Sub-Projects of SFB 535
Invasion and Replication Strategies of Pathogenes
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SP A11

The production of Shiga toxin
and its relevance for enteric E. coli infections in cattle



Dr. Christian Menge

Prof. Dr. Georg Baljer

Institut f. Hygiene u.
Infektionskrankheiten d. Tiere (FB 10)

Justus-Liebig-Universität, Gießen



Summary


A considerable number of cattle is persistently infected with Shigatoxin-producing Escherichia coli (STEC) and thereby represent a source of infections of man with human pathogenic STEC strains (syn. enterohemorrhagic E. coli (EHEC)). Intervention strategies to effectively prevent human EHEC infections must be aimed at the limitation of bovine STEC infections, therefore. At the beginning of the project, the mechanisms that form the basis of the persistence were poorly understood. In the course of the past funding periods we were able to prove that the production of Shiga toxins (Stxs) plays an important role in that Stxs suppress the local and systemic immune response in cattle. Stx1 accelerates the transcription of il-4 in intraepithelial lymphocytes (IEL) in vitro and eventually blocks the activation of the IEL. In addition Stx1 induces the transcription of certain chemokine genes in intestinal epithelial cells and mucosal macrophages, newly identified target cells for Stx in cattle. As a consequence, the integrity of the local immune defense is disturbed to an extend that changes in the IEL composition can be observed in calves after experimental STEC infection. Since Stx1 blocks the activation of peripheral lymphocytes in early phases in vitro, the toxin is capable of delaying the development of a systemic immune response against STEC antigens in calves orally infected with the bacteria. We therefore conclude that an intervention strategy that prevents the establishment of a persistent STEC infection in cattle has to efficiently block the immunosuppressive effect of Stx at the time of the first infection. This blockade needs to be effective prior to binding of the toxin to its cellular receptor, because we have evidence that sole binding of the enzymatically inactive B-subunit is cabable of suppressing bovine lymphocytes. Therefore, the objectives of the project in the upcoming funding period are to investigate receptor derived signals by the use of alternate ligands and to evaluate their meaning relative to the cytoplasmic inhibition of the protein synthesis. Another focus will be put on the characterisation of the Stx1 effects on antigen-presenting macrophages. Finally, it will be examined by biochemical and functional methods 1) against what part of the toxin molecules the antibodies are directed that naturally occur in the serum and mucosal secretions of cattle upon STEC infections, 2) at what age of calves these antibodies appear first and 3) why they are unable to prevent the persistence of the STEC infection. Obtained findings will be eventually used to develop a vaccination strategy efficacy of which will be tested in calves.
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