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Pathogenic bacteria produce a variety of effectors and/or toxins, which subvert target cell/tissue functions in the infected hosts. Some of those effectors/toxins also perturb host defense mechanism, thereby making up more complicated pathophysiological conditions. Such bacterial effectors/toxins may have been positively selected during evolution because they directly strike vulnerable points in the host system. In turn, this indicates that systemic exploration of molecules and signaling pathways targeted by bacterial effectors/toxins provides a powerful tool in digging up an unexpected Achilles' heel(s), malfunctioning of which gives rise to disorders not restricted to infectious diseases. Based on this viewpoint, this review shows molecular basis underlying host susceptibility and vulnerability to diseases through the studies of host molecules targeted by bacterial effectors and toxins.

Helicobacter pylori infects human stomach and cause various gastric diseases including gastric cancer. The species is also known for rapid evolution and wide geographical diversity of genome sequence. Our team sequenced whole genome sequences of H. pylori strains isolated from Japanese patients and compared with whole genome sequences of H. pylori strains with other geographic origin and found that not only the gene repertoire but also genome structures and epigenetic modifications such as DNA methylations had large diversity with various mechanisms. Genome inversion events were geography specific and some of them were found to occur with gene duplication at their termini. DNA methylation states of H. pylori genomes suggested that they are diversified by both existence/absence repertoire of methyltransferase genes and by the movement of target recognition domain in the methyltransferase genes. Omics analysis revealed that methylation target sequence and transcriptome status are actually diversified by the domain sequence movement. We suggested that H. pylori utilizes these genome structure and methylome diversity for its adaptive evolution.

Chronic infection with Helicobacter pylori is involved in a variety of clinical outcomes including gastric cancer. In the present study, we focused on the infection strategies of H. pylori associated with establishment of chronic infection. As a result, the following four findings revealed. 1) alpha-ketoglutarate oxidoreductase (KOR) is an essential survival enzyme for energy metabolism in the coccoid form of H. pylori, and inactivation of the KOR activity exerted a potent bactericidal action against H. pylori by preventing induction of the coccoid form. 2) SodB expression is derepressed by amino acids mutation of ferric uptake regulator (Fur), which is associated with the development of Metronidazole resistance. 3) FecA1 is an important determinant of the host-colonization ability through Fe(2+) supply to SodB, suggesting that FecA1 may be a possible target for the development of a novel bactericidal drug. 4) Intracellular CagA oncoprotein is degraded by autophagy and therefore short lived. However, in the CD44v9-expressing gastric cells, CagA specifically accumulated through the repression of autophagy induction.

This year eradication of H. pylori was applied for not only peptic ulcer but also chronic gastritis on National insurance system. However recently decrease in first line eradication rate of H. pylori using PPI/AC regimen. Certainly eradication rate after 2000 decreased in intention to treat (ITT) and per protocol(PP) compared to that before 2000. This tendency was induced by increase in CAM-resistant H. pylori. But after 2007 eradication rate decreased only in ITT, eradication rate didn't decrease in PP. That tendency was induced by bad compliance and evaluation of the eradication.

Infection with Helicobacter pylori (Hp) is considered a prerequisite for gastric carcinogenesis and gastric mucosal atrophy that develops in association with the infection is a risk factor for gastric cancer. The gastric cancer risk can be diagnosed by the ABC classification consisted of a combination of serum Hp antibody and the pepsinogen (PG) method. The ABC classification may contribute to gastric cancer screening as well as to primary care of digestive organ practice. However, we should remember that we cannot diagnose the gastric cancer by only the ABC classification, and an imaging examination is required.

On a global scale, gastric carcinoma is the second leading course of the cancer-related deaths. Recent studies have provided evidence that cagA-positive Helicobacter pylori plays a causal role for the development of gastric carcinoma. The cagA-encoded CagA protein is delivered into H. pylori-attached gastric epithelial cells via the bacterial type IV secretion system (TFSS). Delivered CagA undergoes tyrosine phosphorylation by Src family kinases at the conserved EPIYA motifs and then specifically binds and deregulates SHP-2 tyrosine phosphatase, a bona fide oncoprotein involved in human malignancies. As a result, CagA causes aberrant mitogenic signal as well as elevated cell motility in gastric epithelial cells. Also, CagA specifically interacts with and inhibits PAR1b/MARK2 polarity-regulating kinase to disrupt tight junctions and cause loss of epithelial apical-basolateral cell polarity. These CagA activities have been suspected to play an important role in gastric carcinogenesis. Indeed, recently generated cagA-transgenic mice expressing CagA systemically developed gastrointestinal carcinomas as well hematopoietic malignancies such as myeloid leukemia and B-cell lymphoma. The observations collectively indicate that H. pylori CagA is the first identified bacterial oncoprotein involved in gastric carcinogenesis.

Helicobacter pylori (H. pylori) is a spiral gram-negative bacterium, characterized by positive urease, catalase and oxidase activity. The complete resolution of the full genome has elucidated the biological characteristics, the pathogenicity, and the bacterial evolution. The infection is acquired in childhood by oral-oral transmission in developed countries, probably an intra-familiar transmission. The infection has an association with chronic histological gastritis, peptic ulcer, gastric cancer and MALT lymphoma in the stomach. All patients with H. pylori infection have histological gastritis and most of them remain asymptomatic for life. Only a minority of the infected individuals occurs ulceration or gastric cancer. Cure of the infection prevents recurrence of peptic ulcer without persistent treatments against ulceration. Concerning gastric cancer, WHO concluded in 1994 that H. pylori is a definite carcinogen in humans on the basis of epidemiological studies. Evidences that the infection leads to the development of gastric cancer have been accumulated in animal models as well as in vitro experimental studies. Such clinical diversities are caused by variations of H. pylori pathogenicity, host susceptibility, environmental factors including foods and those interactions. At present, an eradication treatment of H. pylori, combined with a proton-pump inhibitor and two antibiotics (clarithromycin and amoxicillin) is restrictedly approved in the patients with gastric or duodenal ulcer by Japanese health care system.

H. pylori plays important roles in the pathogenesis of active gastritis, peptic ulcer, and gastric cancer. Culture of H. pylori from suspicious materials is one of gold standard methods for the diagnosis of its infection. H. pylori has two types of morphological manifestation, spiral (mobile) and coccoid (immobile) forms. Morphological conversion from spiral to coccoid form and its reversion may be important role in its pathophysiology including bacterial properties, pathogenicity, and etiology. However, the mechanism and significance of such transformation of H. pylori have remained unknown. In this chapter, we introduce the conventional and new culture methods of H. pylori and review the current knowledge regarding both two types of morphological manifestation and pathophysiological significance of such transformation.

Many virulence factors of Helicobacter pylori have been reported. Analysis of such virulence factors in relation to the occurrence of gastroduodenal diseases is discussed. Several adhesins of H. pylori are involved in its adhesion to gastric epithelial cells, and urease activity is necessary for its colonization in acidic gastric mucosa. Vacuolation cytotoxin(VacA)-positive Type I strains are frequently isolated from the patients with peptic ulcer diseases in western countries, but not in east Asia. CagA has been reported to be transported into epithelial cells through type IV secretion machinery coded by genes in cag pathogenicity island(PAI) and phosphorylated by cellular tyrosine kinase. Heat shock protein is also considered to be a virulence factor to play a role of triggering autoimmune response, stimulating its adhesion and inducing several cytokines.

H. pylori is a well-recognized pathogen that infects up to 50% of humans in the world. H. pylori lives for decades in the hostile environment of the human stomach. H. pylori is closely associated with histologic gastritis, gastric ulceration, duodenal ulceration, gastric cancer and MALT lymphoma. These various clinical outcomes are considered by 1) different virulence, 2) host response, 3) other environmental factors, and their interactions. Since the whole genome was sequenced in 1997, the virulence genes have been investigated in molecular genetic aspects. The cag pathogenicity island (cagPAI) is a complex of virulence genes, which code approximately 30 proteins. The cagPAI acquired by horizontal transfer and is coding for type 4 secretion machinery system. Via this system, many virulence gene products or other interactive proteins are transferred into the host cells.

To understand pathogenesis of H. pylori in stomach diseases including gastric cancer, molecular bacteriological studies are important. The studies are greatly advanced by information of the whole genome sequence of this bacterium in 1997. Various methods of gene manipulation to identify the genes involved in pathogenesis are now available such as transformation followed by construction of knockout mutants, complementation using H. pylori-E. coli shuttle vectors, random insertion mutagenesis, and RT-PCR or proteome analysis of in vivo-expressed genes. The molecular mechanism of persistent infection of H. pylori is discussed in light of recent findings on molecular mechanisms of bacterial attachment and colonization as well as on gastric physiology.

Helicobacter pylori strains are divided into two broad families, type I and type II, based on whether or not they possess the cag pathogenicity island (cagPAI). It has been suggested that cagPAI is inherited by horizontal transfer from an unknown microorganism, and the genes of cag are thought to be encoded by a putative type IV secretory system. In addition, CagA may be delivered from attached H. pylori into the host crytoplasm by this system and is tyrosine phosphorylated in gastric epithelial cells. The phosphorylated CagA may play a crucial role in promoting the inflammatory responses of gastric mucosa. These findings suggest that type I H. pylori is a pathogenic H. pylori.