Co-infection of Helicobacter pylori with Epstein-Barr virus in gastric organoids enhances cell proliferation and morphogenesis

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ABSTRACT Helicobacter pylori ( H. pylori ) is a key cause of chronic inflammation and gastric cancer, and Epstein-Barr virus (EBV) also contributes to gastric tumorigenesis. However, the role of EBV co-infection in H. pylori -related cancers remains unclear because of the lack of efficient ex vivo models. Organoids, which are derived from self-renewing stem cells, closely mimic in situ tissue structure and function, making them ideal for disease modeling. Here, we developed patient-derived normal gastric organoids (NGOs) and used high-accuracy microinjection to introduce EBV and H. pylori (NCTC11637 strain). We found that the co-infection of H. pylori and EBV induced a significant structural change and upregulated the expression of TFF1 , VIL1 , and Lgr5 to promote cell proliferation and tissue morphogenesis. Analysis of transmission electron microscopy revealed an increase of H. pylori internal location in NGOs after co-infection. Moreover, all tested H. pylori strains isolated from patients displayed similar toxicities when co-infected with EBV. These findings provide a fundamental basis for evaluating pathogen toxicity, predicting disease progression, and advancing the clinical treatment of gastric cancer. IMPORTANCE Helicobacter pylori ( H. pylori ) infection is a major contributor to chronic inflammation and the development of gastric cancer. Furthermore, Epstein-Barr virus (EBV) has been shown to play a role in the oncogenic process of gastric cancer by promoting chronic inflammation and increasing tissue damage. However, the mechanism by which co-infection contributes to gastric carcinogenesis remains unclear. In this study, we used patient-derived gastric organoids as a model to establish EBV- H. pylori co-infection using microinjection technology and found that co-infection causes significant structural changes and promotes cell proliferation. This model will not only contribute to a better understanding of the pathogenesis of gastric cancer but will also be important for drug efficacy evaluation and the development of new therapeutic approaches.

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