3. • late 19th and early 20th centuries - identification of
spiral microorganisms in the stomachs of animals and
humans.
• 1982/83 - Barry Marshall and Robin Warren won 2005
Nobel prize for the discovery of Helicobacter pylori (H.
pylori).
• H. pylori lead to a variety of upper gastrointestinal
disorders, such as chronic gastritis and peptic ulcer,
and is a class 1 carcinogen in gastric cancer.
Fig.1: Barry Marshall and Robin
Warren.
3
4. Morphology
• Spiral.
• Gram-negative.
• Length of 2.5 – 5.0 μm.
• Width of 0.5 – 1.0 μm.
• 2-6 unipolar flagella (approximate length of 3 μm
and thickness of 2.5 nm) with a distinctive bulb at
its end.
4
Fig.2: Structure of
H. pylori
bacterium.
5. • Surface consists of lipopolysaccharides (LPS) urease, and adhesins.
5
growth requirements.
• Microaerophile.
• Optimal growth conditions:
• O2: 2 – 5%
• CO2: 5 – 10%
• High humidity
• 34 – 40 °C optimum (37°C)
• Neutralophile: 5.5 to 8.0 pH (will survive brief exposure to pHs of < 4)
6. • Fastidious microbe. Ex:- requires supplements
such as blood, serum, yeast extract, lysed human
erythrocytes, IsoVitaleX, hemin, cyclodextrin,
cholesterol, etc.
• Isolated from gastric biopsy specimens.
• Colonies appear between 3 – 14 days.
• H. pylori form small (~1-mm), translucent, smooth
colonies.
• Urease, catalase, and oxidase positive.
6
Fig.3: H. pylori
colonies on blood
agar.
7. • The prevalence of H. pylori is >80% in developing countries.
• The prevalence of H. pylori in developed countries is <40%.
• Prevalence of H. pylori inversely correlates with socioeconomic status.
• Infection mainly occurs during childhood and persists lifelong if untreated.
• Human to human transmission:
7
• oral-oral,
• fecal-oral,
• and/or iatrogenic routes.
8. • After entering the host stomach, four steps are critical for disease pathogenesis:-
8
Fig.4: major
steps in H.
pylori
infection and
pathogenesis
.
9. 9
• pH of the gastric mucosa = 4 –
6.5 pH.
• Urease enzyme activity.
• Converts urea into ammonia and
carbamate.
• Ammonia produced increases the
pH.
• Decreases the viscosity.
Step 1: Survival in the acidic stomach.
Fig.5: urease activity in H. pylori.
10. • Action of flagella helps to reach the basal layer
(pH~7).
• Chemotaxis towards gastric epithelium.
• Mucinase, protease, and phospholipase – mucus
disruption.
10
Step 2: Flagella movement toward epithelial cells.
Fig.6: H. pylori
movement toward
epithelium cells.
11. Step 3: Adhesion to host cells via adhesin-receptor interaction.
• OMPs are the main adhesins of H.
pylori:
• Pilus surface adhesin CagL – binds to
β1 integrins.
11
• Blood group antigen-binding adhesion
(BabA) – binds to Lewis b antigen.
• Sialic acid-binding adhesion (SabA) –
binds Lewis x and a antigen.
• AlpA and B – binds to laminin.
Fig.8: interaction between host cells receptors and adhesins
of H. pylori.
12. Step 4: Toxin release and host tissue damage.
• Cytotoxin-associated
gene A (CagA).
• Delivery into host cells –
type IV secretion system
(T4SS).
• Tyrosine phosphorylation
of CagA.
12
Fig.9: signaling
pathways triggered
by CagA.
13. • Vacuolating cytotoxin A (VacA) – oligomeric structure – immunomodulator.
• Delivery - type V secretion system.
• Membrane embedded vacA acts as an anion selection channel.
• Leakage of nutrients by disruption of tight junction barriers.
• Endocytosed vacA leads to the vacuolation of host cells.
• Cell apoptosis via the mitochondrial-dependent pathway.
13
Fig.10:
functions
of VacA.
14. • Bacterial contact with TLRs
(Ex:TLR4) on monocytes and
other APCs leads to production
of proinflammatory cytokines. Ex:
TNF-α (tumour necrosis factor-
α), IL-1β and IL-8.
• Proinflammatory cytokines act as
chemoattractants.
• Granulocytic infiltration.
14
Fig.11: innate immune
response to H. pylori.
15. 15
• Th1-predominant host
immune response –
further elevates pro-
inflammatory cytokines
IL-12, IL-18 and TNF-α.
• Th17 – inflammatory
response – gastric
cancer.
• Production of IgA and
IgG. Fig.12: adaptive immune response
to H. pylori.
16. • Evasion of recognition by pattern recognition receptors – LPS.
• Inhibition of phagocytic killing – VacA and etc.
• Inhibition of killing by reactive oxygen and nitrogen species – arginase, catalase, and
superoxide dismutase.
• Apoptosis of macrophages and monocytes – VacA.
• Inhibition of antigen presentation– VacA and CagA.
• Apoptosis of gastric epithelial cells – VacA and etc.
• Inhibition of T cell function – CagA and VacA.
16
17. 17
• Laboratory identification methods:
• Culturing, staining or urease activity
of gastric biopsy specimens.
• Detection of serum IgG.
• urea breath test.
• urinary excretion of (15N) ammonia.
• stool antigen assays.
Fig.13: rapid urease test kit.
18. • Treatment is two-pronged:
18
• Drugs to decrease stomach acid: bismuth subsalicylate (Pepto-Bismol).
• Antibiotics to kill the bacteria: metronidazole and either tetracycline or amoxicillin;
clarithromycin, ranitidine, and bismuth citrate; or clarithromycin, amoxicillin, and
lansoprazole.
Fig.14: three regimens of H.
pylori treatment kit.
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