Department of Bacteriology
Our major research interest is to elucidate the etiologic agents isolated from pathogenic bacteria related to the worldwide emerging and reemerging diseases and to know the virulence mechanisms of bacterial pathogens.
Members
- Professor Toshiya Hirayama
- Senior Assistant Professor Akihiro Wada
- Assistant professor Masahiko Ehara
- Technologist Mamoru Iwami
- Technician Kayo Maeda
- Postdoctral Fellow Masaaki Nakayama
- Postgraduate Student Jyunzo Hisatsune
To the Site of our department»
Activities
Helicobacter pylori is a bacterial pathogen found in the stomach mucosa of more than 50% of the world population and more common (over 80%) in developing and tropical countries. Infection with H. pylori plays a major role in the development of chronic gastritis and peptic ulcer, and is a risk factor for gastric cancer. Pathogenic strains of H. pylori secrete a potent protein toxin, a vacuolating cytotoxin, termed VacA, which causes progressive vacuolation of epithelial cells and gastric injury. We found that VacA induces multiple effects on epithelial cells, including mitochondrial damage [1] and apoptosis [2] .These actions of VacA appear to result from activation of cellular pathways, independent of those leading to vacuolation. Similarly, VacA-induced phosphorylation of G protein-coupled receptor kinase-interactor 1 (Git 1), which may be responsible for epithelial cell detachment caused by VacA, leading to peptic ulceration [3], and VacA-induced activation of p 38/ATF-2-mediated signal pathway [4] are independent of VacA effects on cellular vacuolation. Analysis of VacA receptors provided new insights into the molecular basis of VacA function. We reported that two VacA proteins, termed m 1 VacA and m 2 VacA, which were defined by sequence differences in the middle of the molecules, interacted with target cells by binding to two types of receptorlike protein tyrosine phosphatases (RPTPs), i. e., RPTPα and RPTPβ, resulting in toxin internalization and vacuolation of the human gastric adenocarcinoma cell lines AZ-521 and G 401 [5, 6, 7]. By analysis of the pathological responses of wild type and RPTPβ-deficient mice to oral administration of VacA, we found that RPTPβ functions as a receptor for VacA and produces the disease associated with VacA toxicity including gastritis and gastric ulcer [3]. Receptor-dependent translocation of VacA to lipid rafts is critical for signaling pathways leading to p 38 MAP kinase/ATF-2 activation and vacuolation [8]. To know a potential mechanism of how H. pylori establishes infection, we also investigate the hostparasite relationships of H. pylori , focusing on VacA as well as CagA, which is an effecter protein injected by its typesecretion system into host cells. C onsistent with suppression of nuclear translocation of nuclear factor of activated T cells, NFAT, in Jurkat T cells, VacA counteracted CagA-induced activation of NFAT in AGS cells, suggesting that the two major H. pylori virulence factors inversely control NFAT activity [9]. Deregulation of NFAT, either positively or negatively, may contribute to cellular dysfunctions that underlie diverged clinical manifestations caused by H. pylori infection.
References:
[1] Microb. Pathog. 31: 29-36, 2001, [2] J. Biol. Chem. 281, 11250-11259, 2006,
[3] Nat. Genet. 33: 375-381, 2003, [4] J. Biol. Chem. 279, 7024-7028, 2004,
[5] J. Biol. Chem. 278: 19183-19189, 2003, [6] J. Biol. Chem. 279: 51013-51021, 2004,
[7] Cell Microbiol 7, 1285-293, 2005, [8] Infect Immun. 74, 6571-65 80, 2006,
[9] Proc. Natl. Acad. Sci. USA. 102, 9661-9666, 2005.
