular mechanism by which H. pylori dynamically modulates cagA copy number, which affects CagA expression and activity and may impact downstream development of gastric disease.
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Chen YL, Mo XQ, Huang GR, Huang YQ, Xiao J, Zhao LJ, Wei HY, Liang Q. Gene polymorphisms of pathogenic Helicobacter pylori in patients with different types of gastrointestinal diseases. World J Gastroenterol 2016; 22:9718-9726. [PMID: 27956795 PMCID: PMC5124976 DOI: 10.3748/wjg.v22.i44.9718] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2016] [Revised: 08/17/2016] [Accepted: 09/06/2016] [Indexed: 02/06/2023] Open
Abstract
Helicobacter pylori (H. pylori) is a kind of chronic infectious pathogen which can cause chronic gastritis, peptic ulcer, gastric cancer and other diseases. The genetic structure of the pathogenic genes of H. pylori varies largely, which contributes to the differences in virulence among various strains, and in clinical symptoms. Virulence genes of H. pylori can be categorized into three main classes: those related to adhesion and colonization, those related to gastric mucosal injury, and others. This review focuses on the relationship between genetic polymorphisms of the three classes of virulence genes of H. pylori and diseases. Most of the genetic polymorphisms of the main virulence factors of H. pylori are summarized in this paper.
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Helicobacter pylori outer membrane protein, HomC, shows geographic dependent polymorphism that is influenced by the Bab family. J Microbiol 2016; 54:846-852. [DOI: 10.1007/s12275-016-6434-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2016] [Revised: 09/19/2016] [Accepted: 09/20/2016] [Indexed: 02/07/2023]
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Kim A, Servetas SL, Kang J, Kim J, Jang S, Cha HJ, Lee WJ, Kim J, Romero-Gallo J, Peek RM, Merrell DS, Cha JH. Helicobacter pylori bab Paralog Distribution and Association with cagA, vacA, and homA/B Genotypes in American and South Korean Clinical Isolates. PLoS One 2015; 10:e0137078. [PMID: 26317221 PMCID: PMC4552749 DOI: 10.1371/journal.pone.0137078] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2015] [Accepted: 08/13/2015] [Indexed: 12/19/2022] Open
Abstract
Helicobacter pylori genetic variation is a crucial component of colonization and persistence within the inhospitable niche of the gastric mucosa. As such, numerous H. pylori genes have been shown to vary in terms of presence and genomic location within this pathogen. Among the variable factors, the Bab family of outer membrane proteins (OMPs) has been shown to differ within subsets of strains. To better understand genetic variation among the bab genes and to determine whether this variation differed among isolates obtained from different geographic locations, we characterized the distribution of the Bab family members in 80 American H. pylori clinical isolates (AH) and 80 South Korean H. pylori clinical isolates (KH). Overall, we identified 23 different bab genotypes (19 in AH and 11 in KH), but only 5 occurred in greater than 5 isolates. Regardless of strain origin, a strain in which locus A and locus B were both occupied by a bab gene was the most common (85%); locus C was only occupied in those isolates that carried bab paralog at locus A and B. While the babA/babB/- genotype predominated in the KH (78.8%), no single genotype could account for greater than 40% in the AH collection. In addition to basic genotyping, we also identified associations between bab genotype and well known virulence factors cagA and vacA. Specifically, significant associations between babA at locus A and the cagA EPIYA-ABD motif (P<0.0001) and the vacA s1/i1/m1 allele (P<0.0001) were identified. Log-linear modeling further revealed a three-way association between bab carried at locus A, vacA, and number of OMPs from the HOM family (P<0.002). En masse this study provides a detailed characterization of the bab genotypes from two distinct populations. Our analysis suggests greater variability in the AH, perhaps due to adaptation to a more diverse host population. Furthermore, when considering the presence or absence of both the bab and homA/B paralogs at their given loci and the vacA genotype, an association was observed. Our results highlight the multifactorial nature of H. pylori mediated disease and the importance of considering how the specific combinations of H. pylori virulence genes and their multiple interactions with the host will collectively impact disease progression.
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Affiliation(s)
- Aeryun Kim
- Department of Oral Biology, Oral Science Research Center, Yonsei University College of Dentistry, Seoul, South Korea
- Department of Applied Life Science, BK21 Plus Project, Yonsei University College of Dentistry, Seoul, South Korea
| | - Stephanie L. Servetas
- Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd., Bethesda, Maryland, 20814, United States of America
| | - Jieun Kang
- Department of Oral Biology, Oral Science Research Center, Yonsei University College of Dentistry, Seoul, South Korea
- Department of Applied Life Science, BK21 Plus Project, Yonsei University College of Dentistry, Seoul, South Korea
| | - Jinmoon Kim
- Department of Oral Biology, Oral Science Research Center, Yonsei University College of Dentistry, Seoul, South Korea
- Department of Applied Life Science, BK21 Plus Project, Yonsei University College of Dentistry, Seoul, South Korea
| | - Sungil Jang
- Department of Oral Biology, Oral Science Research Center, Yonsei University College of Dentistry, Seoul, South Korea
| | - Ho Jin Cha
- Department of Oral Biology, Oral Science Research Center, Yonsei University College of Dentistry, Seoul, South Korea
| | - Wan Jin Lee
- Department of Oral Biology, Oral Science Research Center, Yonsei University College of Dentistry, Seoul, South Korea
| | - June Kim
- Department of Oral Biology, Oral Science Research Center, Yonsei University College of Dentistry, Seoul, South Korea
| | - Judith Romero-Gallo
- Departments of Cancer Biology and Medicine, Vanderbilt University, Nashville, Tennessee, 37240, United States of America
| | - Richard M. Peek
- Departments of Cancer Biology and Medicine, Vanderbilt University, Nashville, Tennessee, 37240, United States of America
| | - D. Scott Merrell
- Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd., Bethesda, Maryland, 20814, United States of America
- * E-mail: (DSM); (JHC)
| | - Jeong-Heon Cha
- Department of Oral Biology, Oral Science Research Center, Yonsei University College of Dentistry, Seoul, South Korea
- Department of Applied Life Science, BK21 Plus Project, Yonsei University College of Dentistry, Seoul, South Korea
- * E-mail: (DSM); (JHC)
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The Role of Helicobacter pylori Outer Membrane Proteins in Adherence and Pathogenesis. BIOLOGY 2013; 2:1110-34. [PMID: 24833057 PMCID: PMC3960876 DOI: 10.3390/biology2031110] [Citation(s) in RCA: 114] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/04/2013] [Revised: 07/26/2013] [Accepted: 08/13/2013] [Indexed: 12/12/2022]
Abstract
Helicobacter pylori is one of the most successful human pathogens, which colonizes the mucus layer of the gastric epithelium of more than 50% of the world’s population. This curved, microaerophilic, Gram-negative bacterium induces a chronic active gastritis, often asymptomatic, in all infected individuals. In some cases, this gastritis evolves to more severe diseases such as peptic ulcer disease, gastric adenocarcinoma, and gastric mucosa-associated lymphoid tissue lymphoma. H. pylori has developed a unique set of factors, actively supporting its successful survival and persistence in its natural hostile ecological niche, the human stomach, throughout the individual’s life, unless treated. In the human stomach, the vast majority of H. pylori cells are motile in the mucus layer lining, but a small percentage adheres to the epithelial cell surfaces. Adherence to the gastric epithelium is important for the ability of H. pylori to cause disease because this intimate attachment facilitates: (1) colonization and persistence, by preventing the bacteria from being eliminated from the stomach, by mucus turnover and gastric peristalsis; (2) evasion from the human immune system and (3) efficient delivery of proteins into the gastric cell, such as the CagA oncoprotein. Therefore, bacteria with better adherence properties colonize the host at higher densities. H. pylori is one of the most genetically diverse bacterial species known and is equipped with an extraordinarily large set of outer membrane proteins, whose role in the infection and persistence process will be discussed in this review, as well as the different receptor structures that have been so far described for mucosal adherence.
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