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Aar (\n                    <jats:underline>A<\/jats:underline>\n                    ggR-\n                    <jats:underline>a<\/jats:underline>\n                    ctivated\n                    <jats:underline>r<\/jats:underline>\n                    egulator), the best-characterized member of the ANR family, regulates the master transcriptional regulator of virulence AggR and the global regulator HNS in enteroaggregative\n                    <jats:italic>Escherichia coli<\/jats:italic>\n                    (EAEC) by protein\u2013protein interactions. On the other hand, Rnr (\n                    <jats:underline>R<\/jats:underline>\n                    egA-\n                    <jats:underline>n<\/jats:underline>\n                    egative\n                    <jats:underline>r<\/jats:underline>\n                    egulator) is an ANR homolog identified in attaching and effacing (AE) pathogens, including\n                    <jats:italic>Citrobacter rodentium<\/jats:italic>\n                    and enteropathogenic\n                    <jats:italic>Escherichia coli<\/jats:italic>\n                    (EPEC), sharing only 25% identity with Aar. We previously found that\n                    <jats:italic>C. rodentium<\/jats:italic>\n                    lacking Rnr exhibits prolonged shedding and increased gut colonization in mice compared to the parental strain. To gain mechanistic insights into this phenomenon, we characterized the regulatory role of Rnr in the virulence of prototype EPEC strain E2348\/69 by genetic, biochemical, and human organoid-based approaches. Accordingly, RNA-seq analysis revealed more than 500 genes differentially regulated by Rnr, including the type-3 secretion system (T3SS). The abundance of EspA and EspB in whole cells and bacterial supernatants confirmed the negative regulatory activity of Rnr on T3SS effectors. We found that besides HNS and Ler, twenty-six other transcriptional regulators were also under Rnr control. Most importantly, the deletion of\n                    <jats:italic>aar<\/jats:italic>\n                    in EAEC or\n                    <jats:italic>rnr<\/jats:italic>\n                    in EPEC increases the adherence of these pathogens to human intestinal organoids. In contrast, the overexpression of ANR drastically reduces bacterial adherence and the formation of AE lesions in the intestine. Our study suggests a conserved regulatory mechanism and a central role of ANR in modulating intestinal colonization by these enteropathogens despite the fact that EAEC and EPEC evolved with utterly different virulence programs.\n                  <\/jats:p>","DOI":"10.1038\/s41598-023-33997-0","type":"journal-article","created":{"date-parts":[[2023,4,29]],"date-time":"2023-04-29T06:01:49Z","timestamp":1682748109000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Highly-conserved regulatory activity of the ANR family in the virulence of diarrheagenic bacteria through interaction with master and global regulators"],"prefix":"10.1038","volume":"13","author":[{"given":"Diana","family":"Rodriguez-Valverde","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jorge A.","family":"Giron","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James P.","family":"Nataro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernando","family":"Ruiz-Perez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Araceli E.","family":"Santiago","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,4,29]]},"reference":[{"key":"33997_CR1","doi-asserted-by":"publisher","first-page":"142","DOI":"10.1128\/CMR.11.1.142","volume":"11","author":"JP Nataro","year":"1998","unstructured":"Nataro, J. 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