title: Ribonucleotide reductase NrdR as a novel regulator for motility and chemotaxis during adherent-invasive Escherichia coli infection.
abstract: A critical step in the life cycle of all organisms is the duplication of the genetic material during cell division. Ribonucleotide reductases (RNRs) are essential enzymes for this step because they control the de novo production of the deoxyribonucleotides required for DNA synthesis and repair. Enterobacteriaceae have three functional classes of RNRs (Ia, Ib, and III), which are transcribed from separate operons and encoded by the genes nrdAB, nrdHIEF, and nrdDG, respectively. Here, we investigated the role of RNRs in the virulence of adherent-invasive Escherichia coli (AIEC) isolated from Crohn's disease (CD) patients. Interestingly, the LF82 strain of AIEC harbors four different RNRs (two class Ia, one class Ib, and one class III). Although the E. coli RNR enzymes have been extensively characterized both biochemically and enzymatically, little is known about their roles during bacterial infection. We found that RNR expression was modified in AIEC LF82 bacteria during cell infection, suggesting that RNRs play an important role in AIEC virulence. Knockout of the nrdR and nrdD genes, which encode a transcriptional regulator of RNRs and class III anaerobic RNR, respectively, decreased AIEC LF82's ability to colonize the gut mucosa of transgenic mice that express human CEACAM6 (carcinoembryonic antigen-related cell adhesion molecule 6). Microarray experiments demonstrated that NrdR plays an indirect role in AIEC virulence by interfering with bacterial motility and chemotaxis. Thus, the development of drugs targeting RNR classes, in particular NrdR and NrdD, could be a promising new strategy to control gut colonization by AIEC bacteria in CD patients.
authors.affiliation: Clermont Université, "M2iSH Microbe intestin inflammation et Susceptibilité de l'Hôte," UMR 1071 Inserm/Université d'Auvergne, Clermont-Ferrand, France Unité Sous Contrat Institut National de la Recherche Agronomique 2018, Clermont-Ferrand, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Dreux
authors.affiliation: Institute for Bioengineering of Catalonia (IBEC), Bacterial infections and antimicrobial therapies group, Barcelona, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: del Mar Cendra
authors.affiliation: Clermont Université, "M2iSH Microbe intestin inflammation et Susceptibilité de l'Hôte," UMR 1071 Inserm/Université d'Auvergne, Clermont-Ferrand, France Unité Sous Contrat Institut National de la Recherche Agronomique 2018, Clermont-Ferrand, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Massier
authors.affiliation: Clermont Université, "M2iSH Microbe intestin inflammation et Susceptibilité de l'Hôte," UMR 1071 Inserm/Université d'Auvergne, Clermont-Ferrand, France Unité Sous Contrat Institut National de la Recherche Agronomique 2018, Clermont-Ferrand, France Institut Universitaire de Technologie, Génie Biologique, Aubière, France.
authors.forename: Arlette
authors.initials: A
authors.lastname: Darfeuille-Michaud
authors.affiliation: Clermont Université, "M2iSH Microbe intestin inflammation et Susceptibilité de l'Hôte," UMR 1071 Inserm/Université d'Auvergne, Clermont-Ferrand, France Unité Sous Contrat Institut National de la Recherche Agronomique 2018, Clermont-Ferrand, France Institut Universitaire de Technologie, Génie Biologique, Aubière, France nicolas.barnich@udamail.fr etorrents@ibecbarcelona.eu.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Barnich
authors.affiliation: Institute for Bioengineering of Catalonia (IBEC), Bacterial infections and antimicrobial therapies group, Barcelona, Spain nicolas.barnich@udamail.fr etorrents@ibecbarcelona.eu.
authors.forename: Eduard
authors.identifier: http://orcid.org/0000-0002-3010-1609
authors.initials: E
authors.lastname: Torrents
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis* / Q000235:genetics; D001422:Bacterial Adhesion / Q000235:genetics*; D015815:Cell Adhesion Molecules / Q000096:biosynthesis* / Q000235:genetics; D002633:Chemotaxis / Q000235:genetics*; D003424:Crohn Disease / Q000382:microbiology; D004926:Escherichia coli / Q000235:genetics / Q000276:immunology / Q000472:pathogenicity*; D004927:Escherichia coli Infections / Q000235:genetics / Q000473:pathology; D029968:Escherichia coli Proteins / Q000096:biosynthesis / Q000235:genetics*; D058851:GPI-Linked Proteins / Q000096:biosynthesis / Q000235:genetics; D015964:Gene Expression Regulation, Bacterial; D006801:Humans; D007413:Intestinal Mucosa / Q000382:microbiology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D046228:Microarray Analysis; D011401:Promoter Regions, Genetic; D012264:Ribonucleotide Reductases / Q000235:genetics; D037521:Virulence Factors / Q000096:biosynthesis / Q000235:genetics
chemical_list: D015703:Antigens, CD; C504117:CEACAM6 protein, human; D015815:Cell Adhesion Molecules; D029968:Escherichia coli Proteins; D058851:GPI-Linked Proteins; C523273:NrdR protein, E coli; D037521:Virulence Factors; D012264:Ribonucleotide Reductases; C101141:anaerobic ribonucleotide reductase