An infectious bacterium: Helicobacter pylori Tony 10/07/2005

Condensed Matter Theory & Biophysics Lab

Condensed Matter Theory & Biophysics Lab Helicobacter pylori A spiral shaped, Gram- negative, microaerophilic, and flagellated bacterium, living in the stomach and duodenum About 3 microns long with a diameter of about 0.5 micron Causing up to 80% of peptic ulcers, more than 90% of duodenal ulcers, and some types of gastritis ( Rediscovered in 1982 by the laureates and made connection with stomach ulcers and gastritis Helicobacter pylori (blue bars, curved, 2-4 microns) localized in the mucus on the mucosa surface, at the intercellular lines. Photo: tangential section of the gastric mucosa

Condensed Matter Theory & Biophysics Lab Symptoms The most common ulcer symptom is burning pain in the epigastrium (the upper middle region of the abdomen). The pain typically occurs when the stomach is empty. Less common symptoms include nausea, vomiting, and loss of appetite. Bleeding can also occur. Recent studies have shown an association between long-term infection and the development of gastric cancer, which is the most common cancer in China.

Condensed Matter Theory & Biophysics Lab Epidemiology Approximately two-thirds of the world's population is infected with H. pylori.  70% - 90% in developing countries  25% - 50% in developed countries Over half the population is infected in early childhood in China. Most of those infected never have symptoms. The bacteria are most likely spread from person to person through fecal-oral or oral-oral routes. Possible environmental reservoirs include contaminated water sources. The source of H.pylori is not yet known.

Condensed Matter Theory & Biophysics Lab Pathogenicity H.pylori lives in the mucus lining to escape from the highly acidic gastric juice. (Its helical shape facilitates its penetration of the mucus layer.) It can fight the acid by excreting an enzyme called urease. The immune system responds to the infection by sending white cells, killer T cells, and other infection fighting agents. However, they cannot easily get through stomach lining to reach the infection. As the immune response grows, immune cells die and release destructive compounds on the stomach lining cells. Within a few days, gastritis and perhaps eventually a peptic ulcer results. Gastric epithelium Stomach acid

Condensed Matter Theory & Biophysics Lab Virulence factors Adhesion  adhesin-receptor interaction between BabA (from H.pylori) and Lewis b antigen, the blood group antigen expressed by gastric epithelial cells Colonization factors  Urease ureAb genes encode two units of the enzyme ureEFGH genes encode the accessory proteins responsible for incorporating nickel in the center of the enzyme ureI encodes the protein responsible for transport of urea  Phospholipase A & B Responsible for destruction of the protective mucous zone Loss of this protective barrier allows the stomach acid and digestive enzymes to have direct access to the gastric epithelium. Toxins  Cytotoxin associated gene A (CagA) Part of the cagPAI, a 40Kb DNA fragment containg between 27 and 31 genes. Injected into host cells and cause the deregulation of cell growth  Vacuolating cytotoxin A gene (VacA) The vacuolating cytotoxin can target several cellular types: gastric epithelial cells, macrophages, neutrophils and mast cells, and several cellular compartments  Secretion of VacA and injection of CagA to host cells ultimately induce the release of chemotactic cytokines, which recruit inflammatory cells to the area. H.Pylori has been divided into Type I and Type II strains based upon the presense of CagA and the secretion of VacA. O’Mahony et al., Sci Prog. 2004

Condensed Matter Theory & Biophysics Lab Treatment & Prevention Antibiotic  The currently accepted management for the eradication of H.pylori is a proton pump inhibitor combined with two antibiotics: clarithromycin and either amoxycillin or metronidazole (used in place of amoxycillin in those allergic to penicillin). Vaccine  Vaccines are being tested in animals and humans. It is very early days yet. Inhibitors of adhesion (some vegetables & plant fruits)  Cranberry juice  Seaweed Cladosiphon fucoidan  Spice turmeric  Fruit of okra plant

Condensed Matter Theory & Biophysics Lab Genome Two sequenced genomes available:  Strain  Strain J99 Genome size: ~1.6M bp  1,667,867 for strain Number of genes: ~1600  1609 for strain In silico model of metabolic network  Constructed by Palsson’s group at UCSD  341 metabolic genes  476 internal reactions  78 exchange reactions  485 metabolites

Condensed Matter Theory & Biophysics Lab The way to the prize Gastroenterologists resisted Marshall & Warren’s idea.  “It was hard for them to accept that the disease could be simple infection.” Drug companies that profited from the anti-ulcer drug market were so actively resistant. Bacteriologists were suspicious --- the stomach had long been assumed to be too acidic to host bacteria. In frustration, Marshall did the cause-and-effect experiment:  He swallowed a solution containing the bacteria, and came down with gastritis and ulcers. (He later recovered without treatment.) The critics has not been softened, because of his youth, and the fact that Royal Perth hospital has no strong academic reputation. In 1991, the centers for disease control and prevention declared a link between H.pylori and gastric disease. In 1994, the national institute of health published an opinion stating that most recurrent gastric ulcers were caused by H.pylori. In 2005, Warren & Marshall were awarded the nobel prize.

Condensed Matter Theory & Biophysics Lab Thank you for your attention!