Helicobacter Pylori VacA Transcription is Genetically-determined and Stratifies the Level of Human Gastric Inflammation and Atrophy

Overview

Journal J Clin Pathol

Specialty Pathology

Date 2016 May 19

PMID 27189958

Citations 5

Authors

Charlotte G Sinnett

Darren P Letley

Geetha L Narayanan

Sapna R Patel

Nawfal R Hussein

Abed M Zaitoun

Karen Robinson

John C Atherton

Affiliations

Soon will be listed here.

Abstract

Aims: Helicobacter pylori infection is the major cause of peptic ulceration and gastric cancer, and an important virulence determinant is its vacuolating cytotoxin vacA. Previously, we have described allelic variation in vacA which determines toxin activity and disease risk. Here we aimed to quantify vacA mRNA expression in the human stomach, define its genetic determinants and assess how well it predicts gastric pathology.

Methods: Gastric biopsies were donated by 39 patients with H. pylori infection attending for endoscopy at Queen's Medical Centre, Nottingham, UK. Total RNA was extracted, and vacA mRNA quantified by reverse transcriptase quantitative PCR. Separate biopsies were histologically scored for inflammation and atrophy using the updated Sydney system. H. pylori strains were isolated from further biopsies, and the nucleotide sequence upstream of vacA determined.

Results: vacA mRNA levels in human stomachs varied by two orders of magnitude independently of vacA allelic type. Among vacA i1-type (toxic) strains, increased vacA expression was strongly associated with higher grade gastric inflammation (p<0.02), neutrophil infiltration (p<0.005) and the presence of atrophy (p<0.01). A polymorphism at nucleotide +28 near the base of a potential stem-loop structure within the 5' untranslated region was significantly associated with vacA transcript level and inflammation.

Conclusions: Increased gastric vacA expression during H. pylori infection is associated with inflammation and premalignant pathology. The +28 nucleotide within the vacA 5' stem-loop stratifies disease risk among toxic vacA i1-type strains.

Citing Articles

Kill Two Birds with One Stone? The Effect of Eradication in Decreased Prevalence of Gastric Cancer and Colorectal Cancer.

Kuo Y, Ko H, Yu L, Shih S, Wang H, Lin Y Cancers (Basel). 2024; 16(22).

PMID: 39594836 PMC: 11592957. DOI: 10.3390/cancers16223881.

Role of Bacterial and Viral Pathogens in Gastric Carcinogenesis.

Palrasu M, Zaika E, El-Rifai W, Que J, Zaika A Cancers (Basel). 2021; 13(8).

PMID: 33919876 PMC: 8070847. DOI: 10.3390/cancers13081878.

CD103 Promotes the Pro-inflammatory Response of Gastric Resident CD4 T Cell in -Positive Gastritis.

Chen P, Ming S, Lao J, Li C, Wang H, Xiong L Front Cell Infect Microbiol. 2020; 10:436.

PMID: 32974219 PMC: 7472738. DOI: 10.3389/fcimb.2020.00436.

Infection, Virulence Genes' Distribution and Accompanying Clinical Outcomes: The West Africa Situation.

Ofori E, Adinortey C, Bockarie A, Kyei F, Tagoe E, Adinortey M Biomed Res Int. 2019; 2019:7312908.

PMID: 31886245 PMC: 6925786. DOI: 10.1155/2019/7312908.

Pleiotropic cytotoxicity of VacA toxin in host cells and its impact on immunotherapy.

Fahimi F, Tohidkia M, Fouladi M, Aghabeygi R, Samadi N, Omidi Y Bioimpacts. 2017; 7(1):59-71.

PMID: 28546954 PMC: 5439391. DOI: 10.15171/bi.2017.08.

References

Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M . Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2014; 136(5):E359-86. DOI: 10.1002/ijc.29210. View

Kim I, Blanke S . Remodeling the host environment: modulation of the gastric epithelium by the Helicobacter pylori vacuolating toxin (VacA). Front Cell Infect Microbiol. 2012; 2:37. PMC: 3417592. DOI: 10.3389/fcimb.2012.00037. View

Ogiwara H, Sugimoto M, Ohno T, Vilaichone R, Mahachai V, Graham D . Role of deletion located between the intermediate and middle regions of the Helicobacter pylori vacA gene in cases of gastroduodenal diseases. J Clin Microbiol. 2009; 47(11):3493-500. PMC: 2772588. DOI: 10.1128/JCM.00887-09. View

Stein M, Ruggiero P, Rappuoli R, Bagnoli F . Helicobacter pylori CagA: From Pathogenic Mechanisms to Its Use as an Anti-Cancer Vaccine. Front Immunol. 2013; 4:328. PMC: 3796731. DOI: 10.3389/fimmu.2013.00328. View

Forsyth M, Atherton J, Blaser M, Cover T . Heterogeneity in levels of vacuolating cytotoxin gene (vacA) transcription among Helicobacter pylori strains. Infect Immun. 1998; 66(7):3088-94. PMC: 108317. DOI: 10.1128/IAI.66.7.3088-3094.1998. View

Telford J, Ghiara P, DellOrco M, Comanducci M, Burroni D, Bugnoli M . Gene structure of the Helicobacter pylori cytotoxin and evidence of its key role in gastric disease. J Exp Med. 1994; 179(5):1653-58. PMC: 2191472. DOI: 10.1084/jem.179.5.1653. View

Letley D, Atherton J . Natural diversity in the N terminus of the mature vacuolating cytotoxin of Helicobacter pylori determines cytotoxin activity. J Bacteriol. 2000; 182(11):3278-80. PMC: 94518. DOI: 10.1128/JB.182.11.3278-3280.2000. View

Atherton J . The pathogenesis of Helicobacter pylori-induced gastro-duodenal diseases. Annu Rev Pathol. 2007; 1:63-96. DOI: 10.1146/annurev.pathol.1.110304.100125. View

Rhead J, Letley D, Mohammadi M, Hussein N, Mohagheghi M, Hosseini M . A new Helicobacter pylori vacuolating cytotoxin determinant, the intermediate region, is associated with gastric cancer. Gastroenterology. 2007; 133(3):926-36. DOI: 10.1053/j.gastro.2007.06.056. View

10.

Dixon M, Genta R, Yardley J, Correa P . Classification and grading of gastritis. The updated Sydney System. International Workshop on the Histopathology of Gastritis, Houston 1994. Am J Surg Pathol. 1996; 20(10):1161-81. DOI: 10.1097/00000478-199610000-00001. View

11.

Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V . Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012; 380(9859):2095-128. PMC: 10790329. DOI: 10.1016/S0140-6736(12)61728-0. View

12.

Amilon K, Letley D, Winter J, Robinson K, Atherton J . Expression of the Helicobacter pylori virulence factor vacuolating cytotoxin A (vacA) is influenced by a potential stem-loop structure in the 5' untranslated region of the transcript. Mol Microbiol. 2015; 98(5):831-46. PMC: 4843948. DOI: 10.1111/mmi.13160. View

13.

Pfaffl M . A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res. 2001; 29(9):e45. PMC: 55695. DOI: 10.1093/nar/29.9.e45. View

14.

Jang S, Jones K, Olsen C, Joo Y, Yoo Y, Chung I . Epidemiological link between gastric disease and polymorphisms in VacA and CagA. J Clin Microbiol. 2009; 48(2):559-67. PMC: 2815640. DOI: 10.1128/JCM.01501-09. View

15.

Aviles-Jimenez F, Letley D, Gonzalez-Valencia G, Salama N, Torres J, Atherton J . Evolution of the Helicobacter pylori vacuolating cytotoxin in a human stomach. J Bacteriol. 2004; 186(15):5182-5. PMC: 451639. DOI: 10.1128/JB.186.15.5182-5185.2004. View

16.

McClain M, Cao P, Iwamoto H, Szabo G, Shao Z, Cover T . A 12-amino-acid segment, present in type s2 but not type s1 Helicobacter pylori VacA proteins, abolishes cytotoxin activity and alters membrane channel formation. J Bacteriol. 2001; 183(22):6499-508. PMC: 95478. DOI: 10.1128/JB.183.22.6499-6508.2001. View

17.

Letley D, Rhead J, Twells R, Dove B, Atherton J . Determinants of non-toxicity in the gastric pathogen Helicobacter pylori. J Biol Chem. 2003; 278(29):26734-41. DOI: 10.1074/jbc.M304071200. View

18.

Aviles-Jimenez F, Reyes-Leon A, Nieto-Patlan E, Hansen L, Burgueno J, Ramos I . In vivo expression of Helicobacter pylori virulence genes in patients with gastritis, ulcer, and gastric cancer. Infect Immun. 2011; 80(2):594-601. PMC: 3264312. DOI: 10.1128/IAI.05845-11. View

19.

Basso D, Zambon C, Letley D, Stranges A, Marchet A, Rhead J . Clinical relevance of Helicobacter pylori cagA and vacA gene polymorphisms. Gastroenterology. 2008; 135(1):91-9. DOI: 10.1053/j.gastro.2008.03.041. View

20.

Ohnishi N, Yuasa H, Tanaka S, Sawa H, Miura M, Matsui A . Transgenic expression of Helicobacter pylori CagA induces gastrointestinal and hematopoietic neoplasms in mouse. Proc Natl Acad Sci U S A. 2008; 105(3):1003-8. PMC: 2242726. DOI: 10.1073/pnas.0711183105. View