Download An infectious disease

An infectious bacterium:
Helicobacter pylori
Tony
10/07/2005
http://nobelprize.org/medicine/laureates/2005/index.html
Condensed Matter Theory & Biophysics Lab
Helicobacter pylori
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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
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A spiral shaped, Gramnegative, 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
http://www.pathologyatlas.ro/Helicobacter%20pylori.html
Condensed Matter Theory & Biophysics Lab
Symptoms
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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
Condensed Matter Theory & Biophysics Lab
Epidemiology
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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
Condensed Matter Theory & Biophysics Lab
Pathogenicity
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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.
http://www.helico.com/
Gastric epithelium
Condensed Matter Theory & Biophysics Lab
Virulence factors
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Adhesion
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adhesin-receptor interaction between BabA (from H.pylori) and Lewis b antigen, the blood group
antigen expressed by gastric epithelial cells
Colonization factors
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Urease
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Phospholipase A & B
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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
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
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Cytotoxin associated gene A (CagA)
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Vacuolating cytotoxin A gene (VacA)
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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
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
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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
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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 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
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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!
Condensed Matter Theory & Biophysics Lab