Campylobacter jejuni Cytolethal Distending Toxin C Exploits Lipid Rafts to Mitigate Helicobacter pylori-Induced Pathogenesis

Jia-Yin Yeh; Hwai-Jeng Lin; Chia-Jung Kuo; Chun-Lung Feng; Chia-Huei Chou; Chia-Der Lin; Hui-Yu Wu; Chen-Yi Li; Cheng-Hsun Chiu; Chih-Ho Lai

doi:10.3389/fcell.2020.617419

Campylobacter jejuni Cytolethal Distending Toxin C Exploits Lipid Rafts to Mitigate Helicobacter pylori-Induced Pathogenesis

Front Cell Dev Biol. 2021 Feb 23:8:617419. doi: 10.3389/fcell.2020.617419. eCollection 2020.

Authors

Jia-Yin Yeh¹, Hwai-Jeng Lin^{2

3}, Chia-Jung Kuo^{4

5}, Chun-Lung Feng^{6

7}, Chia-Huei Chou^{7

8}, Chia-Der Lin^{7

8}, Hui-Yu Wu¹, Chen-Yi Li¹, Cheng-Hsun Chiu^{1

5

9}, Chih-Ho Lai^{1

7

9

10}

Affiliations

¹ Department of Microbiology and Immunology, Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan.
² Division of Gastroenterology and Hepatology, Department of Internal Medicine, Shuang-Ho Hospital, New Taipei, Taiwan.
³ Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
⁴ Chang Gung Microbiota Therapy Center, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou, Taiwan.
⁵ College of Medicine, Chang Gung University, Taoyuan, Taiwan.
⁶ Division of Gastroenterology and Hepatology, Department of Internal Medicine, China Medical University Hsinchu Hospital, Hsinchu, Taiwan.
⁷ Department of Microbiology, School of Medicine, China Medical University, Taichung, Taiwan.
⁸ Department of Infectious Disease, Department of Otolaryngology-Head and Neck Surgery, China Medical University Hospital, Taichung, Taiwan.
⁹ Molecular Infectious Disease Research Center, Department of Pediatrics, Chang Gung Memorial Hospital, Linkou, Taiwan.
¹⁰ Department of Nursing, Asia University, Taichung, Taiwan.

Abstract

Helicobacter pylori infection is associated with several gastrointestinal diseases, including gastritis, peptic ulcer, and gastrointestinal adenocarcinoma. Two major cytotoxins, vacuolating cytotoxin A (VacA) and cytotoxin-associated gene A (CagA), interact closely with lipid rafts, contributing to H. pylori-associated disease progression. The Campylobacter jejuni cytolethal distending toxin consists of three subunits: CdtA, CdtB, and CdtC. Among them, CdtA and CdtC bind to membrane lipid rafts, which is crucial for CdtB entry into cells. In this study, we employed recombinant CdtC (rCdtC) to antagonize the functions of H. pylori cytotoxin in cells. Our results showed that rCdtC alleviates cell vacuolation induced by H. pylori VacA. Furthermore, rCdtC reduces H. pylori CagA translocation, which decreases nuclear factor kappa-B activation and interleukin-8 production, resulting in the mitigation of gastric epithelial cell inflammation. These results reveal that CdtC hijacks cholesterol to compete for H. pylori cytotoxin actions via lipid rafts, ameliorating H. pylori-induced pathogenesis.

Keywords: Helicobacter pylori; cytolethal distending toxin; cytotoxin-associated gene A; lipid rafts; vacuolating cytotoxin A.