Regulatory and functional co‐operation of flagella and type 1 pili in adhesive and invasive abilities of AIEC strain LF82 isolated from a patient with Crohn's disease

Barnich, Nicolas; Boudeau, Jérôme; Claret, Laurent; Darfeuille‐Michaud, Arlette

doi:10.1046/j.1365-2958.2003.03468.x

Cited by 125 publications

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“…8). Flagella of the AIEC LF82 strain have established roles in the adhesion to and invasion of intestinal epithelial cells (43,44). Electronic microscopy analysis of the wild-type and LF82 ⌬nrdR isogenic mutant demonstrated reduced flagellar expression when the nrdR gene was attenuated.…”

Section: Discussionmentioning

confidence: 99%

“…It is well described that flagella contribute to AIEC virulence. Indeed, the nonmotile aflagellar LF82 mutants (⌬fliC or ⌬fliA mutants) exhibit a drastic reduction in adherence and invasion ability (43,44), and the flagellar sigma factor FliA regulates the adhesion and invasion of Crohn's disease-associated Escherichia coli via a cyclic dimeric GMP-dependent pathway (44). In addition, Crohn's disease-associated virulent AIEC LF82 bacteria, via flagellar expression, are able to potentiate an inflammatory mucosal immune response in the dextran sulfate sodium (DSS)-injured colons of BALBc/J mice via increased expression of Toll-like receptor 5 (TLR5) and IPAF flagellin receptors (45).…”

Section: Discussionmentioning

confidence: 99%

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Ribonucleotide Reductase NrdR as a Novel Regulator for Motility and Chemotaxis during Adherent-Invasive Escherichia coli Infection

et al. 2015

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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.R ibonucleotide reductase (RNR) is an essential enzyme in all living organisms. It catalyzes the reduction of ribonucleotides (nucleoside triphosphates [NTPs]) to their corresponding 2=-deoxyribonucleotides (deoxynucleoside triphosphates [dNTPs]) and therefore plays an essential role in DNA synthesis and repair. Three RNR classes (classes I, II, and III) exist; these classes exhibit different primary structures, subunit cofactor requirements, and quaternary three-dimensional (3D) structures, but they all are allosterically regulated and share similar catalytic mechanisms (1, 2). Class I RNRs are oxygendependent enzymes that occur in eubacteria, eukaryotes, and some viruses. This class comprises two main subgroups (Ia and Ib). Class Ia RNRs are encoded by an operon containing nrdA and nrdB genes. These genes encode the NrdA subunit, which is catalytically and allosterically regulated, and the NrdB subunit, which possesses radical-generating activity. Class Ib RNRs are encoded by an operon containing the nrdH, nrdI, nrdE, and nrdF genes, which encode the corresponding specific redoxin NrdH, the activating subunit NrdI, the catalytic subunit NrdE, and the radical-generating subunit NrdF. Class III RNRs are present in facultative anaerobic and strict anaerobic microorganisms and use S-adenosylmethionine and iron-sulfur clusters in the NrdG accessory protein to create a stab...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Ribonucleotide Reductase NrdR as a Novel Regulator for Motility and Chemotaxis during Adherent-Invasive Escherichia coli Infection

et al. 2015

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“…1B), supporting the idea that QseC regulates flagellar protein production. Given that flagella are required for LF82 virulence (13,14) and that qseC inactivation suppresses the expression of flagellar genes and proteins ( Fig. 1 A and B), we assessed flagella function via plate-based motility assays.…”

Section: Resultsmentioning

confidence: 99%

“…A key mechanism driving this virulence, although undoubtedly not the sole virulence mechanism, is the production of flagella. Inactivating the flagellar gene fliC blocks LF82 invasion and reduces its adhesion to cultured IECs (13). In the setting of dextran sodium sulfate (DSS)-induced mucosal injury, LF82 can exacerbate colonic inflammation, an effect abrogated in the absence of fliC (14).…”

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confidence: 99%

QseC inhibition as an antivirulence approach for colitis-associated bacteria

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Reeves

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Hosts and their microbes have established a sophisticated communication system over many millennia. Within mammalian hosts, this dynamic cross-talk is essential for maintaining intestinal homeostasis. In a genetically susceptible host, dysbiosis of the gut microbiome and dysregulated immune responses are central to the development of inflammatory bowel disease (IBD). Previous surveys of stool from the T-bet −/− Rag2 −/− IBD mouse model revealed microbial features that discriminate between health and disease states. Enterobacteriaceae expansion and increased gene abundances for benzoate degradation, two-component systems, and bacterial motility proteins pointed to the potential involvement of a catecholamine-mediated bacterial signaling axis in colitis pathogenesis. Enterobacteriaceae sense and respond to microbiota-generated signals and host-derived catecholamines through the two-component quorum-sensing Escherichia coli regulators B and C (QseBC) system. On signal detection, QseC activates a cascade to induce virulence gene expression. Although a single pathogen has not been identified as a causative agent in IBD, adherent-invasive Escherichia coli (AIEC) have been implicated. Flagellar expression is necessary for the IBD-associated AIEC strain LF82 to establish colonization. Thus, we hypothesized that qseC inactivation could reduce LF82's virulence, and found that an absence of qseC leads to down-regulated flagellar expression and motility in vitro and reduced colonization in vivo. We extend these findings on the potential of QseC-based IBD therapeutics to three preclinical IBD models, wherein we observe that QseC blockade can effectively modulate colitogenic microbiotas to reduce intestinal inflammation. Collectively, our data support a role for QseC-mediated bacterial signaling in IBD pathogenesis and indicate that QseC inhibition may be a useful microbiota-targeted approach for disease management.colitis | Escherichia coli | QseC | antivirulence | gut microbiome

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“…This provides evidence that cross-talk can work in both directions to prevent multiple fimbrial expression at the level of the single bacterial cell. Other fimbrial and nonfimbrial adhesins, along with flagella and capsule, are also likely to be regulated co-ordinately at the single-cell level to achieve systematic expression that prolongs the infection and maximizes the number of bacteria produced (Barnich et al, 2003;Schwan et al, 2005). Therefore, while phase The boxplots are as described in Fig.…”

Section: Discussionmentioning

confidence: 99%

Demonstration of regulatory cross-talk between P fimbriae and type 1 fimbriae in uropathogenic Escherichia coli

et al. 2006

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The majority of Escherichia coli strains isolated from urinary tract infections have the potential to express multiple fimbriae. Two of the most common fimbrial adhesins are type 1 fimbriae and pyelonephritis-associated pili (Pap). Previous research has shown that induced, plasmid-based expression of a Pap regulator, papB, and its close homologues can prevent inversion of the fim switch controlling the expression of type 1 fimbriae. The aim of the present study was to determine if this cross-regulation occurs when PapB is expressed from its native promoter in the chromosome of E. coli K-12 and clinical isolates. The regulation was examined in three ways: (1) mutated alleles of the pap regulatory region, including papB and papI, that maintain the pap promoter in either the off or the on phase were exchanged into the chromosome of both E. coli K-12 and the clinical isolate E. coli CFT073, and the effect on type 1 fimbrial expression was measured; (2) type 1 fimbrial expression was determined using a novel fimS : : gfp + reporter system in mutants of the clinical isolate E. coli 536 in which combinations of complete fimbrial clusters had been deleted; (3) type 1 fimbrial expression was determined in a range of clinical isolates and compared with both the number of P clusters and their expression. All three approaches demonstrated that P expression represses type 1 fimbrial expression. Using a number of novel genetic approaches, this work extends the initial finding that PapB inhibits FimB recombination to the impact of this regulation in clinical isolates. INTRODUCTIONUrinary tract infections (UTIs) are common, affecting a large proportion of the population. It is estimated that 20 % of women develop a UTI in their lifetime, and antibiotic treatment results in approximately 110 000 prescriptions per million inhabitants per annum in Europe (Naber, 2000). Escherichia coli strains are the predominant cause of uncomplicated UTIs, responsible for between 60 and 80 % of the cases reported in the UK each year (Graham & Galloway, 2001). Many infections are asymptomatic, especially in the elderly (Nicolle, 2001), but others result in cystitis. If the infection ascends to the kidney, then pyelonephritis can occur. Such infections are a significant origin of Gramnegative sepsis.Fimbrial adhesins are important virulence factors that allow binding of the bacteria to specific receptors on epithelial cells of the urinary tract. The two adhesins most commonly associated with UTI are type 1 fimbriae, and pyelonephritisassociated pili (Pap) and Pap-related fimbriae (Prf); the last two are collectively termed P fimbriae in this study. Type 1 fimbriae mediate binding to a-D-mannose-containing receptors and extracellular matrix components, whereas P fimbriae bind to glycoreceptors containing the aGal(1-4)bGal moiety (Lindberg et al., 1984). Although type 1 fimbriae are common to the majority of E. coli isolates, the FimH adhesin has been shown to be important in a mouse model of UTI, and a degranulation response to the fimbriae is asso...

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Regulatory and functional co‐operation of flagella and type 1 pili in adhesive and invasive abilities of AIEC strain LF82 isolated from a patient with Crohn's disease

Cited by 125 publications

References 50 publications

Ribonucleotide Reductase NrdR as a Novel Regulator for Motility and Chemotaxis during Adherent-Invasive Escherichia coli Infection

Ribonucleotide Reductase NrdR as a Novel Regulator for Motility and Chemotaxis during Adherent-Invasive Escherichia coli Infection

QseC inhibition as an antivirulence approach for colitis-associated bacteria

Demonstration of regulatory cross-talk between P fimbriae and type 1 fimbriae in uropathogenic Escherichia coli

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