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CC BY 4.0 · Thromb Haemost
DOI: 10.1055/a-2805-9903
Original Article: Blood Cells, Inflammation and Infection

Shiga Toxin 1a Blunts Shiga Toxin 2a-pathogenic Effects in Blood

Authors

  • Elisa Varrone

    1   Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy

  • Luciano Consagra

    1   Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy

  • Giorgia Rossi

    1   Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy

  • Domenica Carnicelli

    1   Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy

  • Paola Paterini

    1   Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy
    2   Center for Applied Biomedical Research-CRBA, University of Bologna, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy

  • Barbara Brunetti

    3   Department of Veterinary Medical Sciences (DIMEVET), University of Bologna, Ozzano dell'Emilia, Bologna, Italy

  • Francesca Ricci

    4   IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy

  • Pier Luigi Tazzari

    4   IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy

  • Gianluca Storci

    4   IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy

  • Massimiliano Bonafè

    1   Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy
    4   IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy

  • Gianluigi Ardissino

    5   Center for HUS Control, Prevention and Management, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy

  • Maurizio Brigotti

    1   Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy

Funding Information This work was funded by grants from Progetto Alice Associazione per la lotta alla SEU - ETS (to M.B.), and from the University of Bologna (RFO and Proof of Concept funds to M.B.).
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Graphical Abstract

ABSTRACT

Background

Once released into human blood, Shiga toxins (Stx) interact with platelets and leukocytes, stimulating them to form aggregates and to release pathogenic extracellular vesicles (EV) containing Stx. These EV are considered the trigger driving the transition from bloody diarrhea to the life-threatening hemolytic uremic syndrome (HUS) during human infections by Stx-producing Escherichia coli (STEC). In children, HUS is characterized by hemolytic anemia, thrombocytopenia, and acute renal failure. The risk of any STEC-infected patient of developing HUS varies significantly depending on the Stx type produced by the bacteria, i.e., it is negligible for Shiga toxin 1 (Stx1), relevant for Shiga toxin 2 (Stx2), and considerably reduced when both toxins are present.

Material and Methods

To mimic what happens in the bloodstream of patients, human blood was challenged with Stx2a, Stx1a, or both toxins, and the formation of leukocyte/platelet aggregates was evaluated by direct-flow cytometric analysis. Pathogenic blood cell-derived EV were then isolated, their number and size determined by nanoparticle tracking analysis, and their proteins characterized by capillary Western blotting.

Results

We found that the presence of Stx1a during Stx2a challenge significantly reduced the formation of pathogenic EV, particularly the large (>300 nm) EV population causing HUS development. Notably, the amount of Stx2a significantly decreased in Stx1a + Stx2a-triggered EV with respect to Stx2a-induced EV.

Conclusion

Our findings suggest that in STEC-infected children the presence of Stx1 in association with Stx2 reduces the risk of developing HUS by lowering the release of Stx2-containing blood cell-derived EV which are considered the main culprits for HUS onset.

Keywords

hemolytic uremic syndrome - acute renal failure - bacterial toxins - Shiga toxin-producing Escherichia coli

Contributors' Statement

E.V., L.C., G.R., D.C., P.P., B.B., F.R., P.L.T., and G.S.: performed the experiments; E.V., L.C., G.R., D.C., P.P., B.B., F.R., P.L.T., G.S., M.Bo., G.A., and M.B.: analyzed the data; E.V. and M.B.: wrote the manuscript; M.B.: designed the study. All authors read the manuscript and approved the final version.


Supplementary Material



Publication History

Received: 03 April 2025

Accepted after revision: 16 October 2025

Accepted Manuscript online:
06 February 2026

Article published online:
24 February 2026

© 2026. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/).

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