{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T18:42:20Z","timestamp":1791139340334,"version":"4.1.0"},"reference-count":54,"publisher":"American Society for Microbiology","issue":"5","license":[{"start":{"date-parts":[[2013,8,27]],"date-time":"2013-08-27T00:00:00Z","timestamp":1377561600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-sa\/3.0\/"},{"start":{"date-parts":[[2013,11,1]],"date-time":"2013-11-01T00:00:00Z","timestamp":1383264000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["mBio"],"published-print":{"date-parts":[[2013,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            <jats:named-content content-type=\"genus-species\">Vibrio cholerae<\/jats:named-content>\n            is an aquatic organism that causes the severe acute diarrheal disease cholera. The ability of\n            <jats:named-content content-type=\"genus-species\">V. cholerae<\/jats:named-content>\n            to cause disease is dependent upon the production of two critical virulence determinants, cholera toxin (CT) and the toxin-coregulated pilus (TCP). The expression of the genes that encode for CT and TCP production is under the control of a hierarchical regulatory system called the ToxR regulon, which functions to activate virulence gene expression in response to\n            <jats:italic>in vivo<\/jats:italic>\n            stimuli. Cyclic dipeptides have been found to be produced by numerous bacteria, yet their biological function remains unknown.\n            <jats:named-content content-type=\"genus-species\">V. cholerae<\/jats:named-content>\n            has been shown to produce cyclo(Phe-Pro). Previous studies in our laboratory demonstrated that cyclo(Phe-Pro) inhibited\n            <jats:named-content content-type=\"genus-species\">V. cholerae<\/jats:named-content>\n            virulence factor production. For this study, we report on the mechanism by which cyclo(Phe-Pro) inhibited virulence factor production. We have demonstrated that exogenous cyclo(Phe-Pro) activated the expression of\n            <jats:italic>leuO<\/jats:italic>\n            , a LysR-family regulator that had not been previously associated with\n            <jats:named-content content-type=\"genus-species\">V. cholerae<\/jats:named-content>\n            virulence. Increased\n            <jats:italic>leuO<\/jats:italic>\n            expression repressed\n            <jats:italic>aphA<\/jats:italic>\n            transcription, which resulted in downregulation of the ToxR regulon and attenuated CT and TCP production. The cyclo(Phe-Pro)-dependent induction of\n            <jats:italic>leuO<\/jats:italic>\n            expression was found to be dependent upon the virulence regulator ToxR. Cyclo(Phe-Pro) did not affect\n            <jats:italic>toxR<\/jats:italic>\n            transcription or ToxR protein levels but appeared to enhance the ToxR-dependent transcription of\n            <jats:italic>leuO<\/jats:italic>\n            . These results have identified\n            <jats:italic>leuO<\/jats:italic>\n            as a new component of the ToxR regulon and demonstrate for the first time that ToxR is capable of downregulating virulence gene expression in response to an environmental cue.\n          <\/jats:p>\n          <jats:p>\n            <jats:bold>IMPORTANCE<\/jats:bold>\n            The ToxR regulon has been a focus of cholera research for more than three decades. During this time, a model has emerged wherein ToxR functions to activate the expression of\n            <jats:named-content content-type=\"genus-species\">Vibrio cholerae<\/jats:named-content>\n            virulence factors upon host entry.\n            <jats:named-content content-type=\"genus-species\">V. cholerae<\/jats:named-content>\n            and other enteric bacteria produce cyclo(Phe-Pro), a cyclic dipeptide that we identified as an inhibitor of\n            <jats:named-content content-type=\"genus-species\">V. cholerae<\/jats:named-content>\n            virulence factor production. This finding suggested that cyclo(Phe-Pro) was a negative effector of virulence factor production and represented a molecule that could potentially be exploited for therapeutic development. In this work, we investigated the mechanism by which cyclo(Phe-Pro) inhibited virulence factor production. We found that cyclo(Phe-Pro) signaled through ToxR to activate the expression of\n            <jats:italic>leuO<\/jats:italic>\n            , a new virulence regulator that functioned to repress virulence factor production. Our results have identified a new arm of the ToxR regulon and suggest that ToxR may play a broader role in pathogenesis than previously known.\n          <\/jats:p>","DOI":"10.1128\/mbio.00366-13","type":"journal-article","created":{"date-parts":[[2013,8,28]],"date-time":"2013-08-28T02:02:03Z","timestamp":1377655323000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":53,"title":["Vibrio cholerae ToxR Downregulates Virulence Factor Production in Response to Cyclo(Phe-Pro)"],"prefix":"10.1128","volume":"4","author":[{"given":"X. 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