Immunostimulatory membrane proteins potentiate H. pylori-induced carcinogenesis by enabling CagA translocation

Matthew G. Varga, Cecily R. Wood, Julia Butt, Mackenzie E. Ryan, Wei Cheng You, Kaifeng Pan, Tim Waterboer, Meira Epplein, Carrie L. Shaffer

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Infection with Helicobacter pylori is the single greatest risk factor for developing gastric adenocarcinoma. In prospective, population-based studies, seropositivity to the uncharacterized H. pylori proteins Hp0305 and Hp1564 was significantly associated with cancer risk in East Asia. However, the mechanism underlying this observation has not been elucidated. Here, we show that Hp0305 and Hp1564 act in concert with previously ascribed H. pylori virulence mechanisms to orchestrate cellular alterations that promote gastric carcinogenesis. In samples from 546 patients exhibiting premalignant gastric lesions, seropositivity to Hp0305 and Hp1564 was significantly associated with increased gastric atrophy across all stomach conditions. In vitro, depletion of Hp0305 and Hp1564 significantly reduced levels of gastric cell-associated bacteria and markedly impaired the ability of H. pylori to stimulate pro-inflammatory cytokine production. Remarkably, our studies revealed that Hp1564 is required for translocation of the oncoprotein CagA into gastric epithelial cells. Our data provide experimental insight into the molecular mechanisms governing novel H. pylori pathogenicity factors that are strongly associated with gastric disease and highlight the potential of Hp0305 and Hp1564 as robust molecular tools that can improve identification of individuals that are highly susceptible to gastric cancer. We demonstrate that Hp0305 and Hp1564 augment H. pylori-mediated inflammation and gastric cancer risk by promoting key bacteria-gastric cell interactions that facilitate delivery of oncogenic microbial cargo to target cells. Thus, therapeutically targeting microbial interactions driven by Hp0305/Hp1564 may enable focused H. pylori eradication strategies to prevent development of gastric malignancies in high-risk populations.

Original languageEnglish
Pages (from-to)1-13
Number of pages13
JournalGut Microbes
Volume13
Issue number1
DOIs
StatePublished - 2021

Bibliographical note

Funding Information:
CLS was supported by NIH P30 GM110787, NIH P20 GM130456, and NIH R01 CA174853. MGV was supported by NIH T32 CA057726. ME was supported by NIH R01 CA174853. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. MGV, CLS, and ME designed the study and analyzed the data. MGV, CRW, JB, MER, WCY, KP, and TW conducted and analyzed the research. CLS and ME supervised the research. MGV, ME, and CLS wrote the manuscript with input from all authors.

Funding Information:
This work was supported by the NIH [T32 CA057726]; NIH [R01 CA174853]; NIH [P20 GM130456]; NIH [P30 GM110787]. CLS was supported by NIH P30 GM110787, NIH P20 GM130456, and NIH R01 CA174853. MGV was supported by NIH T32 CA057726. ME was supported by NIH R01 CA174853. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. MGV, CLS, and ME designed the study and analyzed the data. MGV, CRW, JB, MER, WCY, KP, and TW conducted and analyzed the research. CLS and ME supervised the research. MGV, ME, and CLS wrote the manuscript with input from all authors.

Publisher Copyright:
© 2020 The Author(s). Published with license by Taylor & Francis Group, LLC.

Keywords

  • CagA
  • Helicobacter pylori
  • bacterial pathogenesis
  • epidemiology
  • gastric cancer

ASJC Scopus subject areas

  • Microbiology
  • Gastroenterology
  • Microbiology (medical)
  • Infectious Diseases

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