{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T08:48:07Z","timestamp":1791276487632,"version":"4.1.0"},"reference-count":64,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2011,7,1]],"date-time":"2011-07-01T00:00:00Z","timestamp":1309478400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2011,7,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Shiga toxin (Stx)-producing E.coli O157:H7 has become a global threat to public health; it is a primary cause of diarrhea-associated hemolytic uremic syndrome (HUS), a disorder of thrombocytopenia, microangiopathic hemolytic anemia, and acute renal failure with thrombi occluding renal microcirculation. In this study, we explored whether Stx triggers complement-dependent microvascular thrombosis in in vitro and in vivo experimental settings of HUS. Stx induced on human microvascular endothelial cell surface the expression of P-selectin, which bound and activated C3 via the alternative pathway, leading to thrombus formation under flow. In the search for mechanisms linking complement activation and thrombosis, we found that exuberant complement activation in response to Stx generated an increased amount of C3a that caused further endothelial P-selectin expression, thrombomodulin (TM) loss, and thrombus formation. In a murine model of HUS obtained by coinjection of Stx2 and LPS and characterized by thrombocytopenia and renal dysfunction, upregulation of glomerular endothelial P-selectin was associated with C3 and fibrin(ogen) deposits, platelet clumps, and reduced TM expression. Treatment with anti\u2013P-selectin Ab limited glomerular C3 accumulation. Factor B-deficient mice after Stx2\/LPS exhibited less thrombocytopenia and were protected against glomerular abnormalities and renal function impairment, indicating the involvement of complement activation via the alternative pathway in the glomerular thrombotic process in HUS mice. The functional role of C3a was documented by data showing that glomerular fibrin(ogen), platelet clumps, and TM loss were markedly decreased in HUS mice receiving C3aR antagonist. These results identify Stx-induced complement activation, via P-selectin, as a key mechanism of C3a-dependent microvascular thrombosis in diarrhea-associated HUS.<\/jats:p>","DOI":"10.4049\/jimmunol.1100491","type":"journal-article","created":{"date-parts":[[2011,6,4]],"date-time":"2011-06-04T04:33:58Z","timestamp":1307162038000},"page":"172-180","source":"Crossref","is-referenced-by-count":211,"title":["Alternative Pathway Activation of Complement by Shiga Toxin Promotes Exuberant C3a Formation That Triggers Microvascular Thrombosis"],"prefix":"10.1093","volume":"187","author":[{"given":"Marina","family":"Morigi","sequence":"first","affiliation":[{"name":"Mario Negri Institute for Pharmacological Research, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso , 24126 Bergamo ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miriam","family":"Galbusera","sequence":"additional","affiliation":[{"name":"Mario Negri Institute for Pharmacological Research, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso , 24126 Bergamo ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Gastoldi","sequence":"additional","affiliation":[{"name":"Mario Negri Institute for Pharmacological Research, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso , 24126 Bergamo ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica","family":"Locatelli","sequence":"additional","affiliation":[{"name":"Mario Negri Institute for Pharmacological Research, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso , 24126 Bergamo ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simona","family":"Buelli","sequence":"additional","affiliation":[{"name":"Mario Negri Institute for Pharmacological Research, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso , 24126 Bergamo ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Pezzotta","sequence":"additional","affiliation":[{"name":"Mario Negri Institute for Pharmacological Research, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso , 24126 Bergamo ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Pagani","sequence":"additional","affiliation":[{"name":"Mario Negri Institute for Pharmacological Research, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso , 24126 Bergamo ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Noris","sequence":"additional","affiliation":[{"name":"Mario Negri Institute for Pharmacological Research, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso , 24126 Bergamo 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,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Remuzzi","sequence":"additional","affiliation":[{"name":"Mario Negri Institute for Pharmacological Research, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso , 24126 Bergamo ,","place":["Italy"]},{"name":"Unit\u00e0 di Nefrologia e Dialisi, Azienda Ospedaliera Ospedali Riuniti di Bergamo , 24128 Bergamo ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlamaria","family":"Zoja","sequence":"additional","affiliation":[{"name":"Mario Negri Institute for Pharmacological Research, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso , 24126 Bergamo ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2011,7,1]]},"reference":[{"key":"2025032410180775700_r1","first-page":"1073","article-title":"Shiga-toxin-producing Escherichia coli and 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Nephrol."},{"key":"2025032410180775700_r3","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.1681\/ASN.2004100861","article-title":"Hemolytic uremic syndrome","volume":"16","author":"Noris","year":"2005","journal-title":"J. Am. Soc. Nephrol."},{"key":"2025032410180775700_r4","doi-asserted-by":"crossref","first-page":"1360","DOI":"10.1001\/jama.290.10.1360","article-title":"Long-term renal prognosis of diarrhea-associated hemolytic uremic syndrome: a systematic review, meta-analysis, and meta-regression","volume":"290","author":"Garg","year":"2003","journal-title":"JAMA"},{"key":"2025032410180775700_r5","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1385\/MB:26:2:117","article-title":"Infection by Shiga toxin-producing Escherichia coli: an overview","volume":"26","author":"Karmali","year":"2004","journal-title":"Mol. Biotechnol."},{"key":"2025032410180775700_r6","doi-asserted-by":"crossref","first-page":"1425","DOI":"10.1007\/s00467-008-0820-3","article-title":"Enterohaemorrhagic Escherichia coli and Shigella dysenteriae type 1-induced haemolytic uraemic syndrome","volume":"23","author":"Mark Taylor","year":"2008","journal-title":"Pediatr. Nephrol."},{"key":"2025032410180775700_r7","doi-asserted-by":"crossref","first-page":"4868","DOI":"10.1073\/pnas.0710834105","article-title":"Variation in virulence among clades of Escherichia coli O157:H7 associated with disease outbreaks","volume":"105","author":"Manning","year":"2008","journal-title":"Proc. Natl. Acad. Sci. 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