Transient Inability to Manage Proteobacteria Promotes Chronic Gut Inflammation in TLR5-Deficient Mice

Carvalho, Frédéric A.; Koren, Omry; Goodrich, Julia K.; Johansson, Malin; Nalbantoglu, ILKe; Aitken, Jesse D.; Su, Yueju; Chassaing, Benoît; Walters, William A.; González, Antonio; Clemente, José C.; Cullender, Tyler C.; Barnich, Nicolas; Darfeuille‐Michaud, Arlette; Vijay‐Kumar, Matam; Knight, Rob; Ley, Ruth E.; Gewirtz, Andrew T.

doi:10.1016/j.chom.2012.07.004

Cited by 457 publications

(373 citation statements)

References 38 publications

Supporting

Mentioning

352

Contrasting

Unclassified

Order By: Relevance

“…In addition, flagellin receptor TLR5-deficient mice (T5KO) display elevated intestinal proinflammatory gene expression and colitis. The Crohn's disease-associated E. coli LF82 strain induced chronic colitis in T5KO, which persisted well after the exogenously introduced bacterial species had been eliminated (46).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2015

Self Cite

View full text Add to dashboard Cite

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...

show abstract

Section: Discussionmentioning

confidence: 99%

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

et al. 2015

Self Cite

View full text Add to dashboard Cite

show abstract

“…It appears that Proteobacteria represents a persistent phylum in the absence of IgA. Because of the observed association between Proteobacteria and intestinal inflammation, 4,31 we investigated if the Proteobacteria-enriched microbiota seen in IgA deficient mice result in elevated levels of colonic pro-inflammatory mediators. Both WT and Igha -/-had comparable and elevated expression of MIP-2, TNF-α and IFN-γ in their colons at 1-week of life likely due to the high frequency of Proteobacteria seen in both strains of mice (Fig.…”

Section: Iga Deficiency Leads To Increased Colonization By Protebactementioning

confidence: 99%

“…3 In addition, the involvement of immune mechanisms in regulation of the gut bacterial composition is suggested by altered microbiota in genetically modified mice or during experimental intestinal infections. 4,5 However, the precise innate and adaptive immune mechanisms regulating the composition of the microbiota from birth to adulthood are still poorly understood.…”

Section: Introductionmentioning

confidence: 99%

Proteobacteria-specific IgA regulates maturation of the intestinal microbiota

et al. 2013

View full text Add to dashboard Cite

“…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). This flagella-mediated mucosal immune response is elicited via direct signaling through its cognate pattern-recognition receptor, Toll-like receptor 5 (14,15). Flagellin, a principal flagellar protein, continues to be implicated as a dominant antigen in CD and as a target of both innate and adaptive immune responses central to the immunopathogenesis of IBD (16,17).…”

mentioning

confidence: 99%

QseC inhibition as an antivirulence approach for colitis-associated bacteria

Rooks

Veiga

Reeves

et al. 2016

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

View full text Add to dashboard Cite

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

show abstract

Transient Inability to Manage Proteobacteria Promotes Chronic Gut Inflammation in TLR5-Deficient Mice

Cited by 457 publications

References 38 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

Proteobacteria-specific IgA regulates maturation of the intestinal microbiota

QseC inhibition as an antivirulence approach for colitis-associated bacteria

Contact Info

Product

Resources

About