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Effects of BabA expression during H. pylori infection of Mongolian gerbils
Department of Medicine-Gastroenterology, Michael E. DeBakey Vetrans Medical Center and Baylor College of Medicine, Houston, Texas, USA.
Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik. Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Oral mikrobiologi.
Department of Diagnostic Science and Special Therapies (Pathology Unit), University of Padova, Padova, Italy.
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(Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
Abstract [en]

Objective: Helicobacter pylori outer membrane proteins, such as the BabA adhesin are associated with severe pathological outcome.  However, the in vivo role of the BabA adhesin during long-term infection is not clear.  Design and Setting: Mongolian gerbils were inoculated with the H. pylori TN2GF4 and were necropsied at 1, 3, 6, and 18 months.  Main outcome measures: Bacterial clones recovered from the infected gerbils were evaluated by immunoblot for BabA expression, radioimmunoassay for Leb-binding, and bacterial binding to gastric tissue.  H1 antigen expression and the increase in sialylation levels were monitored by immunohistochemistry.  Results: BabA expression increased, then progressively decreased, and was completely absent by 6 months post-infection.  Loss of BabA expression was caused by nucleotide changes/deletions within the babA gene that resulted in a truncated BabA.  Infection with a BabA-expressing H. pylori caused severe mucosal injury, whereas infection with a BabA non-expressing strain caused only mild inflammation.  In response to the infection, changes in the epithelial glycosylation pattern were observed, similar to responses observed in humans and monkeys.  Conclusion: Down-regulation of BabA is probably a result of adaptation to the host response during long-term H. pylori infection.  BabA expression is most likely not essential for colonisation, but for the obtained gerbil host response, which confirms the role of BabA adhesin as a virulence factor and its impact in the induction of a severe inflammatory response.  The changes in glycosylation of gastric mucosa demonstrate the relevance of the Mongolian gerbil as a model for H. pylori infection and host responses.

Identifikatorer
URN: urn:nbn:se:umu:diva-25930OAI: oai:DiVA.org:umu-25930DiVA, id: diva2:235105
Tillgänglig från: 2009-09-13 Skapad: 2009-09-13 Senast uppdaterad: 2018-06-08Bibliografiskt granskad
Ingår i avhandling
1. Helicobacter pylori: molecular mechanisms for variable adherence properties
Öppna denna publikation i ny flik eller fönster >>Helicobacter pylori: molecular mechanisms for variable adherence properties
2009 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

More than half of all people worldwide are infected with H. pylori. The infection always cause a gastric inflammation that may develop into peptic ulcer disease or gastric cancer. Attachment proteins, adhesins, mediate specific adherence of H. pylori to receptor structures on the human gastric mucosa. The best-characterized H. pylori adhesin-receptor interactions are the BabA adhesin and the binding to the fucosylated blood group antigens ABO/Lewis b (Leb) and the SabA adhesin and its binding to the inflammation associated sialyl-Lewis x antigen. During H. pylori infection the availability of receptor structures on the human gastric mucosa changes as a consequence of the host inflammatory and immune responses. Consequently the bacterial population need to adjust its adherence properties to stay colonized. This thesis describes mechanisms that generate H. pylori populations with variable adherence properties and mechanisms for adjustment of adhesin expression levels.In H. pylori strains devoid of Leb-binding, we found bacterial cells with Leb-binding. Isolation of such H. pylori clones demonstrated that the change in receptor binding phenotype was obtained via the mechanisms of homologous recombination and slipped strand mispairing (SSM). Disease presentation in relation to BabA expression was studied in H. pylori infected Mongolian gerbils. We showed that BabA was not essential for colonization but caused severe injury to the gastric mucosa and was turned off during long-term infection by nucleotide changes within the babA gene. Gerbils infected with BabA-weak-expressing strains maintained BabA expressing clones for a longer period than gerbils that were infected with BabA-high-expressing strains. Studies of the gerbil gastric mucosal glycosylation showed that gerbils respond in a similar way as humans and Rhesus monkeys which support gerbils to be a model suitable for studying H. pylori infection and disease outcome in relation to adherence.We studied the SSM mechanism of SabA phase variation and the cognate shift in sLex-binding phenotype and we show sLex-binding activity to be growth phase dependent. H. pylori vesicles were characterized for the major phosholipid and protein components. Virulence factors e.g., VacA, and CagA were identified and both the BabA and the SabA adhesins was shown to be located on the vesicle surface and to mediate specific binding to their cognate receptors present on the human gastric mucosa. H. pylori generate bacterial cells with different receptor binding phenotypes via the mechanisms of homologous recombination, SSM and nucleotide changes. These mechanisms will probably contribute to bacterial fitness by the generation of quasi species populations where some of the clones will be better adapted to the environmental chances during persistent infection.

Ort, förlag, år, upplaga, sidor
Umeå: Umeå university, 2009. s. 57
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 1280
Nyckelord
H. pylori, adherence, BabA, SabA, Leb, sLex, phase variation, recombination, vesicles
Identifikatorer
urn:nbn:se:umu:diva-25931 (URN)978-91-7264-820-3 (ISBN)
Distributör:
Oral mikrobiologi, 901 87, Umeå
Disputation
2009-10-09, KBC3A9, plan 3, KBC-huset, Umeå Universitet, Umeå, 09:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2009-09-21 Skapad: 2009-09-13 Senast uppdaterad: 2018-06-08Bibliografiskt granskad

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Vallström, AnnaArnqvist, Anna

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