Sebastian Suerbaum & Christine Josenhans

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Sebastian Suerbaum & Christine Josenhans Helicobacter pylori evolution and phenotypic diversification in a changing host Sebastian Suerbaum & Christine Josenhans Asolina Braun 11.01.2010

History Barry Marshall & Robin Warren, 1982 colonizes the stomach link to gastritis and ulcers Marshall ingests H. pylori => gastritis 2005 Nobel prize „for their discovery of the bacterium H. pylori and its role in gastritis and peptic ulcer disease”

Clinics colonizes 50% of the world‘s population infection during infancy via family members 5,5% of all cancer cases

Success Strategy extreme genetic diversity host interaction mutagenesis recombination host interaction outstanding evation of immune system immune suppression thouthands in 1 nL no higher incidence in immunocompromised

Diversity extraordinary genetic heterogeneity every infected individual harbors their own strain(s) strains change during infection high recombination events (multilocus enzyme electrophoresis data, homoplasy test)

Geographical Distribution data based on multilocus sequence typing MLST set of housekeeping genes housekeeping genes not under high selective pressure none of modern strains derived from one ancestor big migration waves can be traced

Diversification by Mutagenesis defect mismatch repair defect base excision repair long repetitive sequences => frameshift altered expression if located inside regulators intragenomic deletions/rearrangements mismatch repair during replication, methylated strand = ok BER alcylation, ROS, deaminated repetitions in antimutator gene => regulation of mutation by mutation last: cagA, amiA (peptidoglycan), fucosylation, LPS

Diversification by Recombination recombination of short DNA fragments (~417 bp vs. 2-10 kbp) 50% exchange of genome in 40 years 1,111 conserved genes + ~400 frequent gene exchange seldom gene loss/gain (1 in 650 events) still some debate about numbers

Host Interaction BabA and SabA adhesins bind Lewis b and sialyl-Lewis on epithelium phase-variable expression adaptation to niches, acid conditions, … geographical correlation with blood groups phase-variable => at any time some H.p. don‘t express it BabA generalists vs BabA specialist (O AmerIndians)

Host Interaction vacuolating cytotoxin (Vac A) LPS vacuolation, tissue damage inhibits proliferation of T cells inhibits antigen presentation by B cells LPS Lewis antigens (on O-antigen side chains) binding of H. pylori to DCs via DC-SIGN => TH1 response diminished, ↓IL6, ↑IL10 => immune suppression heterogenous expression

Host Interaction flagellar motility cag PAI (a chromosome segment) implications unknown cag PAI (a chromosome segment) type IV SS destruction of the basal membrane atrophic gastritis, peptic ulcers, adenocarcinoma (Ishikawa et al., PNAS, 2005) vaccine cagA

Outlook prevalence in Western countries declines vaccination (Cag A) due to less mixed infections? due to better hygiene, antibiotics, broccoli? vaccination (Cag A)

Summary high prevalence of 50% extreme genetic diversity defective mutation repair systems many repetitive regions prone to mutations many recombination events outstanding evation of immune system BabA and SabA Vac A LPS Cag PAI

Thank you for your attention