Pathogenesis of H Pylori Infection

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Pathogenesis of H Pylori Infection

• Ghassan Hemadeh, MD
• October 1, 2005

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Amphibiosis Concept Theodore Rose bury 1962

• Micro organism have either pathogenic or
  symbiotic
• relationship with their hosts depending on the
  context
• H. Pylori has colonized the gastric mucosa of
  human since time immemorial
• The prevalence of H. Pylori colonization is
  decreasing
• There is increasing evidence of strains diversity
• H. Pylori is one of over 20 M.O. for which
  complete sequence data are available.

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Natural History of Helicobacter pylori Infection
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H. Pylori Pathogenesis and Application of Cutting
Edge Technologies
Molecular biology
Genetics
Imaging
Cell culture models
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H. Pylori Genome

• (1.65 million bp) codes for about 1500
  protein.(1, 2)
• The discovery of 32 related outer membrane
  proteins (Hop Protein) Adhesins
• Many genes can be switched on and off
• Phase-variable genes include enzymes that modify
  the antigenic structure of surface molecules,
  control the entry of foreign DNA into the
  bacteria and influence bacterial motility
• The genome changes continuously (DNA
  importing)(3)

(1) Tomb JF, et al. Nature 1997388539-547 (2)
Alm RA, et al. Nature 1999397176-180 (3)
Flaush D, et al. Proct Natl Acad Sci USA
200198150-156
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H. Pylori Pathogenesis
Questions for Answer
Bacterial Host factors
Interaction with gastric mucosa (
Binding-Evasion) and host immune response
Infection outcome
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H. Pylori PathogenesisBacterial Virulence Factors

• Ingestion Evasion Entrance of Mucus
• 1 Layer (Motility Ure
  I)
• 2 Binding
• 3 Insertion
• 4 Intra cellular pathway

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H. Pylori PathogenesisThe Role of Urease

• Ure I opens at low PH and shuts down the influx
  of urea under neutral conditions(1)

(1) Weeks DL, Science 2000287482-485
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H. Pylori PathogenesisBinding To Epithelial Cells

• Adhesin, Bab A, Binds to the fucosylated Lewis B
  blood-group antigen(1)
• Other adhesins (Hop protein family)

(1) IIver D, et al. Science 1998279373-377
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H. Pylori PathogenesisBacterial Virulence
FactorsVacuolating Cytotoxin A (I)

• Hexamine anion-selective voltage dependant
  channel (HCO3-organic anions)

• Asecreted exotoxin that inserts itself into the
  epithelial cell membrane.(1)

Target mitochondrial membrane
Cytochrome C induce apoptosis(2)

• Szabo I, et al. EMBO J 1999185517-5527
• Galmiche A, et al. EMBO J 2000196361-6370

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H. Pylori PathogenesisBacterial Virulence
FactorsVacuolating Cytotoxin A (II)

• Induces cytoplasmic vacuolation
• Vac A gene is present in all H. Pylori strains
• Two divergent regions
• (Sla/ Slb/ S2) (m1/m2)
• Sl /mstrains Higher toxin activity
• ? Inflammation(1)
• Vac A associate lipid raft micro domains in
  epithelial cell lines (RPTPß) (RPTPa)
• The signaling cascades for both have to be deduced

• Atherton JC, et al. J Biol Chem
  199527017771-17777

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H. Pylori PathogenesisBacterial Virulence
Factors(Cag- PAI)( 37000 B-P 29 genes)

• Type IV secretions apparatus(1) (translocate cag
  A)
• Possible insertion by needle like organelle
  coated with a sheath (Cag 7 protein) Rohde et
  al
• Phosphorylated binds to SHP-2 tyrosine
  Phosphates
• Cytokine Production Growth Factor
• IL- 8 chemokines Like cellular
  response

• Odenbreit S, et al. Science 20002871497-1500

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The cag Pathogenicity Island
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H. Pylori PathogenesisThe Role of Cytokines

• Alter secretion of mucus
• TNFa ILIß, INF- 1Y
• ? Gastrin release Stimulate parietal cells
• ? Acid secretion
• TNFa ? D cells number
• ? Somatostatin
• ? Acid secretion

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Host Response To H. Pylori (I)

• Mainly triggered by adhesion binding
• It can bind MHC class II molecules on surface of
  gastric epithelial cells apoptosis
• Recruitment of Neutrophils
• TB Lympho
• Plasma Cells
• Macrophages

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H. Pylori Specific T Cell and B Cell Responses
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Host Response To H. Pylori (II)

• Systemic mucosal humoral response
• Some H. Pylori infected patients have auto AB
  directed against H/ K ATPase of gastric cells
  atrophy of the corpus
• (Th) o cells expressing CD4 differentiate into
• (Gastritis) Th1 IL-2, Interferon ? (I.C
  pathogen)
• (Protective) Th2 IL-4, IL-5, IL-10
• sti. B. cells (extra cell pathogen)

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Epithelial Cells Damage

• Cag-PAI mediated translocation of proteins
• Reactive O2 radicals
• Nitrogen specis
• Apoptosis in chronic inflammation
• ? Cell-turn over and apoptosis
• Fas-mediated contacts
• INF ?

Secreted by neutrophils
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Persistence of H Pylori Infection Possible
Mechanisms

• Escape via IC survival within host cells.
  (survival within vacuoles)
• The ability of type I H. Pylori strains to
  survive within macrophage phagosomes??
• Inhibition of Ag presentation
• Induction of T-cell apoptosis
• Vac A can arrest cell cycle in T-cells (block
  proliferation)

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Conclusion

• The literature is growing substantially with the
  studies into the function and nature of the gene
  products of H. Pylori
• Helicobacter infection induces inflammation and
  stimulate an ineffective immune response
• Alteration of epithelial cell growth and enhanced
  apoptosis play a role in H. Pylori disease
  manifestations, as failure of mucosal adaptation
  ulceration, and abnormal repair may
  predispose to malignancy