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Exploring the multi-protein assembly of the enzymes of the de novo purine nucleotide biosynthetic pathway from Pseudomonas aeruginosa
No full textInternational audiencePurine nucleotide biosynthesis is a crucial metabolic pathway responsible for producing building blocks essential for a plethora of cellular processes. In bacteria, the de novo purine nucleotide biosynthetic pathway (DNPNB) involves fifteen chemical steps catalysed by fourteen different enzymes. While the mammalian orthologues have been extensively shown to interact and form a metabolon named “purinosome”, the possible existence of a prokaryotic equivalent was only recently revealed for the case of Escherichia coli. In this study, we explored the potential conservation of a bacterial purinosome-like complex in Pseudomonas aeruginosa, an opportunistic pathogen known for its high antibiotic resistance. Using a bacterial two-hybrid system, we mapped protein-protein interactions among all tested DNPNB enzymes in P. aeruginosa and revealed a dense interaction network. An in-silico protein-protein docking approach on three core enzymes allowed the structural reconstitution of a complex composed of PurK, PurE and PurC with a 4:8:8 stoichiometry, respectively. Interestingly, a tunnel connecting the different active sites has been revealed, showing a metabolon-like property for possible efficient substrate channelling. These findings support a conserved regulatory organization of purine biosynthesis in bacteria, providing deeper insights into bacterial metabolism and paving the way for potential antibiotic targets
Characterization of broad host range bacteriophages vKpIN31 and vKpIN32 against hospital-acquired Klebsiella pneumoniae in Dakar, Senegal
No full textInternational audienceKlebsiella pneumoniae, a common gut colonizer, has become a major opportunistic pathogen, especially with the rise of multidrug-resistant (MDR) strains. This study aimed to characterize two lytic bacteriophages against MDR K. pneumoniae strains isolated from hospital associated infections in Senegal. Among 28 MDR K. pneumoniae strains tested, phage vKpIN31 effectively lyse 15 strains encompassing 12 distinct K locus types. While phage vKpIN32 lysed 12 strains with 9 different K locus types, demonstrating broad host range activity. The isolated phages exhibited thermal and pH stability. One-step growth analysis revealed a latent period of 25 and 20 minutes and burst sizes of 281 and 246 PFU/cell for vKpIN31 and vKpIN32 respectively. The in vitro lytic activity of phages vKpIN31 and vKpIN32 at different multiplicity of infection (1, 10⁻¹, and 10⁻³) revealed variable lysis efficacy against three K. pneumoniae strains (KP6, KP7, and KP17), with the highest effectiveness observed at an MOI of 10⁻³ for both phages. Also, combination of both phages as cocktail led to improved efficacy against the targeted strains Also, both phages significantly reduced biofilm levels, from 18.6% to 67.9% for 24-hour mature biofilms and from 18.1% to 58.7% for 48-hour mature biofilms. Genomic analysis identified both phages as linear dsDNA viruses belonging to the Caudoviricetes class, and Sugarlandvirus sugarland species. No genes associated with a temperate life cycle, integrases, transposable elements, antibiotic resistance, or bacterial virulence were detected in their genomes. These findings highlight vKpIN31 and vKpIN32 as promising candidates for phage therapy. Additionally, their potential extends to serving as sources for antibacterial and antibiofilm agents, signifying their clinical relevance and therapeutic potential
Higher stability of novel live-attenuated oral poliovirus type 2 (nOPV2) despite the emergence of a neurovirulent double recombinant strain in Uganda
No full textInternational audienceThe novel oral poliovirus vaccine type 2 (nOPV2) was developed to reduce the risk of circulating vaccine-derived poliovirus outbreaks by incorporating genetic modifications to enhance genetic stability and reduce reversion to virulence while retaining protection. Here we report the characterization of 231 nOPV2 isolates from Uganda during a 1-year period following nOPV2 use. Whole-genome sequencing revealed that most isolates retained nOPV2’s genetic modifications, with limited mutations in the VP1 region indicating no relevant virus transmission. However, a double recombinant strain identified in a sewage sample lost all key nOPV2 modifications through recombination with enterovirus C strains upstream and downstream of the capsid coding region. This resulted in high neurovirulence comparable to that of wild-type 2 poliovirus. Despite this, the strain did not spread widely, probably due to high vaccination coverage. These findings underscore the enhanced genetic stability of nOPV2 and its reduced risk of reversion compared with Sabin monovalent OPV2 (mOPV2), while highlighting the importance of surveillance to detect rare recombination events. Continued use of nOPV2 and inactivated polio vaccine, combined with robust immunization and monitoring, remains essential for achieving and sustaining global polio eradication
Validating and refining a psychoacoustic test to diagnose hyperacusis
No full textInternational audienceDecreased sound tolerance refers to conditions like hyperacusis and misophonia, in which everyday sounds may provoke discomfort or distress. Hyperacusis is characterized by exaggerated loudness perception and aversive reactions to moderate to loud sounds, often leading to significant impairment. Despite its estimated prevalence of 10–15 %, no objective clinical test exists. Current assessment relies on interviews, questionnaires, and loudness discomfort levels (LDLs), which lack reliability and ecological validity. Recent work has shown that pleasantness ratings of natural sounds can differentiate individuals with hyperacusis from controls. A subset of seven natural sounds, termed Core Discriminant Sounds (CDShyper), was identified post-hoc as particularly effective, yielding 81 % sensitivity and 88 % specificity in prior lab-based testing. A similar approach for misophonia identified ten distinct trigger sounds (CDSmiso). This study aimed to validate a tablet-based version of the CDS test to diagnose hyperacusis prospectively. Forty-nine participants (20 with hyperacusis, 29 controls) completed the test that presented randomly CDShyper and CDSmiso sounds at 60, 70, and 80 dBA. Participants rated each sound presentation on visual analog scales for pleasantness and loudness. Hyperacusis was defined by clinical complaints, Hyperacusis Questionnaire scores (≥22), and LDLs (≤77 dB HL). Results showed that individuals with hyperacusis rated CDShyper sounds as significantly less pleasant (means score of 39 vs 25 for hyperacusis vs controls, p = .002, η² = 0.185) and louder (means score of 71 vs 63 for hyperacusis vs controls, p = .024, η² = 0.104) than controls. No group differences emerged for misophonia trigger sounds (CDSmiso sounds). The sensitivity and specificity for the combined CDShyper scores of pleasantness and loudness at detecting hyperacusis were 90 % and 69 %, respectively. These findings validate the tablet-based test as an efficient, ecologically valid tool for diagnosing hyperacusis
NMR, a tool for biology [meeting report]
No full textInternational audienceEvery 2 years the "NMR, a tool for biology" conference brings together renowned experts and emerging scientists to explore the application of nuclear magnetic resonance (NMR) in addressing fundamental biological questions. This international event in Paris showcases the latest methodological and application advances that reinforce NMR's impact in structural biology. Here, we present key highlights from the XIVth edition
Impaired stem cell migration and divisions in Duchenne muscular dystrophy revealed by live imaging
No full textInternational audienceAbstract Dysregulation of stem cell properties is a hallmark of many pathologies, but the dynamic behaviour of stem cells in their microenvironment during disease progression remains poorly understood. Using the mdx mouse model of Duchenne Muscular Dystrophy, we developed innovative live imaging of muscle stem cells (MuSCs) in vivo, and ex vivo on isolated myofibres. We show that mdx MuSCs have impaired migration and precocious differentiation through unbalanced symmetric divisions, driven by p38 and PI3K signalling pathways, in contrast to the p38-only dependence of healthy MuSCs. Cross-grafting shows that MuSC fate decisions are governed by fibre-independent cues, whereas their migration behaviour is determined by the myofibre niche. This study provides the first dynamic analysis of dystrophic MuSC properties in vivo, reconciling conflicting reports on their function. Our findings establish DMD as a MuSC disease with niche dysfunctions, offering strategies to restore stem cell functions for improved muscle regeneration
Chemical inhibition of SUMOylation activates the FSHD locus
No full textInternational audienceFacioscapulohumeral muscular dystrophy (FSHD) is a progressive and debilitating muscle disease for which no cure currently exists. In the majority of cases, FSHD is associated with the contraction of the D4Z4 macrosatellite repeat array at the 4q35 locus, leading to the inappropriate activation of DUX4 , normally expressed during early embryogenesis. In FSHD, the genetic contraction is accompanied by hypomethylation of the D4Z4 array. Although a connection between DNA hypomethylation and DUX4 expression has been suggested, the precise mechanisms that regulate DUX4 transcription remain incompletely defined. The post-translational modification by SUMO was shown previously to repress the expression of Dux , the DUX4 homolog, in mouse embryonic stem cells. Based on these findings, we explored here the contribution of SUMOylation in the regulation of DUX4 in human muscle cells. We demonstrate that TAK‑981 (subasumstat), a selective SUMOylation inhibitor, promotes transcriptional reprogramming of the 4q35 locus and induces DUX4 expression. Importantly, this activation occurs independently of changes in DNA methylation or SMCHD1 ATPase activity. Our findings identify SUMOylation inhibition as a novel regulatory process driving DUX4 expression. This work uncovers the importance of SUMOylation in the epigenetic control of the 4q35 locus and DUX4 transcription, providing a potential therapeutic strategy to modulate DUX4 expression in FSHD
Biodiversité du microbiote intestinal et alimentation moderne : impact en santé humaine
No full textInternational audienceThe advent of the modern diet — characterized by increased consumption of ultra-processed foods rich in saturated fats and simple sugars, but deficient in fiber and micronutrients — has profoundly altered the biodiversity of the intestinal microbiota. This dysbiosis disrupts the intricate metabolic, immune, and nutritional interactions between the host and its microbiota, leading to significant downstream impacts on human health. Dietary imbalances result in reduced production of beneficial microbial metabolites, increased intestinal permeability, chronic inflammation, and heightened risks of obesity, diabetes, and inflammatory diseases. Conversely, diversified diets rich in fiber, unsaturated fatty acids, and plant-based proteins support a resilient and diverse microbial ecosystem that enhances gut barrier function, immunity, and the synthesis of protective compounds. A deeper understanding of these complex host-microbiota-nutrition interactions can pave the way for preventive and therapeutic strategies targeting the microbiome to promote human health.L’essor de l’alimentation moderne, caractérisée par la consommation accrue de produits dits ultra-transformés, pauvres en fibres et riches en graisses saturées ainsi qu’en sucres simples, bouleverse l’écosystème du microbiote intestinal. Cette altération de la biodiversité microbienne, essentielle à la santé humaine, entraîne des modifications profondes des interactions métaboliques, immunitaires et nutritionnelles entre l’hôte et son microbiote. Une compréhension approfondie de ces relations ouvre la voie à des approches alimentaires préventives et thérapeutiques innovantes. Cette revue présente une synthèse des mécanismes par lesquels les différents composants alimentaires modernes modulent la composition et les fonctions du microbiote intestinal, et discute de leurs conséquences sur le risque de maladies chroniques
Human rabies in Avignon, France, following exposure in Morocco, 2025
No full textInternational audienceObjectivesIn early 2025, a patient died in the South of France with confirmed rabies following a dog bite while traveling in Morocco to visit relatives. This report summarizes the patient’s clinical course and the subsequent public health investigation.MethodsDemographics, epidemiological, and medical data from the infected patient and from contacts at risk of exposure were retrospectively retrieved from medical files.ResultsThe patient presented with fever, cardiac and neurological symptoms. Initial clinical presentation mimicking psychiatric disorders and suggesting a myocarditis led to multiple exposures of family members and health care workers (HCWs). Rabies virus was retrieved from saliva, skin biopsy, and post-mortem brain biopsy. A total of 44 potentially exposed persons were identified among family and community contacts and among HCWs who cared for the patient, and received rabies post-exposure prophylaxis (RPEP). Most family members shared food and drinks with the patient, notably during a large family meal with potential mucosal exposure to infected saliva. Several HCWs had a contact with the patient’s body fluids without application of standard of isolation precautions.ConclusionsRecommendations for RPEP in contacts with a human rabies case differ between countries, and practices differ between teams. The dramatic nature of the disease often leads to irrational fear that may compromise the strict application of recommendations. Travelers to North African countries, including those visiting friends and relatives should be informed about the risk for rabies when injured by dogs or cats and about the need to receive an adequate RPEP
The essential integration of sex and gender in immunological research
No full textInternational audienc