Department of Bacteriology

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.


  • Senior Assistant Professor Akihiro Wada
  • Assistant professor Masayuki Nakano
  • Assistant Yoshiki Tsutada


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 proteincoupled receptor kinase-interactor 1 (Git 1), which may be responsible for epithelial cell detachment caused by VacA, leading to peptic ulceration [3], and VacAinduced activation of p38/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 m1 VacA and m2 VacA, which were defined by sequence differences in the middle of the molecules, interacted with target cells by binding to two types of receptor-like protein tyrosine phosphatases (RPTPs), i. e., RPTPα and RPTPβ, resulting in toxin internalization and vacuolation of the human gastric adeno-carcinoma cell lines AZ-521 and G401 [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].
More recently, we purified from AZ-521 cells, a human gastric epithelial cell line, a surface membrane protein, p500, which binds VacA, and identified it as low-density lipoprotein receptor-related protein-1 (LRP1). LRP1 binding of VacA was shown to be specifically responsible for VacA-induced autophagy and apoptosis, but not activation of the Wnt/β-catenin signaling pathway. Similar to RPTPα and RPTPβ, LRP1 mediates VacA internalization in AZ-521 cells, but in contrast to RPTPα and RPTPβ, LRP1 targeted downstream pathways leading to autophagy and apoptosis. VacA-induced autophagy via LRP1 binding precedes apoptosis suggesting that an excessive autophagic activity can also lead to cell death. This is the first study to provide evidence that LRP1 mediates autophagy [8]. Surprisingly, CagA, which is an oncogenic protein injected by its type IV secretion system into host cells, was degraded by autophagy induced by m1 VacA, but not m2 VacA, whereas CagA in CD44v9-expressing cancer stem-like cells escaped this autophagy system, resulting in accumulation of CagA in cells [9].

[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] J. Biol. Chem. 287:3104-3115, 2012,
[9] Cell Host Microbe. 12: 764-777. 2012.

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