Skip to main content

Advertisement

SpringerLink
Log in

A novel chimeric flagellum fused with the multi-epitope vaccine CTB-UE prevents Helicobacter pylori-induced gastric cancer in a BALB/c mouse model

  • Biotechnologically relevant enzymes and proteins
  • Published:
Applied Microbiology and Biotechnology Aims and scope Submit manuscript

Abstract

Helicobacter pylori (H. pylori) infection causes peptic ulcers, gastric adenocarcinoma, and mucosa-associated lymphoid tissue (MALT) lymphoma. The eradication of H. pylori might be an effective means of preventing gastric cancer. A dual-antigen epitope and dual-adjuvant vaccine called CTB-UE-CF (CCF) was constructed by combining a multi-epitope vaccine CTB-UE with a novel chimeric flagellum (CF) to simultaneously activate Toll-like receptor (TLR) 5-agonist activity and preserve the immunogenicity of H. pylori flagellum FlaA. The evaluation of efficacy to reduce H. pylori colonization was performed using BALB/c mice by oral immunization with a triple dose of this vaccine strain. Two weeks after the last immunization, mice were sacrificed to determine specific antibody levels and proinflammatory cytokine production. To determine the presence of H. pylori, we detected the number of H. pylori by real-time quantitative PCR (qPCR) and measured the urease activity in the gastric tissue. The results showed that the immunogenicity and mucosal immune responses of CCF performed significantly better than those of CTB-UE. This dual-antigen epitope and dual-adjuvant system might greatly contribute to the development of a safe and efficient therapeutic vaccine for humans against H. pylori infection.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Andersen-Nissen E, Smith KD, Strobe KL, Barrett SL, Cookson BT, Logan SM, Aderem A (2005) Evasion of toll-like receptor 5 by flagellated bacteria. Proc Natl Acad Sci U S A 102(26):9247–9252

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Eaton KA, Morgan DR, Krakowka S (1992) Motility as a factor in the colonisation of gnotobiotic piglets by Helicobacter pylori. J Med Microbiol 37(2):123–127

    Article  CAS  PubMed  Google Scholar 

  • Ferrero RL, Lee A (1991) The importance of urease in acid protection for the gastric-colonising bacteria Helicobacter pylori and Helicobacter felis sp. nov. Microb Ecol Health Dis 4(3):121–134

    Article  Google Scholar 

  • Gewirtz AT, Yu Y, Krishna US, Israel DA, Lyons SL, Peek Jr RM (2004) Helicobacter pylori flagellin evades toll-like receptor 5-mediated innate immunity. J Infect Dis 189(10):1914–1920

    Article  CAS  PubMed  Google Scholar 

  • Gómez-Duarte OG, Lucas B, Yan ZX, Panthel K, Haas R, Meyer TF (1998) Protection of mice against gastric colonization by Helicobacter pylori by single oral dose immunization with attenuated Salmonella typhimurium producing urease subunits A and B. Vaccine 16(5):460–471

    Article  PubMed  Google Scholar 

  • Graham DY, Shiotani A (2008) New concepts of resistance in the treatment of Helicobacter pylori infections. Nat Clin Pract Gastroenterol Hepatol 5(6):321–331

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Guo L, Li X, Tang F, He Y, Xing Y, Deng X, Xi T (2012a) Immunological features and the ability of inhibitory effects on enzymatic activity of an epitope vaccine composed of cholera toxin B subunit and B cell epitope from Helicobacter pylori urease A subunit. Appl Microbiol Biotechnol 93(5):1937–1945

    Article  CAS  PubMed  Google Scholar 

  • Guo L, Liu K, Xu G, Li X, Tu J, Tang F, Xing Y, Xi T (2012b) Prophylactic and therapeutic efficacy of the epitope vaccine CTB-UA against Helicobacter pylori infection in a BALB/c mice model. Appl Microbiol Biotechnol 95(6):1437–1444

    Article  CAS  PubMed  Google Scholar 

  • Guo L, Yin R, Liu K, Lv X, Li Y, Duan X, Chu Y, Xi T, Xing Y (2014) Immunological features and efficacy of a multi-epitope vaccine CTB-UE against H. pylori in BALB/c mice model. Appl Microbiol Biotechnol 98(8):3495–3507

    Article  CAS  PubMed  Google Scholar 

  • Guy B, Hessler C, Fourage S, Haensler J, Vialon-Lafay E, Rokbi B, Millet MJ (1998) Systemic immunization with urease protects mice against Helicobacter pylori infection. Vaccine 16(8):850–856

    Article  CAS  PubMed  Google Scholar 

  • He Q, Wang JP, Osato M, Lachman LB (2002) Real-time quantitative PCR for detection of Helicobacter pylori. J Clin Microbiol 40(10):3720–3728

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huleatt JW, Jacobs AR, Tang J, Desai P, Kopp EB, Huang Y, Song L, Nakaar V, Powell TJ (2007) Vaccination with recombinant fusion proteins incorporating Toll-like receptor ligands induces rapid cellular and humoral immunity. Vaccine 25(4):763–775

    Article  CAS  PubMed  Google Scholar 

  • Lee CK, Weltzin R, Thomas Jr WD, Kleanthous H, Ermak TH, Soman G, Hill JE, Ackerman SK, Monath TP (1995) Oral immunization with recombinant Helicobacter pylori urease induces secretory IgA antibodies and protects mice from challenge with Helicobacter felis. J Infect Dis 172(1):161–172

    Article  CAS  PubMed  Google Scholar 

  • Leying H, Suerbaum S, Geis G, Haas R (1992) Cloning and genetic characterization of a Helicobacter pylori flagellin gene. Mol Microbiol 6(19):2863–2874

    Article  CAS  PubMed  Google Scholar 

  • Lv X, Yang J, Song H, Li T, Guo L, Xing Y, Xi T (2014a) Therapeutic efficacy of the multi-epitope vaccine CTB-UE against Helicobacter pylori infection in a Mongolian gerbil model and its microRNA-155-associated immuno-protective mechanism. Vaccine 32(41):5343–5352

    Article  CAS  PubMed  Google Scholar 

  • Lv X, Song H, Yang J, Li T, Xi T, Xing Y (2014b) A multi-epitope vaccine CTB-UE relieves Helicobacter pylori-induced gastric inflammatory reaction via up-regulating microRNA-155 to inhibit Th17 response in C57/BL6 mice model. Hum Vaccin Immunother 10(12):3561–3569

    Article  PubMed  PubMed Central  Google Scholar 

  • O’Connor A, Vaira D, Gisbert JP, O’Morain C (2014) Treatment of Helicobacter pylori infection 2014. Helicobacter Suppl 1:38–45

    Article  Google Scholar 

  • Ottemann KM, Lowenthal AC (2002) Helicobacter pylori uses motility for initial colonization and to attain robust infection. Infect Immun 70(4):1984–1990

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Papastergiou V, Georgopoulos SD, Karatapanis S (2014) Treatment of Helicobacter pylori infection: past, present and future. World J Gastrointest Pathophysiol 5(4):392–399

    Article  PubMed  PubMed Central  Google Scholar 

  • Peek Jr RM, Crabtree JE (2006) Helicobacter infection and gastric neoplasia. J Pathol 208(2):233–248

    Article  CAS  PubMed  Google Scholar 

  • Schülke S, Waibler Z, Mende MS, Zoccatelli G, Vieths S, Toda M, Scheurer S (2010) Fusion protein of TLR5-ligand and allergen potentiates activation and IL-10 secretion in murine myeloid DC. Mol Immunol 48(1–3):341–350

    Article  PubMed  Google Scholar 

  • Shukla SK, Prasad KN, Tripathi A, Ghoshal UC, Krishnani N, Nuzhat H (2011) Quantitation of Helicobacter pylori ureC gene and its comparison with different diagnostic techniques and gastric histopathology. J Microbiol Methods 86(2):231–237

    Article  CAS  PubMed  Google Scholar 

  • Stingl K, Altendorf K, Bakker EP (2002) Acid survival of Helicobacter pylori: how does urease activity trigger cytoplasmic pH homeostasis? Trends Microbiol 10(2):70–74

    Article  CAS  PubMed  Google Scholar 

  • Suerbaum S, Josenhans C, Labigne A (1993) Cloning and genetic characterization of the Helicobacter pylori and Helicobacter mustelae flaB flagellin genes and construction of H. pylori flaA- and flaB-negative mutants by electroporation-mediated allelic exchange. J Bacteriol 175(11):3278–3288

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sun JB, Mielcarek N, Lakew M, Grzych JM, Capron A, Holmgren J, Czerkinsky C (1999) Intranasal administration of a Schistosoma mansoni glutathione S-transferase-cholera toxoid conjugate vaccine evokes antiparasitic and antipathological immunity in mice. J Immunol 163(2):1045–1052

    CAS  PubMed  Google Scholar 

  • Vakil N, Megraud F (2007) Eradication therapy for Helicobacter pylori. Gastroenterology 133(3):985–1001

    Article  CAS  PubMed  Google Scholar 

  • van Ginkel FW, Jackson RJ, Yuki Y, McGhee JR (2000) Cutting edge: the mucosal adjuvant cholera toxin redirects vaccine proteins into olfactory tissues. J Immunol 165(9):4778–4782

    Article  PubMed  Google Scholar 

  • Vyas SP, Sihorkar V (1999) Exploring novel vaccines against Helicobacter pylori: protective and therapeutic immunization. J Clin Pharm Ther 24(4):259–272

    Article  CAS  PubMed  Google Scholar 

  • Weeks DL, Eskandari S, Scott DR, Sachs G (2000) A H+-gated urea channel: the link between Helicobacter pylori urease and gastric colonization. Science 287(5452):482–485

    Article  CAS  PubMed  Google Scholar 

  • Wroblewski LE, Peek Jr RM, Wilson KT (2010) Helicobacter pylori and gastric cancer: factors that modulate disease risk. Clin Microbiol Rev 23(4):713–739

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang D, Zhang G, Hayden MS, Greenblatt MB, Bussey C, Flavell RA, Ghosh S (2004) A toll-like receptor that prevents infection by uropathogenic bacteria. Science 303(5663):1522–1526

    Article  CAS  PubMed  Google Scholar 

  • Zhang S, Lee DS, Morrissey R, Aponte-Pieras JR, Rogers AB, Moss SF (2014) Early or late antibiotic intervention prevents Helicobacter pylori-induced gastric cancer in a mouse model. Cancer Lett 355(1):106–112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhou WY, Shi Y, Wu C, Zhang WJ, Mao XH, Guo G, Li HX, Zou QM (2009) Therapeutic efficacy of a multi-epitope vaccine against Helicobacter pylori infection in BALB/c mice model. Vaccine 27(36):5013–5019

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The National Major Special Program of New Drug Research and Development (No. 2012ZX09103301–008), the Natural Science Foundation of Jiangsu Province (No. BK20130647), the Priority Academic Program Development (PAPD) of Jiangsu Higher Education Institutions, and the Qing Lan Project supported this work.

Conflict of interest

The authors declare that they have no competing interests.

Author information

Authors and Affiliations

  1. School of Life Science and Technology, China Pharmaceutical University, Nanjing, 210009, China

    Hui Song, Xiaobo Lv, Jue Yang, Wei Liu, Huan Yang, Tao Xi & Yingying Xing

  2. Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, 210009, China

    Hui Song, Xiaobo Lv, Jue Yang, Wei Liu, Huan Yang, Tao Xi & Yingying Xing

Authors
  1. Hui Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiaobo Lv
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jue Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wei Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Huan Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tao Xi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yingying Xing
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Tao Xi or Yingying Xing.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Song, H., Lv, X., Yang, J. et al. A novel chimeric flagellum fused with the multi-epitope vaccine CTB-UE prevents Helicobacter pylori-induced gastric cancer in a BALB/c mouse model. Appl Microbiol Biotechnol 99, 9495–9502 (2015). https://doi.org/10.1007/s00253-015-6705-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00253-015-6705-z

Keywords

Search

Navigation