Helicobacter pylori attachment-blocking antibodies protect against duodenal ulcer disease.

The majority of the world population carry the gastric pathogen Helicobacter pylori. Fortunately, most individuals experience only low-grade or no symptoms, but in many cases the chronic inflammatory infection develops into severe gastric disease, including duodenal ulcer disease and gastric cancer. Here we report on a protective mechanism where H. pylori attachment and accompanying chronic mucosal inflammation can be reduced by antibodies that are present in a vast majority of H. pylori carriers. These antibodies block binding of the H. pylori attachment protein BabA by mimicking BabA's binding to the ABO blood group glycans in the gastric mucosa. However, many individuals demonstrate low titers of BabA blocking antibodies, which is associated with an increased risk for duodenal ulceration, suggesting a role for these antibodies in preventing gastric disease.

Helicobacter pylori Genetic Polymorphisms in Gastric Disease Development.

Infecting half of the world's population, Helicobacter pylori is a medically important bacterium that induces a variety of gastric diseases, including gastritis, peptic ulcer disease, and gastric cancer. Sequencing of almost 1000 H. pylori isolates has revealed a diverse genome that contains abundant polymorphic genetic elements; many of these lie in factors likely to be associated with virulence. To ascertain the effect of these varying genetic elements, numerous epidemiological studies have investigated the contribution of the various polymorphisms to gastric disease development; particular focus has been placed on polymorphisms in the outer membrane proteins (OMPs), an effector protein, and a toxin produced by H. pylori. These studies have revealed geographic variation in the prevalence of various polymorphisms as well as in the associations between particular polymorphisms and gastric disease development. Furthermore, researchers have identified polymorphisms in multiple genes that frequently occur in combination. Though no single polymorphic genetic factor alone can fully account for gastric disease development in a population, the evaluation of multiple polymorphisms in a colonizing H. pylori strain can aid in the assessment of the pathogenic potential of the strain. Here we review specific H. pylori genetic polymorphisms (Bab proteins, Hom proteins, HopQ, SabA, SabB, OipA, IceA, VacA and CagA) that have been linked to disease outcome and discuss how geographic location and virulence factor polymorphisms together contribute to H. pylori-induced disease.

Helicobacter pylori Adapts to Chronic Infection and Gastric Disease via pH-Responsive BabA-Mediated Adherence.

The BabA adhesin mediates high-affinity binding of Helicobacter pylori to the ABO blood group antigen-glycosylated gastric mucosa. Here we show that BabA is acid responsive-binding is reduced at low pH and restored by acid neutralization. Acid responsiveness differs among strains; often correlates with different intragastric regions and evolves during chronic infection and disease progression; and depends on pH sensor sequences in BabA and on pH reversible formation of high-affinity binding BabA multimers. We propose that BabA's extraordinary reversible acid responsiveness enables tight mucosal bacterial adherence while also allowing an effective escape from epithelial cells and mucus that are shed into the acidic bactericidal lumen and that bio-selection and changes in BabA binding properties through mutation and recombination with babA-related genes are selected by differences among individuals and by changes in gastric acidity over time. These processes generate diverse H. pylori subpopulations, in which BabA's adaptive evolution contributes to H. pylori persistence and overt gastric disease.

Antibiotic treatment decreases microbial burden associated with pseudomyxoma peritonei and affects ß-catenin distribution.

PURPOSE: Pseudomyxoma peritonei is an understudied cancer in which an appendiceal neoplasm invades the peritoneum and forms tumor foci on abdominal organs. Previous studies have shown that bacteria reside within pseudomyxoma peritonei tumors and mucin. Thus, we sought to analyze the effect of antibiotics on bacterial density and ß-catenin expression within pseudomyxoma peritonei samples. EXPERIMENTAL DESIGN: The study included 48 patients: 19 with disseminated peritoneal adenomucinosis (DPAM) and 29 with peritoneal mucinous carcinomatosis (PMCA). Fourteen patients were given antibiotics (30 mg lansoprazole, 1 g amoxicillin, and 500 mg clarithromycin) twice a day for 14 days. One week after completion of therapy, surgery was conducted and specimens were harvested for pathology, bacterial culture, ISH, and immunohistochemistry. RESULTS: ISH showed the presence of bacteria in 83% of the patient samples, with a higher Helicobacter pylori density observed in PMCA versus DPAM. PMCA patients treated with antibiotics had a significantly lower bacterial density and decreased ß-catenin levels in the cytoplasm, the cell nuclei, and mucin-associated cells. Although not significant, similar trends were observed in DPAM patients. Cell membrane ß-catenin was significantly increased in both DPAM and PMCA patients receiving antibiotics. CONCLUSIONS: Bacteria play an important role in pseudomyxoma peritonei. Antibiotic treatment improved the histopathology of tissue, particularly in PMCA patients. In PMCA, antibiotics decreased bacterial density and were associated with a significant ß-catenin decrease in the cytoplasm, cell nuclei, and mucin along with a small membrane increase. These results suggest that antibiotics offer potential protection against cell detachment, cellular invasion, and metastasis.

Successful culture techniques for Helicobacter species: general culture techniques for Helicobacter pylori.

Half of the world's population is persistently infected with Helicobacter pylori. The chronicity of this infection ultimately elicits clinical manifestations ranging from gastritis and peptic ulcers to adenocarcinoma and MALT lymphoma. Laboratory research following the initial observations of Helicobacter species was greatly hindered by an inability to isolate and culture the bacteria. Thus, the ability to culture bacterial species from this genus is an extremely important step in expanding clinical knowledge and development of therapies. This chapter describes successful techniques for culturing H. pylori on selective horse blood agar media and in Brucella broth liquid media. Additionally, the specific growth requirements of other Helicobacter species are noted.

A Tale of Two Toxins: Helicobacter Pylori CagA and VacA Modulate Host Pathways that Impact Disease.

Helicobacter pylori is a pathogenic bacterium that colonizes more than 50% of the world's population, which leads to a tremendous medical burden. H. pylori infection is associated with such varied diseases as gastritis, peptic ulcers, and two forms of gastric cancer: gastric adenocarcinoma and mucosa-associated lymphoid tissue lymphoma. This association represents a novel paradigm for cancer development; H. pylori is currently the only bacterium to be recognized as a carcinogen. Therefore, a significant amount of research has been conducted to identify the bacterial factors and the deregulated host cell pathways that are responsible for the progression to more severe disease states. Two of the virulence factors that have been implicated in this process are cytotoxin-associated gene A (CagA) and vacuolating cytotoxin A (VacA), which are cytotoxins that are injected and secreted by H. pylori, respectively. Both of these virulence factors are polymorphic and affect a multitude of host cellular pathways. These combined facts could easily contribute to differences in disease severity across the population as various CagA and VacA alleles differentially target some pathways. Herein we highlight the diverse types of cellular pathways and processes targeted by these important toxins.

Polymorphism in the CagA EPIYA motif impacts development of gastric cancer.

Helicobacter pylori causes diseases ranging from gastritis to peptic ulcer disease to gastric cancer. Geographically, areas with high incidences of H. pylori infection often overlap with areas with high incidences of gastric cancer, which remains one of the leading causes of cancer-related deaths worldwide. Strains of H. pylori that carry the virulence factor cytotoxin-associated gene A (cagA) are much more likely to be associated with the development of gastric cancer. Moreover, particular C-terminal polymorphisms in CagA vary by geography and have been suggested to influence disease development. We conducted a large-scale molecular epidemiologic analysis of South Korean strains and herein report a statistical link between the East Asian CagA EPIYA-ABD genotype and the development of gastric cancer. Characterization of a subset of the Korean isolates showed that all strains from cancer patients expressed and delivered phosphorylatable CagA to host cells, whereas the presence of the cagA gene did not strictly correlate to expression and delivery of CagA in all noncancer strains.

Balancing the double-edged sword: metal ion homeostasis and the ulcer bug.

The essential nature of many metals is counterbalanced by the toxic effect that they can exert on both the eukaryotic and prokaryotic cell when not properly controlled. As such, virtually all organisms have developed regulatory systems that are required to maintain metal ion homeostasis. Helicobacter pylori is arguably the most successful bacterial pathogen in the world; the bacterium colonizes more than 50% of the world's population. H. pylori lives in the acidic environment of the stomach and causes a persistent infection that results in disease sequelae such as gastritis, iron-deficiency anemia, ulcer disease and gastric cancer. A requirement of colonization is that the bacterium successfully competes with host cells for available metal ions. As such, it is perhaps no surprise that several crucial colonization factors utilize metal as an essential cofactor. Recent investigations into the absolute requirement for different metal ions and the need to manage their use have shown that metal ion homeostasis is achieved by H. pylori through the utilization of an intricate regulatory cascade that ensures metal uptake without toxic side effects. Herein we discuss this cascade, the role that individual metal ions play in H. pylori colonization and disease and the possibility that these metal homeostasis cascade components may serve as good targets for rational drug design to eradicate H. pylori infection.