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When <jats:italic>V. cholerae<\/jats:italic> is ingested, the bacteria colonize the epithelium of the small intestine and stimulate the Paneth cells to produce large amounts of cationic antimicrobial peptides (CAMPs). Human defensin 5 (HD-5) is the most abundant CAMPs in the small intestine. However, the role of the <jats:italic>V. cholerae<\/jats:italic> response to HD-5 remains unclear. Here we show that HD-5 significantly upregulates virulence gene expression. Moreover, a two-component system, CarSR (or RstAB), is essential for <jats:italic>V. cholerae<\/jats:italic> virulence gene expression in the presence of HD-5. Finally, phosphorylated CarR can directly bind to the promoter region of TcpP, activating transcription of <jats:italic>tcpP<\/jats:italic>, which in turn activates downstream virulence genes to promote <jats:italic>V. cholerae<\/jats:italic> colonization. In conclusion, this study reveals a virulence-regulating pathway, in which the CarSR two-component regulatory system senses HD-5 to activate virulence genes expression in <jats:italic>V. cholerae<\/jats:italic>.<\/jats:p>","DOI":"10.1038\/s42003-022-03525-3","type":"journal-article","created":{"date-parts":[[2022,6,8]],"date-time":"2022-06-08T10:03:24Z","timestamp":1654682604000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Vibrio cholerae senses human enteric \u03b1-defensin 5 through a CarSR two-component system to promote bacterial pathogenicity"],"prefix":"10.1038","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0639-9337","authenticated-orcid":false,"given":"Yutao","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2913-2133","authenticated-orcid":false,"given":"Tingting","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junxi","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yangfei","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingmei","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruiying","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6300-3140","authenticated-orcid":false,"given":"Bin","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7320-291X","authenticated-orcid":false,"given":"Kai","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,6,8]]},"reference":[{"key":"3525_CR1","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1111\/j.1574-6976.2002.tb00605.x","volume":"26","author":"J Reidl","year":"2002","unstructured":"Reidl, J. & Klose, K. 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