The Abi-domain protein Abx1 interacts with the CovS histidine kinase to control virulence gene expression in group B Streptococcus

Group B Streptococcus (GBS), a common commensal of the female genital tract, is the leading cause of invasive infections in neonates. Expression of major GBS virulence factors, such as the hemolysin operon cyl, is regulated directly at the transcriptional level by the CovSR two-component system. Using a random genetic approach, we identified a multi-spanning transmembrane protein, Abx1, essential for the production of the GBS hemolysin. Despite its similarity to eukaryotic CaaX proteases, the Abx1 function is not involved in a post-translational modification of the GBS hemolysin. Instead, we demonstrate that Abx1 regulates transcription of several virulence genes, including those comprising the hemolysin operon, by a CovSR-dependent mechanism. By combining genetic analyses, transcriptome profiling, and site-directed mutagenesis, we showed that Abx1 is a regulator of the histidine kinase CovS. Overexpression of Abx1 is sufficient to activate virulence gene expression through CovS, overcoming the need for an additional signal. Conversely, the absence of Abx1 has the opposite effect on virulence gene expression consistent with CovS locked in a kinase-competent state. Using a bacterial two-hybrid system, direct interaction between Abx1 and CovS was mapped specifically to CovS domains involved in signal processing. We demonstrate that the CovSR two-component system is the core of a signaling pathway integrating the regulation of CovS by Abx1 in addition to the regulation of CovR by the serine/threonine kinase Stk1. In conclusion, our study reports a regulatory function for Abx1, a member of a large protein family with a characteristic Abi-domain, which forms a signaling complex with the histidine kinase CovS in GBS

The surface protein HvgA mediates group B streptococcus hypervirulence and meningeal tropism in neonates

Lethal meningitis triggered by the hypervirulent group B streptococcus clone ST-17 is mediated by a novel surface protein called HvgA

Rôle de l'adhésine HvgA dans la virulence de Streptococcus agalactiae

Streptococcus agalactiae représente la première cause d'infections néonatales invasives. L'infection peut se déclarer dès la première semaine de vie ou plus tardivement. La physiopathologie du syndrome tardif demeure incertaine mais il est très majoritairement imputable à un complexe clonal particulier dit hyper-virulent et la méningite est plus fréquente dans ce contexte. Les souches appartenant au complexe clonal hyper-virulent possèdent de meilleures capacités d'adhésion aux cellules épithéliales intestinales et aux cellules endothéliales de capillaires cérébraux humains. La protéine de surface HvgA, spécifique au complexe clonal hyper-virulent, contribue à la colonisation du tube digestif et à la traversée des barrières intestinale et hémato-encéphalique. La pathogénicité du complexe clonal hyper-virulent pourrait être liée à une meilleure colonisation du tube digestif et à des capacités accrues de franchissement des barrières physiologiques, conférées par la protéine HvgA.Streptococcus agalactiae is the leading cause of bacterial infections in neonates. Neonatal infection may occur within the first week of life or lately. The pathophysiology of late onset disease is uncertain. However, epidemiological data indicate that it is mainly due to a clonal complex thus referred to as the hyper-virulent clonal complex and meningitis is more frequent in this context. Strains that belong to the hyper-virulent clonal complex adhere more efficiently to intestinal epithelial cells and brain endothelial cells. The surface protein HvgA, is specific to the hyper-virulent clonal complex and contributes to intestinal colonization and translocation through intestinal and blood-brain barriers. We hypothesize that the pathogenesis of the hyper-virulent clonal complex may be due to enhanced gut colonization and translocation through physiological barriers. The surface protein HvgA is involved in this particular phenotype.PARIS5-BU Méd.Cochin (751142101) / SudocSudocFranceF

SCROTAL ULCERATION FOLLOWING ALL-TRANS RETINOIC ACID THERAPY FOR ACUTE PROMYELOCYTIC LEUKEMIA

All-trans retinoic acid (ATRA) induces complete remission in most cases of acute promyelocytic leukemia. Toxicity of ATRA has been shown to be mild, consisting of headache, dry skin, dermatitis, and gastrointestinal disorders. We describe a case of scrotal ulceration with ATRA use in a Moroccan patient, an occurrence that has been rarely reported in the medical literature. The pathogenesis of scrotal ulceration remains unknown. Our experience indicates the importance of recognizing genital ulcers associated with ATRA in order that appropriate countermeasures can be taken

Optimisation of bi-therapy inhibition of Staphylococcus aureus in persistent and bacteremic infections

Describes the objectives of a new antimicrobial bitherapy strategy to eliminate Staphylococcus aureus

Group B Streptococcus surface proteins as major determinants for meningeal tropism

International audienceStreptococcus agalactiae (group B Streptococcus, GBS), a normal constituent of the intestinal microbiota is the major cause of human neonatal infections and a worldwide spread 'hypervirulent' clone, GBS ST-17, is strongly associated with neonatal meningitis. Adhesion to epithelial and endothelial cells constitutes a key step of the infectious process. Therefore GBS surface-anchored proteins are obvious potential adhesion mediators of barrier crossing and determinant of hypervirulence. This review addresses the most recent molecular insights gained from studies on GBS surface proteins proven to be involved in the crossing of the brain-blood barrier and emphasizes on the specificity of a hypervirulent clone that displays meningeal tropism

Perinatal hormones favor CC17 Group B Streptococcus intestinal translocation through M cells and hypervirulence in neonates

International audienceGroup B Streptococcus (GBS) is the leading cause of invasive bacterial neonatal infections. Late-onset diseases (LOD) occur between 7 and 89 days of life and are largely due to the CC17 GBS hypervirulent clone. We studied the impact of estradiol (E2) and progesterone (P4), which impregnate the fetus during pregnancy, on GBS neonatal infection in cellular and mouse models of hormonal exposure corresponding to concentrations found at birth (E2-P4 C 0) and over 7 days old (E2-P4 C 7). Using representative GBS isolates, we show that E2-P4 C 7 concentrations specifically favor CC17 GBS meningitis following mice oral infection. CC17 GBS crosses the intestinal barrier through M cells. This process mediated by the CC17-specific surface protein Srr2 is enhanced by E2-P4 C 7 concentrations which promote M cell differentiation and CC17 GBS invasiveness. Our findings provide an explanation for CC17 GBS responsibility in LOD in link with neonatal gastrointestinal tract maturation and hormonal imprint

Disentangling Host-Microbiota Regulation of Lipid Secretion by Enterocytes: Insights from Commensals Lactobacillus paracasei and Escherichia coli

International audienceThe gut microbiota contributes to nutrients absorption and metabolism by enterocytes, but the molecular mechanisms involved remain poorly understood, and most conclusions are inferred from studies comparing germfree and conventional animals colonized with diverse bacterial species. We selected two model commensal microorganisms, Escherichia coli and Lactobacillus paracasei, to assess the role of the small-intestinal microbiota in modulating lipid absorption and metabolism by the epithelium. Using an integrated approach encompassing cellular and murine models and combining metabolic parameters measurement, lipid droplet imaging, and gene expression analysis, we demonstrated that under homeostatic conditions, L. paracasei promotes fat storage in enterocytes, whereas E. coli enhances lipid catabolism and reduces chylomicron circulating levels. The Akt/mammalian target of sirolimus (mTOR) pathway is inhibited by both bacterial species in vitro, indicating that several regulatory pathways are involved in the distinct intracellular lipid outcomes associated with each bacterial species. Moreover, soluble bacterial factors partially reproduce the effects observed with live microorganisms. However, reduction of chylomicron circulating levels in E. coli-colonized animals is lost under high-fat-diet conditions, whereas it is potentiated by L. paracasei colonization accompanied by resistance to hypercholesterolemia and excess body weight gain.IMPORTANCE The specific contribution of each bacterial species within a complex microbiota to the regulation of host lipid metabolism remains largely unknown. Using two model commensal microorganisms, L. paracasei and E. coli, we demonstrated that both bacterial species impacted host lipid metabolism in a diet-dependent manner and, notably, that L. paracasei-colonized mice but not E. coli-colonized mice resisted high-fat-diet-induced body weight gain. In addition, we set up cellular models of fatty acid absorption and secretion by enterocytes cocultured with bacteria and showed that, in vitro, both L. paracasei and E. coli inhibited lipid secretion, through increased intracellular fat storage and enhanced lipid catabolism, respectively