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Pro-inflammatory feedback activation cycle evoked by attack of Vibrio cholerae cytolysin on human neutrophil granulocytes

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Abstract

Vibrio cholerae cytolysin (VCC) is a pore-forming toxin that is secreted in precursor form (pro-VCC) and requires proteolytic cleavage in order to attain membrane-permeabilizing properties. Pro-VCC can be activated both in solution and membrane-bound state. Processing of membrane-bound pro-VCC can in turn be achieved through the action of both cell-associated and soluble proteases. The current investigation describes the interaction of VCC with human neutrophil granulocytes. It is shown that pro-VCC binds to these cells and is cleaved by cell-bound serine proteases. Membrane permeabilization leads to granulocyte activation, as witnessed by the generation of reactive oxygen metabolites and liberation of granule constituents. A mutant toxin with unaltered binding properties but devoid of pore-forming activity did not elicit these effects. The secreted proteases cleave and activate further bound- and non-bound pro-VCC. A positive feedback loop is thus created that results in enhanced cytotoxicity towards both the targeted granulocytes and towards bystander cells that are not primarily killed by the protoxin. Thus, activation of neutrophil granulocytes by VCC fuels a positive feedback cycle that will cripple immune defence, augment inflammation, and enhance the cytotoxic action of the toxin on neighbouring tissue cells.

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Acknowledgments

We thank Gertraud Regula for assistance with statistical analyses. This study was supported by the Deutsche Forschungsgemeinschaft, SFB 490 (project D3).

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Authors and Affiliations

  1. Institute of Medical Microbiology and Hygiene, University of Mainz, Augustusplatz, 55101, Mainz, Germany

    Angela Valeva, Ivan Walev, Silvia Weis, Fatima Boukhallouk & Sucharit Bhakdi

  2. Molecular Microbiology and Genomics Consultants, Zotzenheim, Germany

    Trudy M. Wassenaar

Authors
  1. Angela Valeva
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  2. Ivan Walev
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  3. Silvia Weis
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  4. Fatima Boukhallouk
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  6. Sucharit Bhakdi
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Corresponding author

Correspondence to Angela Valeva.

Additional information

Angela Valeva and Ivan Walev contributed equally to this work.

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Valeva, A., Walev, I., Weis, S. et al. Pro-inflammatory feedback activation cycle evoked by attack of Vibrio cholerae cytolysin on human neutrophil granulocytes. Med Microbiol Immunol 197, 285–293 (2008). https://doi.org/10.1007/s00430-007-0061-2

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  • DOI: https://doi.org/10.1007/s00430-007-0061-2

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