Biology subjects

Tazi, A.

Publications and source records attributed to Tazi, A..

5 recordsLinked to original sources

bioRxiv2024

Vaginal microbiota as a predictor of preterm birth: an observational cohort study

RationaleIncreasing evidence links vaginal microbiota composition and preterm birth (PTB). However, most metagenomic studies are relatively small-sized, do not systematically adjust for confounders, and are difficult to transpose in clinical settings. ObjectiveTo identify, using routine vaginal microbiological cultures, signatures of preterm labor (PTL), preterm premature rupture of membranes (PPROM), and PTB. MethodsWe conducted an observational cohort study from August 2018 until June 2023 in France. Pregnant women were enrolled in three groups: control, PTL and PPROM. Demographic, clinical data, and pregnancy outcome were collected. Vaginal swabs were collected at enrollment and microbiological cultures were performed. The association between bacterial species and PTL, PPROM, and PTB was studied in univariate analyses. Adjusted odds ratio (aOR) and 95% confidence intervals (CI) were calculated in multivariable analyses adjusting for confounding variables. Results1,848 women were included: 1,048 in the control group, 417 with PTL, and 383 with PPROM. Among women with PTL or PPROM, 328/646 (50.8%) spontaneously delivered preterm. Vaginal samples enriched in enterobacteria and in Gardnerella spp. were signatures of PTL. Lactobacilli depletion and enterobacteria enrichment were signatures of PPROM. In multivariable analysis, lactobacilli depletion was the strongest risk factor for spontaneous PTB (aOR 2.29, 95% CI 1.52-3.48). ConclusionsOur study corroborates previous findings demonstrating the protective role of lactobacilli during pregnancy and highlights enterobacteria as signatures of PTL and PPROM. Furthermore, it provides perspectives for the management of women at high risk of PTB using standard microbiological techniques. HighlightsO_LIVaginal microbiological analysis of 800 women with preterm labor or PPROM C_LIO_LIPreterm labor signatures include enterobacteria and Gardnerella enrichment C_LIO_LIPPROM signatures include lactobacilli depletion and enterobacteria enrichment C_LIO_LILactobacilli depletion is the strongest risk factor for preterm birth C_LI

microbiology↗

bioRxiv2024

Coordinated regulation of osmotic imbalance by c-di-AMP shapes beta-lactam tolerance in Group B Streptococcus

Streptococcus agalactiae is among the few pathogens that have not developed resistance to {beta}-lactam antibiotics despite decades of clinical use. The molecular basis of this long-lasting susceptibility has not been investigated, and it is not known whether specific mechanisms constrain the emergence of resistance. In this study, we report the conserved role of the signaling nucleotide cyclic-di-AMP in susceptibility to {beta}-lactams, demonstrating that inactivation of the phosphodiesterase GdpP in S. agalactiae confers {beta}-lactam tolerance. Characterization of the c-di-AMP signaling pathway reveals antagonistic regulation by the transcriptional factor BusR, which is activated by c-di-AMP and negatively regulates {beta}-lactam susceptibility through the BusAB transporter and AmaP/Asp23 cell envelope stress complex. Furthermore, we show that the simultaneous inhibition of osmolyte transporters activity and transcription by c-di-AMP has an additive effect, sustaining {beta}-lactam tolerance. Finally, we expanded the analysis of {beta}-lactam tolerance using random transposon mutagenesis, uncovering a convergent pattern of mutations involving the KhpAB small RNA chaperone and the S protein immunomodulator. Overall, our results demonstrate that c-di-AMP acts as a turgor pressure rheostat, coordinating an integrated response to cell wall weakening due to {beta}-lactam activity, and identify mechanisms that may foster antibiotic resistance in S. agalactiae.

microbiology↗

bioRxiv2024

The hypervirulent Group B Streptococcus HvgA adhesin promotes brain invasion through transcellular crossing of the choroid plexus

BackgroundGroup B Streptococcus (GBS) is the leading cause of neonatal meningitis responsible for a substantial cause of death and disability worldwide. The vast majority of GBS neonatal meningitis cases are due to the CC17 hypervirulent clone. However, the cellular and molecular pathways involved in brain invasion by GBS CC17 isolates remain largely elusive. Here, we studied the specific interaction of the CC17 clone with the choroid plexus, the main component of the blood-cerebrospinal fluid (CSF) barrier. MethodsThe interaction of GBS CC17 or non-CC17 strains with choroid plexus cells was studied using an in vivo mouse model of meningitis and in vitro models of primary and transformed rodent choroid plexus epithelial cells (CPEC and Z310). In vivo interaction of GBS with the choroid plexus was assessed by microscopy. Bacterial invasion and cell barrier penetration were examined in vitro, as well as chemokines and cytokines in response to infection. ResultsGBS CC17 was found associated with the choroid plexus of the lateral, 3rd and 4th ventricles. Infection of choroid plexus epithelial cells revealed an efficient internalization of the bacteria into the cells with GBS CC17 displaying a greater ability to invade these cells than a non-CC17 strain. Internalization of the GBS CC17 strain involved the CC17-specific HvgA adhesin and occurred via a clathrin-dependent mechanism leading to transcellular transcytosis across the choroid plexus epithelial monolayer. CPEC infection resulted in the secretion of several chemokines, including CCL2, CCL3, CCL20, CX3CL1, and the matrix metalloproteinase MMP3, as well as immune cell infiltration. ConclusionOur findings reveal a GBS strain-specific ability to infect the blood-CSF barrier, which appears to be an important site of bacterial entry and an active site of immune cell trafficking in response to infection.

microbiology↗

bioRxiv2024

Signal-independent activation reveals two-component regulatory networks

Each bacterial species has specific regulatory systems to control physiology, adaptation, and host interactions. One challenge posed by this diversity is to define the evolving gene regulatory networks. This study aims to characterise two-component systems (TCS) in Streptococcus agalactiae, the main cause of neonatal meningitis. Here we demonstrate signal-independent activation of signalling pathways by systematically targeting the conserved mechanism of phosphatase activity of the 14 histidine kinases of the two main TCS families. Transcriptomic analysis resolves most pathways with high resolution, encompassing specialized, connected, and global regulatory systems. The activated network notably reveals the connection between CovRS and SaeRS signaling through the adhesin PbsP, linking the main regulators of host interactions to balance pathogenicity. Additionally, constitutive activation of the BceRS system reveals its role in cell envelope homeostasis beyond antimicrobial resistance. Overall, this study demonstrates the generalizability and versatility of TCS genetic activation to uncover regulatory logics and biological processes.

microbiology↗

bioRxiv2022

Specific interaction between Group B Streptococcus CC17 hypervirulent clone and phagocytes

Streptococcus agalactiae also named Group B Streptococcus (GBS) is the most significant pathogen causing invasive infections, such as bacteremia and meningitis, in neonates. Worldwide epidemiological studies have shown that a particular clonal complex (CC) of capsular serotype III, the CC17, is strongly associated with meningitis in neonates and is therefore designated as the hypervirulent clone. Macrophages are a permissive niche for intracellular bacteria of all GBS clones. In this study we deciphered the specific interaction of GBS CC17 strains with macrophages. Our study revealed that CC17 strains are phagocytosed at a higher rate than GBS non-CC17 strains by human monocytes and macrophages both in cellular models and primary cells. CC17 enhanced phagocytosis is due to an initial enhanced-attachment step to macrophages mediated by the CC17 specific surface protein HvgA and the PI-2b pilus (Spb1). We showed that two different inhibitors of scavenger receptors (fucoidan and poly(I)) specifically inhibited CC17 adhesion and phagocytosis while not affecting those of non-CC17 strains. Once phagocytosed, both CC17 and non-CC17 strains remained in a LAMP-1 positive vacuole that ultimately fuses with lysosomes where they can survive at similar rates. Finally, both strains displayed a basal egress which occurs independently from actin and microtubule networks. Our findings provide new insights into the interplay between the hypervirulent GBS CC17 and major players of the hosts innate immune response. This enhanced adhesion leading to higher phagocytosis could reflect a peculiar capacity of the CC17 lineage to subvert the host immune defenses, establish a niche for persistence or disseminate.

microbiology↗