{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T23:23:53Z","timestamp":1788909833660,"version":"build-2803163510"},"reference-count":33,"publisher":"Georg Thieme Verlag KG","license":[{"start":{"date-parts":[[2026,2,6]],"date-time":"2026-02-06T00:00:00Z","timestamp":1770336000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005969","name":"Universit\u00e0 di Bologna","doi-asserted-by":"crossref","award":["Proof of Concept 2021,RFO 2023"],"award-info":[{"award-number":["Proof of Concept 2021,RFO 2023"]}],"id":[{"id":"10.13039\/501100005969","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Progetto ALICE Associazione per la lotta alla SEU - ETS","award":["2024"],"award-info":[{"award-number":["2024"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Thromb Haemost"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n                  <jats:p>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.<\/jats:p>\n                  <jats:p>We found that the presence of Stx1a during Stx2a challenge significantly reduced the formation of pathogenic EV, particularly the large (&gt;300\u2009nm) EV population causing HUS development. Notably, the amount of Stx2a significantly decreased in Stx1a\u2009+\u2009Stx2a-triggered EV with respect to Stx2a-induced EV.<\/jats:p>\n                  <jats:p>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.<\/jats:p>","DOI":"10.1055\/a-2805-9903","type":"journal-article","created":{"date-parts":[[2026,2,6]],"date-time":"2026-02-06T23:52:27Z","timestamp":1770421947000},"source":"Crossref","is-referenced-by-count":2,"title":["Shiga Toxin 1a Blunts Shiga Toxin 2a-pathogenic Effects in Blood"],"prefix":"10.1055","author":[{"given":"Elisa","family":"Varrone","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luciano","family":"Consagra","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giorgia","family":"Rossi","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Domenica","family":"Carnicelli","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Paterini","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy"},{"name":"Center for Applied Biomedical Research-CRBA, University of Bologna, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Brunetti","sequence":"additional","affiliation":[{"name":"Department of Veterinary Medical Sciences (DIMEVET), University of Bologna, Ozzano dell'Emilia, Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Ricci","sequence":"additional","affiliation":[{"name":"IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pier Luigi","family":"Tazzari","sequence":"additional","affiliation":[{"name":"IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gianluca","family":"Storci","sequence":"additional","affiliation":[{"name":"IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimiliano","family":"Bonaf\u00e8","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy"},{"name":"IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gianluigi","family":"Ardissino","sequence":"additional","affiliation":[{"name":"Center for HUS Control, Prevention and Management, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maurizio","family":"Brigotti","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"194","published-online":{"date-parts":[[2026,2,24]]},"reference":[{"issue":"05","key":"ref1","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1016\/j.ajpath.2021.02.011","article-title":"Extracellular vesicles and renal endothelial cells: a fatal attraction in hemolytic uremic syndrome","volume":"191","author":"E Varrone","year":"2021","journal-title":"Am J Pathol"},{"issue":"09","key":"ref2","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1007\/s00431-008-0745-7","article-title":"What's new in haemolytic uraemic syndrome?","volume":"167","author":"S Johnson","year":"2008","journal-title":"Eur J Pediatr"},{"issue":"9464","key":"ref3","first-page":"1073","article-title":"Shiga-toxin-producing Escherichia coli and haemolytic uraemic syndrome","volume":"365","author":"P I Tarr","year":"2005","journal-title":"Lancet"},{"issue":"05","key":"ref4","doi-asserted-by":"crossref","first-page":"345","DOI":"10.3390\/toxins12050345","article-title":"Molecular biology of Escherichia coli Shiga toxins' effects on mammalian cells","volume":"12","author":"C Menge","year":"2020","journal-title":"Toxins (Basel)"},{"issue":"04","key":"ref5","doi-asserted-by":"crossref","first-page":"0007","DOI":"10.1128\/microbiolspec.EHEC-0007-2013","article-title":"The locus of enterocyte effacement and associated virulence factors of enterohemorrhagic Escherichia coli","volume":"2","author":"M P Stevens","year":"2014","journal-title":"Microbiol Spectr"},{"issue":"15","key":"ref6","doi-asserted-by":"crossref","first-page":"1402","DOI":"10.1056\/NEJMra2108739","article-title":"Shiga toxin-producing Escherichia coli and the hemolytic-uremic syndrome","volume":"389","author":"S B Freedman","year":"2023","journal-title":"N Engl J 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