Beta-defensins and Analogs in Helicobacter Pylori Infections: MRNA Expression Levels, DNA Methylation, and Antibacterial Activity

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2019 Sep 20

PMID 31537016

Citations 24

Authors

Raffaela Pero

Tiziana Angrisano

Mariarita Brancaccio

Annarita Falanga

Lucia Lombardi

Francesco Natale

Sonia Laneri

Barbara Lombardo

Stefania Galdiero

Olga Scudiero

Affiliations

Soon will be listed here.

Abstract

Antimicrobial peptides can protect the gastric mucosa from bacteria, but Helicobacter pylori (H. pylori) can equally colonize the gastric apparatus. To understand beta-defensin function in H. pylori-associated chronic gastritis, we investigated susceptibility, human beta-defensin mRNA expression, and DNA methylation changes to promoters in the gastric mucosa with or without H. pylori infection. We studied the expression of HBD2 (gene name DEFB4A), HBD3 (DEFB103A), and HBD4 (DEFB104) using real-time PCR in 15 control and 10 H. pylori infection patient gastric specimens. This study demonstrates that H. pylori infection is related to gastric enhancement of inducible HBD2, but inducible HBD3 and HBD4 expression levels remained unchanged. HBD2 gene methylation levels were overall higher in H. pylori-negative samples than in H. pylori-positive samples. We also assessed antimicrobial susceptibility using growth on blood agar. The H. pylori strain Tox+ was susceptible to all defensins tested and their analogs (3N, 3NI). These results show that HBD2 is involved in gastritis development driven by H. pylori, which facilitates the creation of an epigenetic field during H. pylori-associated gastric tumorigenesis.

Citing Articles

Mucosal immune response in biology, disease prevention and treatment.

Zhou X, Wu Y, Zhu Z, Lu C, Zhang C, Zeng L Signal Transduct Target Ther. 2025; 10(1):7.

PMID: 39774607 PMC: 11707400. DOI: 10.1038/s41392-024-02043-4.

Advancements in Loop Cyclization Approaches for Enhanced Peptide Therapeutics for Targeting Protein-Protein Interactions.

Lombardi L, Granger L, Shattock R, Williams D J Org Chem. 2024; 90(4):1467-1477.

PMID: 39611613 PMC: 11791882. DOI: 10.1021/acs.joc.4c02178.

Recent Advances in Vitamin D3 Intervention to Eradicate Infection.

Ma P, Zhuo L, Yuan L, Qi X J Multidiscip Healthc. 2024; 17:825-832.

PMID: 38434485 PMC: 10906669. DOI: 10.2147/JMDH.S454605.

Immune Biology and Persistence of Helicobacter pylori in Gastric Diseases.

Fuchs S, Gong R, Gerhard M, Mejias-Luque R Curr Top Microbiol Immunol. 2024; 444:83-115.

PMID: 38231216 DOI: 10.1007/978-3-031-47331-9_4.

Designing and development of multi-epitope chimeric vaccine against Helicobacter pylori by exploring its entire immunogenic epitopes: an immunoinformatic approach.

Keshri A, Kaur R, Rawat S, Arora N, Pandey R, Kumbhar B BMC Bioinformatics. 2023; 24(1):358.

PMID: 37740175 PMC: 10517479. DOI: 10.1186/s12859-023-05454-2.

References

Tsunoda T, Takagi T . Estimating transcription factor bindability on DNA. Bioinformatics. 1999; 15(7-8):622-30. DOI: 10.1093/bioinformatics/15.7.622. View

Wada A, Mori N, Oishi K, Hojo H, Nakahara Y, Hamanaka Y . Induction of human beta-defensin-2 mRNA expression by Helicobacter pylori in human gastric cell line MKN45 cells on cag pathogenicity island. Biochem Biophys Res Commun. 1999; 263(3):770-4. DOI: 10.1006/bbrc.1999.1452. View

Kondo Y, Kanai Y, Sakamoto M, Mizokami M, Ueda R, Hirohashi S . Genetic instability and aberrant DNA methylation in chronic hepatitis and cirrhosis--A comprehensive study of loss of heterozygosity and microsatellite instability at 39 loci and DNA hypermethylation on 8 CpG islands in microdissected specimens from.... Hepatology. 2000; 32(5):970-9. DOI: 10.1053/jhep.2000.19797. View

Islam D, Bandholtz L, Nilsson J, Wigzell H, Christensson B, Agerberth B . Downregulation of bactericidal peptides in enteric infections: a novel immune escape mechanism with bacterial DNA as a potential regulator. Nat Med. 2001; 7(2):180-5. DOI: 10.1038/84627. View

Issa J, Ahuja N, Toyota M, Bronner M, Brentnall T . Accelerated age-related CpG island methylation in ulcerative colitis. Cancer Res. 2001; 61(9):3573-7. View

Hamanaka Y, Nakashima M, Wada A, Ito M, Kurazono H, Hojo H . Expression of human beta-defensin 2 (hBD-2) in Helicobacter pylori induced gastritis: antibacterial effect of hBD-2 against Helicobacter pylori. Gut. 2001; 49(4):481-7. PMC: 1728463. DOI: 10.1136/gut.49.4.481. View

Bajaj-Elliott M, Fedeli P, Smith G, Domizio P, Maher L, Ali R . Modulation of host antimicrobial peptide (beta-defensins 1 and 2) expression during gastritis. Gut. 2002; 51(3):356-61. PMC: 1773366. DOI: 10.1136/gut.51.3.356. View

Uehara N, Yagihashi A, Kondoh K, Tsuji N, Fujita T, Hamada H . Human beta-defensin-2 induction in Helicobacter pylori-infected gastric mucosal tissues: antimicrobial effect of overexpression. J Med Microbiol. 2002; 52(Pt 1):41-45. DOI: 10.1099/jmm.0.04985-0. View

Chan A, Lam S, Wong B, Wong W, Yuen M, Yeung Y . Promoter methylation of E-cadherin gene in gastric mucosa associated with Helicobacter pylori infection and in gastric cancer. Gut. 2003; 52(4):502-6. PMC: 1773595. DOI: 10.1136/gut.52.4.502. View

10.

Wehkamp J, Schmidt K, Herrlinger K, Baxmann S, Behling S, Wohlschlager C . Defensin pattern in chronic gastritis: HBD-2 is differentially expressed with respect to Helicobacter pylori status. J Clin Pathol. 2003; 56(5):352-7. PMC: 1769951. DOI: 10.1136/jcp.56.5.352. View

11.

ONeil D . Regulation of expression of beta-defensins: endogenous enteric peptide antibiotics. Mol Immunol. 2003; 40(7):445-50. DOI: 10.1016/s0161-5890(03)00161-5. View

12.

Hase K, Murakami M, Iimura M, Cole S, Horibe Y, Ohtake T . Expression of LL-37 by human gastric epithelial cells as a potential host defense mechanism against Helicobacter pylori. Gastroenterology. 2004; 125(6):1613-25. DOI: 10.1053/j.gastro.2003.08.028. View

13.

Ohata H, Kitauchi S, Yoshimura N, Mugitani K, Iwane M, Nakamura H . Progression of chronic atrophic gastritis associated with Helicobacter pylori infection increases risk of gastric cancer. Int J Cancer. 2004; 109(1):138-43. DOI: 10.1002/ijc.11680. View

14.

Rutter M, Saunders B, Wilkinson K, Rumbles S, Schofield G, Kamm M . Severity of inflammation is a risk factor for colorectal neoplasia in ulcerative colitis. Gastroenterology. 2004; 126(2):451-9. DOI: 10.1053/j.gastro.2003.11.010. View

15.

MacArthur M, Hold G, El-Omar E . Inflammation and Cancer II. Role of chronic inflammation and cytokine gene polymorphisms in the pathogenesis of gastrointestinal malignancy. Am J Physiol Gastrointest Liver Physiol. 2004; 286(4):G515-20. DOI: 10.1152/ajpgi.00475.2003. View

16.

Itzkowitz S, Yio X . Inflammation and cancer IV. Colorectal cancer in inflammatory bowel disease: the role of inflammation. Am J Physiol Gastrointest Liver Physiol. 2004; 287(1):G7-17. DOI: 10.1152/ajpgi.00079.2004. View

17.

Nishi Y, Isomoto H, Mukae H, Ishimoto H, Wen C, Wada A . Concentrations of alpha- and beta-defensins in gastric juice of patients with various gastroduodenal diseases. World J Gastroenterol. 2004; 11(1):99-103. PMC: 4205393. DOI: 10.3748/wjg.v11.i1.99. View

18.

Taha A, Faccenda E, Angerson W, Balsitis M, Kelly R . Gastric epithelial anti-microbial peptides--histological correlation and influence of anatomical site and peptic ulcer disease. Dig Liver Dis. 2005; 37(1):51-6. DOI: 10.1016/j.dld.2004.07.019. View

19.

Ushijima T . Detection and interpretation of altered methylation patterns in cancer cells. Nat Rev Cancer. 2005; 5(3):223-31. DOI: 10.1038/nrc1571. View

20.

Selsted M, Ouellette A . Mammalian defensins in the antimicrobial immune response. Nat Immunol. 2005; 6(6):551-7. DOI: 10.1038/ni1206. View