BabA-mediated Adherence Is a Potentiator of the Helicobacter pylori Type IV Secretion System Activity

• Published in: The Journal of biological chemistry 2011-07, Vol.286 (28), p.25256-25264
• Main Authors: Ishijima, Nozomi, Suzuki, Masato, Ashida, Hiroshi, Ichikawa, Yusuke, Kanegae, Yumi, Saito, Izumu, Borén, Thomas, Haas, Rainer, Sasakawa, Chihiro, Mimuro, Hitomi
• Format: Article
• Language: English
• Subjects: Adhesins, Bacterial - genetics; Adhesins, Bacterial - metabolism; Adhesion; Animals; BabA; Bacteria; Bacterial Adhesion - physiology; Bacterial Secretion Systems - physiology; Cancer Tumor Promoter; Carbohydrate; Carbohydrate-binding Protein; Chemokine CCL5 - biosynthesis; Chemokine CCL5 - genetics; CHO Cells; Cricetinae; Cricetulus; Dogs; Gastric Mucosa - immunology; Gastric Mucosa - metabolism; Gastric Mucosa - pathology; Gene Deletion; Glycoconjugate; Helicobacter Infections - genetics; Helicobacter Infections - metabolism; Helicobacter pylori; Helicobacter pylori - pathogenicity; Helicobacter pylori - physiology; Homeodomain Proteins - biosynthesis; Homeodomain Proteins - genetics; Humans; Inflammation - genetics; Inflammation - metabolism; Inflammation - microbiology; Inflammation - pathology; Interleukin-8 - biosynthesis; Interleukin-8 - genetics; Lewis Blood Group Antigens - genetics; Lewis Blood Group Antigens - metabolism; Metaplasia - genetics; Metaplasia - metabolism; Metaplasia - microbiology; Metaplasia - pathology; Microbiology; Mucin-2 - biosynthesis; Mucin-2 - genetics; Precancerous Conditions - genetics; Precancerous Conditions - metabolism; Precancerous Conditions - microbiology; Precancerous Conditions - pathology; Signal Transduction; Signal Transduction - genetics; Type IV Secretion System
• ISSN: 0021-9258; 1083-351X; 1083-351X
• DOI: 10.1074/jbc.M111.233601

Chronic infection of Helicobacter pylori in the stomach mucosa with translocation of the bacterial cytotoxin-associated gene A (CagA) effector protein via the cag-Type IV secretion system (TFSS) into host epithelial cells are major risk factors for gastritis, gastric ulcers, and cancer. The blood group antigen-binding adhesin BabA mediates the adherence of H. pylori to ABO/Lewis b (Leb) blood group antigens in the gastric pit region of the human stomach mucosa. Here, we show both in vitro and in vivo that BabA-mediated binding of H. pylori to Leb on the epithelial surface augments TFSS-dependent H. pylori pathogenicity by triggering the production of proinflammatory cytokines and precancer-related factors. We successfully generated Leb-positive cell lineages by transfecting Leb-negative cells with several glycosyltransferase genes. Using these established cell lines, we found increased mRNA levels of proinflammatory cytokines (CCL5 and IL-8) as well as precancer-related factors (CDX2 and MUC2) after the infection of Leb-positive cells with WT H. pylori but not with babA or TFSS deletion mutants. This increased mRNA expression was abrogated when Leb-negative cells were infected with WT H. pylori. Thus, H. pylori can exploit BabA-Leb binding to trigger TFSS-dependent host cell signaling to induce the transcription of genes that enhance inflammation, development of intestinal metaplasia, and associated precancerous transformations.