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Dr. Jumana Abbadi
Vibrios, Campylobacters,
Helicobacters (Curved rods)
Chapter 32p.265-577
Introduction
Curved Gram-negative rods includes:
Vibrio cholera, the cause of cholera.
Helicobacter pylori, the cause of gastritis and gastric ulcer disease.
Campylobacter jejuni, one of the most common causes of
diarrhea.
Vibrio species
Vibrios are curved, Gram-negative rods.
Commonly found in saltwater.
They are highly motile with a single polar flagellum,
Non–spore-forming.
Oxidase positive.
They can grow under aerobic or anaerobic
conditions, i.e. facultative anaerobes..
There are many species:
V. cholera
V. mimicus
V. parahemolyticus; causes gastroenteritis
V. vulnificus.
Vibrio Cholera
Vibrio cholera has a low tolerance for acid, but grows under
alkaline (pH 8.0-9.5) conditions.
It is distinguished from other vibrios by biochemical
reactions, lipopolysaccharide (LPS) O antigenic structure,
and production of cholera toxin (CT).
In aquatic environments, V. cholera produces polysaccharide
biofilms, which contain carbohydrate moieties mediating
cell–cell adhesion and attachment to surfaces.
There are over 200 O antigen serotypes, only two of which
produce cholera toxin causing endemic and/or epidemic
cholera:
O1
O139
Non-O1 and non-O139 strains and they cause mild cholera-
like diarrhea. Non-O1 and non-O139 strains have been
sporadically isolated from cases of gastroenteritis but do not
produce CT, and thus not the disease cholera.
Epidemiology
It has a short incubation period (2 days).
Epidemic cholera is spread primarily by contaminated water
under conditions of poor sanitation, particularly where
sewage treatment is absent or defective.
Cholera is currently endemic in the Indian subcontinent,
Africa and inYemen.
The epidemic potential of V. cholera depends on its ability to
survive in both aquatic environments and human hosts.
The organism is fragile, surviving only a few days in the
environment outside its human hosts.
Virulence Factors
1. Motility by flagella: V. cholera must swim to the small
intestine, multiply, and produce virulence factors.
2. Adherence to the epithelial cells by pili: which leads to
colonization of the entire intestinal tract.
3. Cholera Toxin: the outstanding feature of V. cholera
pathogenicity is the ability of virulent strains to secrete CT.
Pathogenesis: Cholera toxin CT is an A-B type ADP-ribosylating
toxin.
Its molecule is an aggregate ofmultiple polypeptide chainsorganized into two toxic subunits(A1,A2) and five binding (B) units.
The B units bind to a GM1-ganglioside receptor found on thesurface of many types of cells. Oncebound, the A1 subunit is released fromthe toxin molecule, and it enters thecell by translocation.
In the cell, The toxic A1
subunit catalyzes the ADP-
ribosylation of the GS
(stimulatory) regulatory
protein, “locking” it in the
active state.
Because the GS protein
activates adenylate cyclase
(AC). The net effect is
persistent activation of
adenylate cyclase.
The increased adenylate cyclase
(AC) activity results in
accumulation of cAMP along the
cell membrane.
This in turn leads to
hypersecretion of chloride,
potassium, bicarbonate,
and associated water
molecules out of the cell
into the intestinal lumen.
The result is dehydration (isotonic fluid loss), hypokalemia
(potassium loss), and metabolic acidosis (bicarbonate loss).
The intestinal mucosa remains unaltered except for some
hyperemia, because V. cholera does not invade or otherwise
injure the enterocyte.
Disease Manifestations Rapid onset, beginning
with abdominal fullnessand discomfort, rushes ofperistalsis, and loose stools.
The stools quickly becomewatery, voluminous, almostodorless, and containmucus flecks (rice-waterstools).
Neither white blood cellsnor blood are in the stools,and the patient is afebrile.
Clinical features of cholera result from the extensive fluid
loss and electrolyte imbalance, which can lead to extreme
dehydration, hypotension, and death within hours if
untreated.
No other disease produces dehydration as rapidly as cholera.
DIAGNOSIS
The initial suspicion of cholera which depends on the typical
clinical features of the diarrhea (rice-water stools).
A bacteriologic diagnosis is accomplished by isolation of V.
cholera from the stool.
The organism grows on common clinical laboratory media
such as blood agar and MacConkey agar, but its isolation is
enhanced by a selective medium thiosulfate–citrate–bile
salt–sucrose agar (TCBS).
V. cholera is oxidase positive.
Tretment The outcome of cholera depends on balancing the diarrheal
fluid and ionic losses with adequate fluid and electrolytereplacement (oral or intravenous).
Oral replacement, particularly if begun early, is sufficientfor all but the most severe cases and has substantially reducedthe mortality from cholera.
Antimicrobial therapy plays a secondary role to fluidreplacement by shortening the duration of diarrhea.
A single dose of azithromycin provides optimal therapy
doxycycline, a fluoroquinolone, or trimethoprim-sulfamethoxazole are also effective agents.
Prevention
Boiling and chlorination of water during epidemics are required.
Cholera associated with ingestion of crabs and shrimp can be
prevented by adequate cooking (10 minutes) and avoidance of
recontamination from containers and surfaces.
Campylobacter species
Motile, curved, oxidase-positive, Gram-negative rods
The cells have polar flagella and are often attached at their
ends giving pairs “S” shapes or a “seagull” appearance.
C. jejuni is by far the most common prototype for intestinal
disease.
Camplybacter jejuni
It is one of the most common causes of infectious
diarrhea.
Like other campylobacters, C. jejuni grows well only on
enriched media under microaerophilic conditions. That
is, it requires oxygen at reduced tension (5%-10%),
presumably because of the vulnerability of some of its
enzyme systems to superoxides.
Growth usually requires 2 to 4 days, sometimes as much as 1
week.
Virulence Factors
Polar flagellum; the cells are actively motile.
It produces a membrane-bound protein called cytolethal
distending toxin (CDT).
Epidemiology
It is the leading cause of gastrointestinal infection in
developed countries followed by Salmonella species.
This high rate of disease is facilitated by the low infecting
dose of C. jejuni; only a few hundred cells are enough to cause
and infection.
Campylobacters are commonly found in the normal
gastrointestinal and genitourinary flora of warm-blooded
animals, including sheep, cattle, chickens, wild birds,
and many others.
The most common source of human infection is undercooked
poultry, but outbreaks have been caused by contaminated
rural water supplies and unpasteurized milk often consumed
as a “natural” food.
Pathogenesis Infection is established by oral
ingestion, followed bycolonization of the intestinalmucosa.
Adherence to enterocytes isfacilitated by action of theflagellum followed by entranceinto cells in endocytotic vacuoles.
injury mechanisms include thecytotoxic CDT. CDT has an A-B toxin structure in which the Asubunit is able to cause cell cyclearrest.
The intestinal pathology is that of an invasive pathogen with
acute inflammation, crypt abscesses, and occasional
seeding of the bloodstream.
There is an association between C. jejuni infection and
Guillain-Barré syndrome, an acute demyelinating
neuropathy that is frequently preceded by an infection.
Up to 40% of patients have culture or serologic evidence of
Campylobacter infection at the time the neurologic symptoms
occur.
Disease Manifestations
The illness typically begins 1 to 7 days after ingestion, with
fever and severe lower abdominal pain.
These are followed within hours by dysenteric stools that
usually contain blood and pus.
The illness is typically self limiting after 3 to 5 days but may
last 1 to 2 weeks.
Diagnoses
The diagnosis is confirmed by isolation of the organism from
the stool.
This requires a special medium made selective for
Campylobacter species; Campy-agar. The plates must be
incubated in microaerophilic atmosphere
Treatment
Patients are usually not treated unless the disease is severe
or prolonged (lasting longer than 1 week).
Erythromycin or azithromycin is considered the
treatment of choice but must be given early for maximal
effect.
Helicobacter It was well known for physicians that the cause of peptic ulcer was
an imbalance between gastric acid–pepsin secretion and an
underlying genetic and lifestyle background (smoking, anxiety,
stress).
In 1983, a pair of Australian microbiologists (Warren and
Marshall) suggested that gastritis and peptic ulcers were
infectious diseases. With time it became established that
Helicobacter pylori is the cause of peptic ulcer and treatment
with antibiotics resolved the disease.
Helicobacter pylori
The cells are slender, curved Gram-negative rods with
multiple polar flagella (rapidly motile).
Growth is slow (3–5 days) and requires a microaerophilic
atmosphere.
Virulence Factors
Urease:
Whose action allows the organism to persist in low pH environments
(stomach) by the generation of ammonia.
Vacuolating cytotoxin (VacA):
A secreted protein which causes apoptosis in eukaryotic cells.
CagA (Cytotoxin-associated gene A) protein:
induces changes in multiple cellular proteins and has a strong
association with virulence.
Injection secretion systems (type IV):
Which delivers bothVacA and CagA into cells.
Epidemiology
Infection with H. pylori causes what is perhaps the most
prevalent disease in the world.
The organism is found in the stomachs of 30% to 50% of
adults in developed countries, and it is almost universal in
developing countries.
The exact mode of transmission is not known, but is
presumed to be person to person by:
fecal–oral route or
gastric secretions
Colonization increases progressively with age.
Helicobacter pylori is the most common cause of gastritis,
gastric ulcer, and duodenal ulcer cases which are not
due to drugs.
H. pylori gastritis may progress into gastric
adenocarcinoma especially in strains that are positive for
cytotoxin-associated gene A (Cag A).
It is also linked to a gastric mucosa-associated
lymphoid tissue (MALT) lymphoma.
Pathogenesis To persist in the stomach, H.
pylori uses many mechanisms toadhere to the gastric mucosa andsurvive the acidic environmentof the stomach. The flagella allows the
organisms to swim to the lessacidic locale beneath the gastricmucin layer.
The urease further creates amore neutral microenvironmentby ammonia production.
At the mucosa, adherence ismediated by multiple outermembrane proteins which bindto the surface of gastricepithelial cells.
The inflammation may be due totoxic effects of the VacAtransported into the gastricepithelial cells by the secretionsystem. The VacA directlyinduces cellular changes(vacuolization) and death.
The CagA protein is injectedinto the gastric epithelial cell bythe secretion system, whereit triggers multiple enzymaticreactions including those thatcause reorganization of the actincytoskeleton and stimulation ofcytokines.
Helicobacter pylori colonization
and inflammation is always
accompanied by a cellular
infiltrate ranging from minimal
mononuclear infiltration of the
lamina propria to extensive
inflammation with neutrophils,
lymphocytes, and microabscess
formation.
This prolonged and aggressive inflammatory response could
lead to epithelial cell death and ulcers.
After decades, this inflammation and assault by the virulence
factors just described could cause metaplasia, and
eventually cancer.
Disease Manifestations Primary infection with H. pylori is either silent or causes an
illness with nausea and upper abdominal pain lasting up to 2weeks.
Later, the findings of gastritis and peptic ulcer diseaseinclude nausea, anorexia, vomiting, epigastric pain.
Many patients are asymptomatic for decades, even up toperforation of an ulcer. Perforation can lead to extensivebleeding and peritonitis due to the leakage of gastric contentsinto the peritoneal cavity.
Diagnosis1. The most sensitive means of diagnosis is endoscopic
examination, with biopsy and culture of the gastricmucosa.
2. Serology:
Detection of antibodies (IgG, IgA) directed against H. pylori.Because IgG or IgA remains elevated as long as the infectionpersists, these tests are valuable both for screening and forevaluation of therapy.
3. Urea breath test:
the patient ingests 13C- or 14C-labeled urea, from which theurease in the stomach produces products that appear as labeledCO2 in the breath.
Urea breath test
Treatment
Cure rates approaching 90% have been achieved with various
combinations of bismuth salts and/or a protein pump
inhibitor plus two antibiotics for at least 2 weeks
Antibiotics:
Clarithromycin plus amoxicillin or metronidazole.
OR
metronidazole plus tetracycline.
Vibrio cholera Campylobacter jejuni Hellicobacter pylori
curved curved curved
Saltwater Animals Humans, gastric secretions
Single flagellum Single flagellum Multiple polar flagella
Oxidase positive Oxidase positive Oxidase positiveUrease positive
Facultative anaerobes Microaerophilic Microaerophilic
Low tolerance for acid Medium tolerance to acid High tolerance for acid
Rice-water diarrhea Diarrhea; dysentery Peptic ulcer and gastritis
Large infection dose Low infecting dose
Cholera toxin Cytolethal distending toxin (CDT) • Vacuolating cytotoxin (VacA)• Cytotoxin-associated gene A (CagA)
Acute Acute Chronic
Diagnosis by culture:• Blood agar• MacConkey agar• Thiosulfate citrate bile
salt sucrose agar
Diagnosis:Culture on Campy agar
Diagnosis:• Endoscopic examination with
biopsy.• Culture of the gastric mucosa.
Azithromycin Erythromycin or azithromycin Bismuth salts and/or a protein pump inhibitor plus two antibiotics
Thank you ☺
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