Small Intestine Early Innate Immunity Response during Intestinal Colonization by Escherichia coli Depends on Its Extra-Intestinal Virulence Status

International audienceUropathogenic Escherichia coli (UPEC) strains live as commensals in the digestive tract of the host, but they can also initiate urinary tract infections. The aim of this work was to determine how a host detects the presence of a new UPEC strain in the digestive tract. Mice were orally challenged with UPEC strains 536 and CFT073, non-pathogenic strain K12 MG1655, and ΔPAI-536, an isogenic mutant of strain 536 lacking all 7 pathogenicity islands whose virulence is drastically attenuated. Intestinal colonization was measured, and cytokine expression was determined in various organs recovered from mice after oral challenge. UPEC strain 536 efficiently colonized the mouse digestive tract, and prior Enterobacteriaceae colonization was found to impact strain 536 colonization efficiency. An innate immune response, detected as the production of TNFα, IL-6 and IL-10 cytokines, was activated in the ileum 48 hours after oral challenge with strain 536, and returned to baseline within 8 days, without a drop in fecal pathogen load. Although inflammation was detected in the ileum, histology was normal at the time of cytokine peak. Comparison of cytokine secretion 48h after oral gavage with E. coli strain 536, CFT073, MG1655 or ΔPAI-536 showed that inflammation was more pronounced with UPECs than with non-pathogenic or attenuated strains. Pathogenicity islands also seemed to be involved in host detection, as IL-6 intestinal secretion was increased after administration of E. coli strain 536, but not after administration of ΔPAI-536. In conclusion, UPEC colonization of the mouse digestive tract activates acute phase inflammatory cytokine secretion but does not trigger any pathological changes, illustrating the opportunistic nature of UPECs. This digestive tract colonization model will be useful for studying the factors controlling the switch from commensalism to pathogenicity

Organised Genome Dynamics in the Escherichia coli Species Results in Highly Diverse Adaptive Paths

The Escherichia coli species represents one of the best-studied model organisms, but also encompasses a variety of commensal and pathogenic strains that diversify by high rates of genetic change. We uniformly (re-) annotated the genomes of 20 commensal and pathogenic E. coli strains and one strain of E. fergusonii (the closest E. coli related species), including seven that we sequenced to completion. Within the ∼18,000 families of orthologous genes, we found ∼2,000 common to all strains. Although recombination rates are much higher than mutation rates, we show, both theoretically and using phylogenetic inference, that this does not obscure the phylogenetic signal, which places the B2 phylogenetic group and one group D strain at the basal position. Based on this phylogeny, we inferred past evolutionary events of gain and loss of genes, identifying functional classes under opposite selection pressures. We found an important adaptive role for metabolism diversification within group B2 and Shigella strains, but identified few or no extraintestinal virulence-specific genes, which could render difficult the development of a vaccine against extraintestinal infections. Genome flux in E. coli is confined to a small number of conserved positions in the chromosome, which most often are not associated with integrases or tRNA genes. Core genes flanking some of these regions show higher rates of recombination, suggesting that a gene, once acquired by a strain, spreads within the species by homologous recombination at the flanking genes. Finally, the genome's long-scale structure of recombination indicates lower recombination rates, but not higher mutation rates, at the terminus of replication. The ensuing effect of background selection and biased gene conversion may thus explain why this region is A+T-rich and shows high sequence divergence but low sequence polymorphism. Overall, despite a very high gene flow, genes co-exist in an organised genome

Cohorte nationale des patients hémodialysés infectés par le VIH en France en 2002 (description socio-démographique, répartition sur le territoire, survie, facteurs pronostiques de mortalité)

PARIS-BIUM (751062103) / SudocCentre Technique Livre Ens. Sup. (774682301) / SudocSudocFranceF

Lactobacillus : ce qu’il fait à l’intérieur, se voit…à l’intérieur

International audienceDans un travail récemment publié, une équipe japonaise montre comment un simple composant du microbiote intestinal peut influencer l’évolution de l’insuffisance rénale chroniqu

Génération de la diversité génétique au sein de l'espèce Escherichia coli et relation avec la phylogénie et la virulence

PARIS5-BU Méd.Cochin (751142101) / SudocSudocFranceF

Néphrotoxicité du ténofovir

International audienceTenofovir is currently the only commercially available nucleotidic reverse-transcriptase inhibitor of human immunodeficiency virus (HIV). It is overall very well tolerated and is prescribed to millions of patients–without any specific monitoring in developing countries. However a significant nephrotoxicity has been described. Acute nephrotoxicity is well characterized. Tenofovir is excreted in urine by proximal tubular epithelial cells. In case of cytoplasmic accumulation, tenofovir inhibits mitochondrial DNA polymerase γ, which causes a dysfunction of the respiratory chain, and in turn an alteration of the energy-deprived cells. Fanconi syndrome is the clinical expression of tenofovir acute toxicity, with sometimes an associated acute kidney failure. These abnormalities are usually reversible, at least partially, when tenofovir is discontinued. Tenofovir chronic toxicity has been debated but seems now well established by several cohort studies, even though it pathophysiology has yet to be understood. It manifests as an accelerated glomerular filtration rate decline in treated patients with no other renal abnormalities. The identification of this chronic toxicity was probably blurred by multiple cofactors, usually excluded from clinical trials. Simple measures such as dose adaptation to kidney function, identification of risk factors, and plasmatic tenofovir concentration monitoring can help decrease the risk of nephrotoxicity.Le ténofovir est le seul inhibiteur nucléotidique de la transcriptase inverse du virus de l’immunodéficience humaine (VIH) actuellement commercialisé. Bien qu’il s’agisse d’un médicament globalement bien toléré prescrit à des millions de patients – sans surveillance particulière dans les pays en voie de développement – une néphrotoxicité considérable a été décrite au cours des années d’utilisation. La toxicité aiguë du ténofovir est maintenant bien comprise. Le ténofovir est excrété par les cellules épithéliales tubulaires proximales. En cas d’accumulation intracytoplasmique, le ténofovir inhibe l’ADN-polymérase γ mitochondriale. Un dysfonctionnement de la chaîne respiratoire s’ensuit, provoquant une altération de ces cellules qui sont privées d’énergie. Cliniquement, le dysfonctionnement tubulaire proximal se manifeste par un syndrome de Fanconi, parfois associé à une insuffisance rénale aiguë. Ces troubles sont (au moins partiellement) réversibles à l’arrêt du ténofovir. La toxicité rénale chronique du ténofovir, longtemps incertaine, semble maintenant assez bien démontrée par plusieurs études de cohortes, même si le mécanisme en reste à ce jour inconnu. Cette toxicité se manifeste par un déclin accéléré de la fonction rénale, sans autre anomalie rénale associée. C’est sans doute la multiplicité des cofacteurs, souvent exclus lors des essais cliniques, qui a rendu difficile sa mise en évidence. Des règles assez simples, telles que l’adaptation posologique à la fonction rénale, la recherche de facteurs de risque ou encore les dosages plasmatiques en ténofovir, permettent de limiter le risque de néphrotoxicité

2010. Effects of single and multiple pathogenicity island deletions on uropathogenic Escherichia coli strain 536 intrinsic extra-intestinal virulence

Please cite this article in press as: Tourret, J., et al. Results: E. coli 536 mutants in which PAIs II or III were deleted showed a significant decrease in virulence compared to the wild type (WT). All other single-PAI deletion mutants were as lethal to mice as was the WT. The mutant in which all seven PAIs were deleted showed milder virulence than the mutants in which PAI III or PAIs III and IV were deleted. The mutant in which PAIs II, III, IV, V, and VII were deleted tended to be less virulent than the mutant with deletion of PAI III only. All together, these results indicate a rough additive effect of PAIs in extra-intestinal virulence. Conclusion: All PAIs of E. coli 536 do not play the same role in extra-intestinal virulence estimated in a mouse septicemia model and PAIs cooperate in an additive manner to achieve extra-intestinal virulence

Effects of single and multiple pathogenicity island deletions on uropathogenic Escherichia coli strain 536 intrinsic extra-intestinal virulence

Escherichia coli strain 536 is a uropathogenic strain harboring 7 pathogenicity islands (PAIs). Whether or not these PAIs additively contribute to extra-intestinal virulence is unknown.; We tested 7 single and several multiple-PAI deletion mutants in a mouse septicemia model by monitoring mouse survival.; E. coli 536 mutants in which PAIs II or III were deleted showed a significant decrease in virulence compared to the wild type (WT). All other single-PAI deletion mutants were as lethal to mice as was the WT. The mutant in which all seven PAIs were deleted showed milder virulence than the mutants in which PAI III or PAIs III and IV were deleted. The mutant in which PAIs II, III, IV, V, and VII were deleted tended to be less virulent than the mutant with deletion of PAI III only. All together, these results indicate a rough additive effect of PAIs in extra-intestinal virulence.; All PAIs of E. coli 536 do not play the same role in extra-intestinal virulence estimated in a mouse septicemia model and PAIs cooperate in an additive manner to achieve extra-intestinal virulence

Immunosuppressive therapy after solid organ transplantation and the gut microbiota: bidirectional interactions with clinical consequences

International audienceOur understanding of the involvement of the gut microbiota (GM) in human health has expanded exponentially over the last few decades, particularly in the fields of metabolism, inflammation, and immunology. Immunosuppressive treatment (IST) prescribed to solid organ transplant (SOT) recipients produces GM changes that affect these different processes. This review aims at describing the current knowledge of how IST changes the GM. Overall, SOT followed by IST results in persistent changes in the GM, with a consistent increase in proteobacteria including opportunistic pathobionts. In mice, Tacrolimus induces dysbiosis and metabolic disorders, and alters the intestinal barrier. The transfer of the GM from Tacrolimus-treated hosts confers immunosuppressive properties, suggesting a contributory role for the GM in this drug's efficacy. Steroids induce dysbiosis and intestinal barrier alterations, and also seem to depend partly on the GM for their immunosuppressive and metabolic effects. Mycophenolate Mofetil, frequently responsible for digestive side effects such as diarrhea and colitis, is associated with pro-inflammatory dysbiosis and increased endotoxemia. Alemtuzumab, m-TOR inhibitors, and belatacept have shown more marginal impact on the GM. Most of these observations are descriptive. Future studies should explore the underlying mechanism of IST-induced dysbiosis in order to better understand their efficacy and safety characteristic

Why kidneys fail post-partum: a tubulocentric viewpoint

International audienceKidneys may fail post-partum in a number of circumstances due, for example, to post-partum haemorrhage, preeclampsia, amniotic fluid embolism or septic abortion. All these conditions in pregnancy and post partum represent a threat not only to the endothelium but also to the renal tubular epithelium, and as such may lead to rapid and also irreversible impairment of the renal function. This paper is a non-systematic review of the literature and of our experience, in which we discuss the main open issues on kidney disease in pregnancy and following delivery, in particular as regards tubular damage, with the aim to help reasoning on acute kidney injury (AKI) following delivery. The review will emphasize the often underestimated importance of the tubular epithelium in the peri-partum period and will: (1) describe the main characteristics of the renal tissues around delivery; (2) define pregnancy-related AKI according to recent Kidney Disease/Improving Global Outcome (KDIGO) guidelines; (3) discuss the most common circumstances of post-partum AKI; and (4) describe the input expected from urinalysis, renal imaging and kidney biopsy