{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T22:11:18Z","timestamp":1773007878805,"version":"3.50.1"},"reference-count":50,"publisher":"American Society for Microbiology","issue":"6","license":[{"start":{"date-parts":[[2024,6,4]],"date-time":"2024-06-04T00:00:00Z","timestamp":1717459200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2024,6,4]],"date-time":"2024-06-04T00:00:00Z","timestamp":1717459200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"name":"MOST | National Key Research and Development Program of China","award":["2023YFC2308403"],"award-info":[{"award-number":["2023YFC2308403"]}]},{"DOI":"10.13039\/100022963","name":"Key Research and Development Program of Zhejiang Province","doi-asserted-by":"crossref","award":["2024SSYS0036"],"award-info":[{"award-number":["2024SSYS0036"]}],"id":[{"id":"10.13039\/100022963","id-type":"DOI","asserted-by":"crossref"}]},{"name":"MOST | NSFC | NSFC-Zhejiang Joint Fund | \u6d59\u6c5f\u7701\u79d1\u5b66\u6280\u672f\u5385 | Natural Science Foundation of Zhejiang Province","award":["LQ23C010001"],"award-info":[{"award-number":["LQ23C010001"]}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Microbiol Spectr"],"published-print":{"date-parts":[[2024,6,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:sec>\n            <jats:title\/>\n            <jats:p>\n              <jats:italic>Paeniclostridium sordellii<\/jats:italic>\n              hemorrhagic toxin (TcsH) and\n              <jats:italic>Clostridioides difficile<\/jats:italic>\n              toxin A (TcdA) are two major members of the large clostridial toxin (LCT) family. These two toxins share ~87% similarity and are known to cause severe hemorrhagic pathology in animals. Yet, the pathogenesis of their hemorrhagic toxicity has been mysterious for decades. Here, we examined the liver injury after systemic exposure to different LCTs and found that only TcsH and TcdA induce overt hepatic hemorrhage. By investigating the chimeric and truncated toxins, we demonstrated that the enzymatic domain of TcsH alone is not sufficient to determine its potent hepatic hemorrhagic toxicity in mice. Likewise, the combined repetitive oligopeptide (CROP) domain of TcsH\/TcdA alone also failed to explain their strong hemorrhagic activity in mice. Lastly, we showed that disrupting the first two short repeats of CROPs in TcsH and TcdA impaired hemorrhagic toxicity without causing overt changes in cytotoxicity and lethality. These findings lead to a deeper understanding of toxin-induced hemorrhage and the pathogenesis of LCTs and could be insightful in developing therapeutic avenues against clostridial infections.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>IMPORTANCE<\/jats:title>\n            <jats:p>\n              <jats:italic>Paeniclostridium sordellii<\/jats:italic>\n              and\n              <jats:italic>Clostridioides difficile<\/jats:italic>\n              infections often cause hemorrhage in the affected tissues and organs, which is mainly attributed to their hemorrhagic toxins, TcsH and TcdA. In this study, we demonstrate that TcsH and TcdA, but not other related toxins. including\n              <jats:italic>Clostridioides difficile<\/jats:italic>\n              toxin B and TcsL, induce severe hepatic hemorrhage in mice. We further determine that a small region in TcsH and TcdA is critical for the hemorrhagic toxicity but not cytotoxicity or lethality of these toxins. Based on these results, we propose that the hemorrhagic toxicity of TcsH and TcdA is due to an uncharacterized mechanism, such as the presence of an unknown receptor, and future studies to identify the interactive host factors are warranted.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1128\/spectrum.00354-24","type":"journal-article","created":{"date-parts":[[2024,5,6]],"date-time":"2024-05-06T13:00:28Z","timestamp":1715000428000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":3,"title":["Identification of a hemorrhagic determinant in\n            <i>Clostridioides difficile<\/i>\n            TcdA and\n            <i>Paeniclostridium sordellii<\/i>\n            TcsH"],"prefix":"10.1128","volume":"12","author":[{"given":"Yangling","family":"Zheng","sequence":"first","affiliation":[{"name":"College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang, China"},{"name":"Center for Infectious Disease Research, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China"},{"name":"Research Center for Industries of the Future and Key Laboratory of Multi-omics in Infection and Immunity of Zhejiang Province, School of Medicine, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China"},{"name":"Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, Zhejiang, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qi","family":"Yang","sequence":"additional","affiliation":[{"name":"College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang, China"},{"name":"Center for Infectious Disease Research, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China"},{"name":"Research Center for Industries of the Future and Key Laboratory of Multi-omics in Infection and Immunity of Zhejiang Province, School of Medicine, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, 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China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liuqing","family":"He","sequence":"additional","affiliation":[{"name":"Center for Infectious Disease Research, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China"},{"name":"Research Center for Industries of the Future and Key Laboratory of Multi-omics in Infection and Immunity of Zhejiang Province, School of Medicine, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China"},{"name":"Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, Zhejiang, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chao","family":"Ma","sequence":"additional","affiliation":[{"name":"Center for Infectious Disease Research, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China"},{"name":"Research Center for Industries of the Future and Key Laboratory of Multi-omics in Infection and Immunity of Zhejiang Province, 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