An%20infectious%20bacterium:%20Helicobacter%20pylori

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An infectious bacterium Helicobacter pylori

• Tony
• 10/07/2005

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http//nobelprize.org/medicine/laureates/2005/inde
x.html
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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 (http//www.cdc.org)
• 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
http//www.pathologyatlas.ro/Helicobacter20pylori
.html
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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.

http//www.cdc.gov/ulcer/md.htm
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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.

http//www.cdc.gov/ulcer/md.htm
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Pathogenicity
Stomach acid

• 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
http//www.helico.com/
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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.
OMahony et al., Sci Prog. 2004
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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

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Genome

• Two sequenced genomes available
• Strain 26695
• Strain J99
• Genome size 1.6M bp
• 1,667,867 for strain 26695
• Number of genes 1600
• 1609 for strain 26695
• In silico model of metabolic network
• Constructed by Palssons group at UCSD
• 341 metabolic genes
• 476 internal reactions
• 78 exchange reactions
• 485 metabolites

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The way to the prize

• Gastroenterologists resisted Marshall Warrens
  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.

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Thank you for your attention!