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Helicobacter pylori
Helicobacter pylori is a bacterium that infects the mucus
lining of the human stomach. It belongs among the proteobacteria.
Many peptic ulcers and some types of gastritis are caused by
H. pylori infection, although most humans are infected and many
infections do not lead to any symptoms. Treatment of these diseases
now often includes antibiotics. Long term infection with the
bacterium may also be associated with gastric cancer.
About 2/3 of the world population are infected by the bacterium.
Under poor sanitory conditions, one commonly finds infected
children; in the U.S., older people (about 50% of those over
the age of 60, 20% of those under the age of 40) and poor people
are more likely to be infected. The infection apparently persists
for life; the immune system cannot fend off the organism. The
bacteria have been isolated from feces, saliva and dental plaque
of infected patients, which suggests possible transmission routes.
One can test for H. pylori infection with blood antibody tests,
breath tests (where the patient drinks 14C or 13C labeled urea,
which the bacterium metabolizes to carbon dioxide that can be
detected in the breath), or endoscopy.
Helicobacter pylori
H. pylori is a spiral-shaped gram-negative bacteria, about
3 micrometers long with a diameter of about 0.5 micrometers.
It has 4-6 flagella. It is microaerophilic, i.e. it requires
oxygen but at lower levels than those contained in the atmosphere.
Genome studies
Several strains are known, and the genomes of two have been
completely sequenced. The Pylori Gene website allows easy access
to genome information for the H. pylori 26695 and H. pylori
J99 strains. There are 62 genes in the "pathogenesis" category
of this database. Both of these sequenced strains have an approximately
40 kb long Cag pathogenicity island that contains over 40 genes.
This pathogenicity island is usually absent from H. pylori strains
isolated from humans who are carriers of H. pylori but remain
asymptomatic.
Study of the H. pylori genome is centered on attempts to understand
the ability of this organism to cause disease. The cagA gene
codes for one of the major H. pylori virulence proteins. Bacterial
strains that have the cagA gene are associated with an ability
to cause severe ulcers. The cagA gene codes for a relatively
long (1186 amino acid) protein. The CagA protein is transported
into human cells where it may disrupt the normal functioning
of the cytoskeleton. The Cag pathogenicity island has about
30 genes that code for a complex type IV secretion system. After
attachment of H.pylori to stomach epithelial cells the CagA
protein is injected into the epithelial cells by type IV secretion
system. The CagA protein is phosphorylated on tyrosine residues
by a host cell membrane-associated tyrosine kinase. Pathogenic
strains of H. pylori have been shown to activate the epidermal
growth factor receptor (EGFR), a membrane protein with a tyrosine
kinase domain. Activation of the EGFR by H. pylori is associated
with altered signal transduction and gene expression in host
epithelial cells that may contribute to pathogenesis. It has
also been suggested that a c-terminal region of the CagA protein
(amino acids 873-1002) can regulate host cell gene transcription
independent of protein tyrosine phosphorylation.
Additional physiology
With its flagella and its spiral shape, it drills through
the mucus layer of the stomach and attaches to epithelial cells.
It contains the enzyme urease which converts urea into ammonia
and bicarbonate. The ammonia is useful to the bacterium since
it partially neutralizes the very acidic environment of the
stomach (whose very purpose is to kill bacteria). Ammonia is
however toxic to the epithelial cells. A molecular model of
the H. pylori urease enzyme is shown to the right.
Gastric cancer (rare) has been associated with H. pylori. Two
related mechanisms by which H. pylori can promote cancer are
under investigation. One mechanism involves the enhanced production
of free radicals near H. pylori and an increased rate of host
cell mutation. The other proposed mechanism has been called
a "perigenetic pathway" [1] and involves enhancement of the
transformed host cell phenotype by means of alterations in cell
proteins such as adhesion proteins. It has been proposed that
H. pylori induces in inflammation and locally high levels of
TNF-alpha. According to the proposed perigenetic mechanism,
inflammation-associated signaling molecules such as TNF-alpha
can alter gastric epithelial cell adhesion and lead to the dispersion
and migration of mutated epithelial cells without the need for
additional mutations in tumor suppressor genes such as genes
that code for cell adhesion proteins.
History
The bacterium and its link to peptic ulcers was described
first in 1982 by two Australian researchers: Robin Warren and
Barry Marshall. Before the discovery, stress or diet were considered
the primary causes of these ulcers. They were treated with drugs
that neutralize stomach acid or decrease its production. While
this worked well, the ulcers very often reappeared. Acceptance
in the medical community of the role of H. pylori was slow.
In 1994, the NIH conducted a conference which ended with a consensus
statement affirming the causative role of H. pylori in these
diseases.
The bacterium was initially called Campylobacter pyloridis,
then C. pylori and finally placed in its own genus Helicobacter.
Some other species of that genus have now been identified in
the stomachs of other mammals and some birds.
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