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| A BACTERIAL CARCINOGEN - HELICOBACTER PYLORI Author: Course # DL-957 © California Association for Medical Laboratory Technology.
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A BACTERIAL CARCINOGEN - HELICOBACTER PYLORI
OBJECTIVES:
Upon completion of this course the participant will be able to
- Describe the principal characteristics of Helicobacter pylori and its habitat
- Outline methods of isolation and identification
- Explain the role of H. pylori in human disease
- List suggested treatment protocol
- Describe virulence factors and discuss host response to infection
- List diagnostic methods currently in use
- Explain the epidemiology of infection in underdeveloped and in developed countries
- Discuss the current prevalence of infection and future trends
- List animal models of infection
- Outline the current status of vaccine development
INTRODUCTION AND HISTORICAL BACKGROUND
Infection with Helicobacter pylori is one of the most common bacterial
infections of humans. The infection is generally acquired early in life and
has a particularly high incidence in countries with poor hygiene conditions.
The bacterium colonizes the gastric mucosa leading to a life-long infection.
A minority of infected individuals develop serious gastrointestinal diseases:
chronic gastritis, gastroduodenal ulcers, adenocarcinoma, and lymphoma.
Extensive seroepidemiologic studies have shown an increased risk of gastric cancer in persons infected with H. pylori. Based on such studies the International Agency for Research on Cancer classified H. pylori as a type I carcinogen in 1994 (1).
The association of H. pylori with the development of gastric and duodenal ulcers has had a profound impact on the diagnosis and treatment of upper gastroduodenal diseases; gastric ulcer is now regarded an infectious disease that can be controlled with antibiotic treatment.
Early studies:
The presence of spiral-shaped bacteria in gastric washings and in the lining
of human stomachs was first observed in the late 19th century. These bacteria
were re-discovered in the early 1980s when Robin Warren and Barry Marshall
were able to culture the unknown bacteria from stomach biopsy specimens taken
from ulcer patients. In order to demonstrate the role of these bacteria in
gastric disease Barry Marshall infected himself by drinking some of the bacterial
culture. Symptoms of gastritis developed and spiral-shaped bacteria were recovered
from his stomach lining, satisfying some of the four Koch’s postulates.
Marshall and Warren’s discovery that a bacterium was responsible for
most cases of gastric disease was recognized in 2005 when they were awarded
the Nobel Prize in physiology or medicine
.
The spiral-shaped bacteria were originally named Campylobacter pyloridis (later
changed of C. pylori). Subsequent studies involving partial sequencing of
bacterial 16S RNA yielded evidence that the isolate belonged to a genus separate
from Campylobacter. This was confirmed by nucleic acid hybridization
profiles, growth characteristics, fatty acid profiles, and enzymatic activities
of the isolate. The genus Helicobacter was established in 1989 and
C. pylori was renamed Helicobacter pylori. In 1994 the Helicobacter
pylori genome was sequenced. This information made possible genotypic
analysis of isolates from infected family members, thus greatly facilitating
epidemiologic studies of H. pylori infection.
The helicobacters are Gram negative rods that colonize the mammalian gastrointestinal tract. Close to two dozen species are included in the genus; of these, H. pylori, H. cinaedi, and H. fennelliae are human pathogens. The habitat for H. cinaedi and H. fennelliae is, most probably, the human gastrointestinal tract. These two species may cause proctitis, enteritis, septicemia, and occasionally, cellulitis and meningitis in immunocompromised patients.
ECOLOGY OF H. pylori AND ITS PRINCIPAL CHARACTERISTICS
H. pylori occurs worldwide; infection is usually acquired in early
childhood. It is estimated that by adulthood over half the world population
is infected. Although primarily a human pathogen, H. pylori has been
found to colonize the stomachs of some non-human primates. For example, captive
rhesus monkeys are commonly infected with H. pylori. This infection
is almost universal in adult animals and appears to be acquired at a very
early age. The consequence of H. pylori infection is a chronic gastritis,
which is similar to that observed in human patients. A few animals develop
atrophic gastritis, a histologic precursor to gastric adenocarcinoma. The
monkeys develop specific cellular immunity and circulating antibody; this
immune response, however, is not sufficient to clear the infection. This resembles
the course of H. pylori infection observed in humans (2).
The primary habitat of H. pylori is human gastric mucosa where it
penetrates the mucous layer and attaches to the epithelial cells but does
not invade the epithelium. The bacterium is well-adapted to its ecologic niche.
It possesses attributes that permit its entry into the mucous layer, attachment
to epithelial cells, neutralization of the acid pH of the stomach, and evasion
of the immune response.
Principal Characteristics:
Morphologically H. pylori has many characteristics in common with
campylobacters; both genera are Gram negative, have a spiral or helical shape,
and are motile by a tuft of polar flagella (3). There is considerable genetic
variability among H. pylori strains with marked variation in virulence.
H. pylori grows best at neutral pH; it is microaerophilic and will grow in the presence of 5% carbon dioxide. Enriched medium supplemented with antibiotics is used, such as Brucella agar with 5% calf serum and the antibiotics trimethoprim, vancomycin, and polymyxin. Other suitable media include Skirrow’s medium with antibiotics (as in Brucella agar), or chocolate agar with vancomycin, nalidixic acid, and amphotericin. Pinhead-sized, translucent colonies appear in 3 to 7 days. Microscopy and biochemical tests demonstrate curved Gram negative organisms that are oxidase positive, catalase positive, and urease positive. The urease reaction is strong and rapid; this reaction is one of the main identifying features of H. pylori.
ROLE OF H. pylori IN HUMAN DISEASE
Identification of clinical consequences of H. pylori infection is
one of the major discoveries in gastroenterology within the past twenty years.
Human gastric mucosa is the natural ecologic niche of H. pylori;
however, unlike the commensal microorganisms that inhabit mucosal surfaces,
H. pylori is capable of causing inflammation and disease at the site
of infection. The inflammatory process does not lead to clearance of this
infection. Possibly this pathogen has adapted to colonization of inflamed
mucosal surfaces, making inflammation a prerequisite to prolonged colonization.
The majority of infected individuals do not suffer from associated gastrointestinal
disease, but a proportion of infected persons develop acute gastritis, peptic
ulcer disease, mucosa-associated lymphoid tissue lymphoma (MALT), or gastric
adenocarcinoma. H. pylori infection is considered a major cause of
these conditions.
Colonization of gastric mucosa - pathogenesis of H. pylori infection
This pathogen, assisted by polar flagella, colonizes the mucous layer overlying
the gastric epithelium, penetrates the mucous layer, but does not invade the
epithelium. The bacterium persists in the gastric mucosa and causes tissue
damage. Its location within the mucous layer helps it escape the acid environment
of the stomach. H. pylori has acid-responsive genes expressed under
acidic conditions: at pH5.5 the transcriptional activity of ammonia-producing
enzymes is increased from four to nine-fold. Urease, in particular, is produced
in abundance and creates a more alkaline microenvironment.
H. pylori adhesins (bacterial outer membrane proteins) enable the pathogen to bind to fucose-containing H and Lewis blood group antigens found in the gastrointestinal mucosa. It is noteworthy that blood type O persons are at a higher risk for ulcer disease than persons whose blood types are A, B, or AB.
H. pylori adherence to stomach mucosa attracts inflammatory and lymphoid cells. Presence of lymphoid cells in gastric mucosa is evidence of persistent inflammation, which can eventually lead to the destruction of normal epithelium, the loss of the mucous layer, and an increased cell turnover. This condition is called atrophic gastritis and is a serious risk for stomach cancer.
Consequences of H. pylori infection
The ability of the gastric mucosa to secrete acid affects the outcome of H.
pylori infection. A higher acid output is likely to lead to ulceration;
with a lower output, either gastric cancer or gastric ulcer may develop. Cytokines
produced during inflammation may affect acid production; for example, interleukin
1-beta is acid-suppressive. This cytokine is commonly produced during a microbial
infection and may play a role in the outcome of H. pylori infections
in developing countries.
Gastritis
In children, H. pylori gastritis appears to be asymptomatic. Adult
patients may have acute dyspeptic symptoms, including pain, nausea, and indigestion;
the symptoms usually last several days to two weeks. Eradication of the pathogen
reduces symptoms in some but not in all patients, suggesting that factors
other than H. pylori infection may cause dyspeptic symptoms in a
general patient population.
Ulcers
Approximately 10% of persons infected with H. pylori develop gastric
or duodenal ulcers. The incidence of ulcers varies with geographic region
and ranges from 3% to 25%. An on-going H. pylori infection is a major
factor in ulcer disease.
Gastric malignancy
A. Gastric lymphoma
H. pylori - related low-grade gastric MALT lymphoma represents the
first described neoplasm susceptible of regression following antibiotic therapy.
Tumor cells of MALT lymphoma are memory B cells still responsive to differentiation
signals and to cytokines produced by antigen-stimulated T-helper cells. These
B cells are dependent on stimulation by H. pylori–specific
T cells for their growth. Eradication of H. pylori infection is a
major factor in regression of MALT lymphoma.
B. Gastric adenocarcinoma
This is one of the leading causes of cancer-related deaths in the world and
is the fifth or sixth most common cause of newly diagnosed cancer in some
European countries. The risk of developing gastric adenocarcinoma is increased
by a factor of two in persons infected with H. pylori. The genotype of the
infecting strain is important, as well as a number of host factors. For instance,
strains with the cytotoxin-associated gene are implicated more frequently
in gastric cancer. Among host-related factors the acquisition of infection
at a very early age, a positive family history of gastric cancer, and bacterial–host
genotype interaction appear important in cancer development.
Other conditions associated with H. pylori infection:
Gastric atrophy may develop in H. pylori infected persons; this condition
shows a relationship to autoimmune chronic gastritis. The latter is an organ
specific inflammatory disease leading to gastric atrophy, hypochloridria,
and eventually to pernicious anemia. In genetically susceptible persons H.
pylori infection can activate cross-reactive gastric T cells leading
to gastric autoimmunity.
Coronary heart disease:
Several studies have investigated a possible involvement of this pathogen
in coronary heart disease with inconclusive results.
Beneficial effects of H. pylori infection:
Infection with H. pylori may protect the host from other gastrointestinal
bacterial infections because of antibacterial peptides produced by H.
pylori.
VIRULENCE FACTORS, HOST RESPONSE, AND METHODS OF DIAGNOSIS
Virulence Factors
A. Helicoidal shape and flagella of H. pylori:
These characteristics assist the bacterium in reaching the gastric mucosa.
H. pylori must cross the oral cavity and the esophageal tract, enter
the acidic environment of the stomach and penetrate the mucus layer which
covers the gastric mucosa.
B. Mucus-hydrolyzing enzymes: these enzymes aid the bacterium in entering the mucus layer of the gastric mucosa.
C. Adhesins: these are immunogenic membrane proteins expressed in a subgroup of H. pylori strains. The bacterium binds, via adhesins, to receptors on the surface of gastric epithelial cells; the process of binding causes reorganization of the plasma membrane of the cells. This provides H. pylori access to nutrients within the damaged gastric epithelium. Adherence to gastric epithelium also stabilizes the bacterium against mucosal shedding into the gastric lumen. Bacterial strains expressing adhesins are associated with intestinal metaplasia and atrophic gastritis.
D. Bacterial virulence proteins: a number of protein factors are produced by H. pylori at the site of colonization; these factors include enzymes involved in nitrogen metabolism, cytotoxin-associated antigens, vacuolating cytotoxin, and neutrophil-activating protein.
E. Enzymes involved in nitrogen metabolism:
Ammonia production is important for H. pylori as a nitrogen source,
as protection against gastric acidity, and as a cytotoxic molecule that produces
tissue damage during colonization. The ammonia-producing enzymes of H.
pylori include urease, deaminases, deamidases, and two aliphatic amidases
which hydrolyze short-chain amides to produce ammonia and the corresponding
organic acid. Of these enzymes, urease is the most abundant, constituting
from 5% to 10% of total protein content. Urease is essential for H. pylori
in colonization of gastric mucosa; it neutralizes gastric acidity and it induces
activation and adherence of inflammatory cells in the area of colonization.
F. Vacuolating cytotoxin (Vac A)
This toxin binds to the plasma membrane of target cells and is internalized
after pore formation. Within cells the toxin induces:
1. rearrangement in the organization of endosomes and lysosomes
2. extensive membrane fusion and swelling
3. vacuole formation
4. facilitation of intracellular survival of H. pylori: the vacoule constitutes
a reservoir of H. pylori which is difficult to access with antibiotics
and by inflammatory cells
The intracellular damage caused by this toxin may interfere with antigen processing
by B lymphocytes, contributing to the long-lasting infection with H. pylori.
G. Cytotoxin-associated antigen (Cag A)
Infection with strains of H. pylori that synthesize Cag A is linked
to peptic ulcer disease and gastric carcinoma. Cag A is coded by a gene within
the so-called cag pathogenicity island (a cluster of genes coding cytotoxins
and associated proteins). Some of these proteins assemble into a molecular
syringe and translocate Cag A into gastric epithelial cells; this causes a
disruption of the epithelial barrier functions and dysplastic alterations
in epithelial cell morphology. Host cell intercellular junctions are targeted
with disruption of junction-mediated functions. (4)
H. Neutrophil-activating protein
When released by bacterial cells this protein binds to the bacterial surface.
It performs a variety of functions:
Neutrophil-activating protein
1. can act as an adhesin, mediating binding to mucus
2. is chemotactic for neutrophils and monocytes
3. promotes neutrophil adhesion to endothelial cells
4. induces neutrophils to produce reactive oxygen radicals
5. can activate mast cells with release of proinflammatory cytokines
6. plays a role in iron uptake by H. pylori (iron is an essential
nutrient for this bacterium)
Host Response to Infection
A. Non specific defense mechanisms
Host response to H. pylori infection is characterized by a strong
inflammatory reaction and production of various cytokines. Interleukin–8
(IL-8) expressed by gastric epithelial cells is chemotactic for neutrophils,
thus contributing to the inflammatory cascade. Activation of macrophages results
in the release of IL-12, IL-1, IL-6, and IL-8, as well as tumor necrosis factor-alpha
and interferon-alpha. These cytokines and particularly IL-12 direct the subsequent
T cell response toward a pattern where T helper (Th) cells of the Th1 subset
predominate.
H. pylori survives within activated macrophages by interfering with
lysosomal proteins.
The inflammatory response is not sufficiently effective to eliminate the infection.
B. Specific immune response
H. pylori infection stimulates a specific response which includes
circulating antibody and secretory immunoglobulin A. In addition to antibody,
activated mucosal and circulating T cells can be demonstrated; these tend
to be Th 1 cells. Studies with adoptive transfer of H. pylori –
activated T cells indicate that Th 2 cells rather than Th 1 mediate protective
immunity. The vigorous immune response of the infected host does not eliminate
H. pylori infection.
Methods of Diagnosis
Diagnostic tests for H. pylori infection fall into two categories:
invasive and non-invasive.
A. Non-invasive tests:
Serology: a number of enzyme immunoassay tests are available; these detect
both past and current infection.
Urea breath test: the patient ingests radioactively-labeled urea; if H.
pylori infection is present, urease produced by the bacterium will hydrolyze
urea to ammonia and bicarbonate. The labeled carbon dioxide is exhaled and
can be detected with a spectrometer or a scintillation counter. The urea breath
test is the preferable non-invasive diagnostic procedure. It detects only
current infection.
Fecal Antigen tests. Several procedures are available:
1. Polymerase chain reaction (PCR) for direct detection of the bacterial DNA
in stool specimens; detection rates vary from 25% to 100%
2. Purification of bacterial DNA from stool using a new gene capture method
followed by PCR
3. Enzyme immunoassays: detection of bacterial antigen in feces
Although cultivation of H. pylori from feces of experimentally colonized
persons and from a few children has been reported, stool culture is not used
for diagnosis of H. pylori infection.
B. Invasive tests: endoscopy and collection of a gastric biopsy specimen,
followed by histology, rapid urease testing, PCR, or culture.
1. Biopsy specimens can be stained with Giemsa or silver stains and examined
directly for typical organisms. Squash preparations of biopsy material can
be Gram-stained using 0.1% basic fuchsin as counterstain.
2. Urease test: a portion of crushed tissue biopsy is placed directly into
urea broth or into commercially available urease agar kits. A positive test
is considered indicative of H. pylori infection.
3. Cultivation: biopsies are placed in vials with Brucella broth for transport
to the laboratory. Tissue is homogenized and plated on enriched medium supplemented
with antibiotics and incubated at 37C in 5% carbon dioxide atmosphere.
4. PCR assay of gastric biopsy specimens can be used in place of culture;
this procedure has 97% sensitivity and 94.6% specificity.
EPIDEMIOLOGY OF H. PYLORI INFECTION
It is estimated that close to half of the world’s population is infected
with H. pylori; there is, however, a distinct difference in the prevalence
of this infection between developed and underdeveloped countries. Humans are
the identified source of infection; contact with animals is not associated
with an increased risk of acquiring infection. (5) .
Transmission
Children acquire the infection as infants. Epidemiologic studies show that
transmission occurs within families. The mother may play a major role in transmitting
the infection to the child; transmission between siblings of similar age may
also occur. DNA typing has shown that the same strain of bacteria is generally
found among family members.
The bacteria have been isolated from feces, saliva, and dental plaque of infected
patients, suggesting a possible fecal-oral transmission route.
Most infections are acquired between the ages of 2 to 5 years. Although infection
with H. pylori is considered chronic and not self-limiting, there
are some indications that elimination of the pathogen may occur. In developed
countries re-infection is infrequent.
Prevalence of infection:
The prevalence of infection in both children and adults shows strong regional
differences. Depending on the child’s age, prevalence varies from 0%
to approximately 30%. Prevalence in adults increases with age and varies among
study populations. Among adults aged 56 to 66 years a high of 82% has been
reported. Since this infection is acquired during childhood, an increase in
the prevalence of infection with age reflects childhood living conditions.
The infection rate in children has been showing a steady decline in developed
countries, possibly as a result of improved sanitation and better hygiene
practices and living conditions. This trend has important implications for
associated diseases in adulthood.
H. pylori infection and gastric malignancy:
In developed countries a decrease in incidence of gastric cancer has been
recorded within the past few decades. On a world-wide scale (both developed
and underdeveloped countries), however, the rate is increasing due to an increasing
life span.
Despite a clear-cut association between H. pylori infection and gastric cancer,
other factors appear to be involved: smoking, the strain of H. pylori, the
presence of certain virulence factors, host genetic make-up, and the host’s
response to chronic infection.
Epidemiology of H. pylori infection in underdeveloped countries.
In addition to person-to-person transmission within families, other possible
sources of infection exist, such as contaminated food or water and pre-mastication
of food by the mother. Transmission by fecal-oral and oral-oral routes is
facilitated by living conditions which include overcrowding, poor hygiene,
sharing of beds during childhood, lack of maternal education, and infected
family members. When mothers are infected, 15% of their infants become infected
by 9 months of age, increasing to 30% by 3 years. In young children spontaneous
clearance of infection may occur, followed by re-infection. By adulthood,
infection rates exceeding 90% are not uncommon. In contrast to developed countries
no decline in childhood infections has been observed.
Disease presentation in underdeveloped countries differs from that in developed
countries (gastritis, peptic ulcer, gastric carcinoma); in underdeveloped
countries symptoms include chronic diarrhea, malnutrition, growth failure,
predisposition to other enteric infections, including typhoid fever and cholera.
EXPERIMENTAL MODELS OF INFECTION
Animal studies have contributed to a better understanding of H. pylori colonization
of the gastric mucosa and of the factors that contribute to progression of
gastrointestinal disease.
Experimental models:
Experimental animal models have included a wide range of species, including
pigs, non-human primates, cats, dogs, and rodents, mice in particular. The
first animal model for Helicobacter infection was developed in mice with a
mouse-adapted H. pylori strain. These studies provided information on bacterial
and host factors involved in disease pathogenesis.
The following bacterial factors were found to be required for colonization
of gastric mucosa:
1. Motility
2. Presence of urease, as well as a minimum threshold level of urease activity
3. Presence of protective enzymes such as superoxide dismutase
4. Effective iron uptake and iron storage mechanisms
By contrast, bacterial virulence factors, such as cag A or vac A were not
essential for bacterial colonization.
Host factors:
1. Normal microbiota
2. Genetic make-up of the host
3. Nature of host immune response, including T-helper cell phenotype and cytokines
produced by Th I or Th 2 cells.
Models of gastric cancer
Gastric adenocarcinoma in Mongolian gerbils:
Long-term infection of Mongolian gerbils provided first experimental evidence
that Helicobacter infection can result in the development of gastric adenocarcinoma.
The pathology is similar to that in humans. Key factors in the neoplastic
process include elevated levels of serum gastrin, decreased gastric acid production,
and elevated levels of interleukin–1 beta and of the regulators of the
cell cycle progression.
Gastric B cell MALT lymphoma:
Models of MALT lymphoma were developed in ferrets and mice. Treatment and
eradication of Helicobacter infection resulted in tumour regression in a high
percentage of test animals.
TREATMENT AND VACCINE DEVELOPMENT
Peptic ulcer disease is now approached as an infectious disease and effective
treatment is available: a number of antimicrobial compounds are active against
H. pylori. Because of gastric acidity, which affects some antimicrobial
agents, an antisecretory compound is usually included with the antibiotics.
A combination of two or more antimicrobial agents increases rates of cure
and reduces the risk of selecting for resistant bacteria. Such “triple
therapies” (combinations of an antisecretory agent with two antimicrobial
compounds) are generally administered for one to two weeks. A number of such
therapies have been evaluated and several treatment regimens have been approved
by the Food and Drug Administration. Several antisecretory compounds are available
for clinical use: omeprazole, pantoprazole, and related compounds. These drugs
are so-called “proton pump” inhibitors; their main action is interference
with the terminal stage in gastric acid secretion.
Antimicrobial agents
The chief antimicrobial agents used are amoxicillin, clarithromycin, metronidazole,
tetracycline, and bismuth. The frequency of clarithromycin resistance is around
10%; resistance to metronidazole ranges between 20% and 30%. Successful treatment
produces cure rates of 80% or higher. In cases where primary treatment had
failed, either because of poor patient compliance or antibiotic resistance,
a second 10 to 14 day treatment course is recommended. The choice of drugs
for the second treatment should be guided by the results of susceptibility
tests; if this information is not available, antibiotics used in primary therapy
are avoided.
Guidelines for treatment of H. pylori infection
Treatment is recommended for the following:
1. Duodenal or gastric ulcer
2. MALT lymphoma
3. Atrophic gastritis
4. Recent resection of gastric cancer
5. First-degree relative of patient with gastric cancer
6. Patient requests treatment after medical consultation
Treatment is advised for the following:
1. Functional dyspepsia
2. Gastroesophageal reflux disease
3. Use of non-steroid anti-inflammatory compounds (NSAIDs), an independent
risk factor for peptic ulcer disease
Antibiotic therapy, although effective, has not eliminated H. pylori infection
for following reasons:
1. Asymptomatic patients are not treated but remain at risk for serious complications
2. Treatment may not be available due to cost or geographic location
3. Re-infection or failure of treatment
Because of these drawbacks of antibiotic therapy, alternate methods for eliminating
H. pylori infection are needed.
Vaccine Development
Vaccines represent one of the most effective approaches for control of infectious
disease.
The development of a vaccine requires a suitable antigen, a strong and effective
adjuvant, and an optimal route of inoculation.
The antigens tested in H. pylori vaccine studies have included inactivated
whole-cell preparations (sonicated or formalin-treated), the urease enzyme,
and several of the virulence factors; purified recombinant proteins proved
poorly immunogenic and required strong mucosal adjuvants.
Adjuvants: the most effective mucosal adjuvants were found to be bacterial
toxins, such as cholera toxin or Escherichia coli heat-labile enterotoxin.
These preparations induce severe diarrhea in humans; non-toxic mutants are
currently being generated and tested.
Route of inoculation: studies of the optimal route of inoculation indicated
that immunization at the intestinal level may induce appropriate recruitment
of specific cells at the gastric level.
Vaccine tests: animal studies
Several animal models have been used: mice, monkeys, and dogs. Prophylactic
protection as well as therapeutic effectiveness was demonstrated in mice and
in monkeys, using H. pylori urease or virulence proteins with E. coli heat-labile
enterotoxin as adjuvant. The search for better vaccine formulations, improved
antigen and adjuvant preparations and a better delivery system is in progress.
Vaccine tests: human studies
Comparatively few studies have been carried out to determine whether positive
results obtained in animals could be duplicated in humans. None of the therapeutic
candidate vaccines tested in human trials has been effective so far.
SUMMARY
Helicobacter pylori is one of the most common bacterial pathogens;
it infects the gastric mucosa in humans and is found world-wide.
When first observed in gastric biopsies and cultivated in the laboratory,
this bacterium was classified as Campylobacter pylori. Subsequent
studies led to establishment of a new genus Helicobacter and the
re-classification of this pathogen as Helicobacter pylori. This bacterium
is Gram-negative, spiral-shaped, and motile by polar flagella. It can be cultured
on enriched medium in the presence of 5% carbon dioxide. Its most notable
biochemical activity is the production of large quantities of urease.
Infection with H. pylori is world-wide; the incidence is high but varies with the geographic area. The majority of infected persons have no symptoms of disease; however, a certain proportion of infected population will develop acute gastritis or gastric or duodenal ulcers. Some persons may develop gastric cancers. Because of strong association between gastric cancer and H. pylori infection this bacterium is classified as a bacterial carcinogen. The strong immune response of the infected host does not eliminate the infection.
H. pylori possesses a number of virulence factors that facilitate colonization of gastric mucosa. The infection can be diagnosed by the urea breath test, serology, stool antigen tests or gastric biopsy accompanied by culture or PCR.
Experimental models of infection have yielded valuable information on factors required for colonization of gastric mucosa. Models of gastric cancer had been developed in several animal species.
Effective antibiotic treatment is available for H. pylori infection; a combination of 2 antimicrobial compounds with an antisecretory agent is used; several treatment regimens have been approved by the Food and Drug Administration.
Intensive work on vaccine development is in progress; prophylactic protection and therapeutic effectiveness have been demonstrated in animal studies but not in human trials.
REFERENCES
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- Forbes BA, Sahm DF, Weissfeld AS. Bailey and Scott’s Diagnostic Microbiology, 11th ed. Elsevier Science; 2002, Chap 39.
- Amieva MR, Vogelmann R, Covacci A, Tompkins LS, Nelson WJ, Falkow S. Disruption of the epithelial apical-junctional complex by Helicobacter pylori Cag A. Science. 2003;300:1430-1434.
- Dietrich Rothenbacher and Hermann Brenner. Burden of Helicobacter pylori and Helicobacter-related diseases in developed countries: recent developments and future implications. Microbes and Infection. 2003;5:693-703.