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Inhibition of the macrophage demethylase LSD1 reverses Leishmania amazonensis-induced transcriptomic changes and causes a decrease in parasite load
No full textIntracellular pathogens exploit host cell functions to favor their own survival. In recent years, the subversion of epigenetic regulation has emerged as a key microbial strategy to modify host cell gene expression and evade antimicrobial immune responses. Using the protozoan parasite Leishmania as a model system, we have recently demonstrated that infection causes histone H3 hypomethylation, which is associated with the establishment of an antiinflammatory phenotype, suggesting that host cell demethylases may play a role in the intracellular survival of these parasites. In this study, we combined pharmacological inhibition with RNA sequencing and quantitative immune-precipitation analysis to investigate the role of the macrophage lysine demethylase LSD1 (KDM1a) in Leishmania intracellular infection in vitro. Treatment of infected macrophages with validated, LSD1-specific inhibitors resulted in a significant reduction in parasite burden. We confirmed the impact of these inhibitors on LSD1 activity within macrophage nuclear extracts using an in vitro demethylase assay and established their LSD1 target engagement in situ by cellular thermal shift assay. RNA-seq analysis of infected and inhibitor-treated macrophages linked parasite killing to a partial reversion of infection-dependent expression changes, restoring the macrophage anti-microbial response and limiting cholesterol biosynthesis. While we ruled out any impact of Leishmania on LSD1 expression or localization, we uncovered significant alterations in LSD1 complex formation within infected macrophages, involving unique interactions with host cell regulatory proteins such as Rcor-1. Our study sheds important new light on the epigenetic mechanisms of macrophage immuno-metabolic subversion by intracellular Leishmania and identifies LSD1 as a potential candidate for host-directed, anti-leishmanial therapy
Marine Bacteria as a Source of Antibiotics Against Staphylococcus aureus: Natural Compounds, Mechanisms of Action, and Discovery Strategies
No full textInternational audienceStaphylococcus aureus is a major opportunistic pathogen responsible for a wide spectrum of human infections, including severe and difficult-to-treat cases. The emergence of multidrug-resistant strains limits the efficacy of conventional antibiotic therapies and poses a significant global public health challenge. In this context, the search for novel antibiotics has intensified, with increasing interest in marine resources, an ecosystem still largely underexplored. Marine bacteria produce a vast array of secondary metabolites with unique structures and potentially novel modes of antibacterial action. Several compounds isolated from marine bacterial strains have demonstrated promising activity against multidrug-resistant S. aureus, including antivirulence effects such as biofilm formation and Quorum-Sensing inhibition. This review explores the potential of marine bacteria as a source of new antibiotics against S. aureus, discusses both classical and advanced strategies for the discovery of bioactive molecules, and highlights the scientific and technological challenges involved in translating these findings into clinical applications
Impacts of wastewater treatment and the exposome on antibiotic resistance gene dynamics: Insights from Guadeloupe, a French Caribbean Island
No full textInternational audienc
ecoXCorr: Lagged Cross-Correlation Analysis of Environmental Time Series
No full textTools for analysing lagged relationships between environmental variables and ecological or epidemiological time series. The package implements a workflow to aggregate meteorological data over multiple lagged intervals, fit regression models for each lag window, and visualise effect strength and direction using cross-correlation maps (CCM)
Eco-epidemiological thresholds for malaria transmission in multi-species, phenotypically structured mosquito populations
No full textUnderstanding how vector richness influences malaria transmission remains a critical challenge in disease ecology and public health. We develop a mathematical model that integrates both interspecific and intraspecific phenotypic diversity within mosquito populations, structured by chronological age and continuous phenotypic traits. Our framework couples these diverse mosquito populations with a human host population to analyze the eco-epidemiological dynamics of malaria transmission. We conduct a detailed analysis of the mosquito population's asymptotic behavior and invasibility analysis. Additionally, we identify an eco-epidemiological threshold parameter that synthesizes mosquito vectorial capacity, intrinsic fitness differences, and ecological competition to predict whether the addition of a new mosquito species amplifies or dilutes epidemic risk. Through this approach, we show that vector species abundance alone is insufficient to determine malaria transmission potential; rather, the interplay between phenotypic variation and ecological interactions governs epidemic outcomes. Our results generalize and extend previous theoretical studies by incorporating structured population dynamics and continuous trait variation, providing a mechanistic basis for anticipating how changes in mosquito community composition may impact malaria transmission risk
The microbiota affects energy production, nitrogen excretion and sterol metabolism in mosquito larvae
No full textPosted December 18, 2025 on bioRxiv.Mosquito larvae rely on a living microbiota for normal development because the microbiota supplies essential nutrients, particularly vitamins. Beyond vitamin provision, transcriptomic data suggest that the microbiota also supports other key nutritional processes. Here, we explored these roles by conducting a metabolomics analysis on Aedes aegypti third instar larvae following microbiota depletion. We sampled larvae and dissected guts 12- and 20-hours post-decolonization and analysed methanol-soluble metabolites using untargeted gas chromatography–mass spectrometry. Our findings reveal a pronounced impact of gut microbial presence on several metabolites involved in the tricarboxylic acid cycle and the uricolytic pathway. Germ-free larvae also had a lower quantity of cholesterol in guts and their long-chain fatty acid profile was altered in guts and whole larvae. Sterols, including cholesterol, are essential precursors for the production of the moulting hormone 20-hydroxyecdysone. We therefore tested how supplementing exogenous cholesterol affects the development of germ-free larvae. The effects proved to be highly concentration-dependent, ranging from a marginally significant increase in successful development to adulthood at low concentrations to a pronounced developmental impairment at higher concentrations. Moreover, bacteria deficient in fatty acids beta-oxidation had a significantly lower ability to support larval development. Together, the observed alterations suggest that microbiota-deprived larvae exhibit a downregulation of metabolic processes related to energy production, nitrogen excretion and sterol metabolism, likely due to the absence of microbiota-derived vitamins essential for these central metabolic functions.ImportanceMosquito larvae depend on gut microbiota for normal growth because microbes supply essential nutrients, particularly B vitamins. To explore microbial roles beyond vitamin provision, we analysed metabolic changes in Aedes aegypti larvae after microbiota removal using gas chromatography-mass spectrometry. Germ-free larvae exhibited decreased metabolites associated with the tricarboxylic acid cycle and uricolytic pathway, indicating a general slowdown in metabolic activity and nitrogen waste processing. Additionally, the absence of a microbiota affected cholesterol and fatty acid metabolism. To validate these findings, we found that supplementing germ-free larvae with low levels of cholesterol modestly improved their development. In contrast, larvae colonized with bacteria deficient in fatty acid metabolism exhibited significantly reduced developmental success. Overall, the findings show that removing the microbiota downregulates key metabolic pathways related to energy production, nitrogen excretion, and sterol metabolism, highlighting that bacterial vitamins and fatty acid degradation are vital for mosquito larval development and successful transformation into adults
PNA aptamer-based bioreceptors for cardiac biomarker (cTnI) detection: Insight into the structural and stability-related aspects
No full textInternational audienceAptamers, nucleic acid molecules that fold into specific three-dimensional structures, have been extensively used in the biosensing field to accomplish sensitive and specific monitoring of a wide range of biomarkers. Peptide nucleic acid (PNA), in this context, can be considered as a potential next-generation scaffold for aptamer synthesis and biomarker sensing, owing to its high stability in comparison to DNA counterparts. In this work, we investigated the performance of a series of PNA aptamers for monitoring of a prominent cardiac biomarker, cardiac troponin I (cTnI), using surface plasmon resonance (SPR) and showed that PNA sequences shorter than those previously reported for DNA can exhibit picomolar affinity, provided the essential structural features are preserved. Two different immobilization strategies (covalent and non-covalent) are validated in parallel for PNAs. The stability of sensor response in the presence of endonucleases such as DNase I was investigated further, as their occurrence in blood, plasma, and serum hydrolyses phosphodiester bonds and could be a limiting factor for point-of-care (PoC) application of DNA aptamers. Owing to their unnatural backbone, PNAs exhibited higher stability against DNase I in comparison to their DNA aptamer counterpart. Additionally, molecular dynamics (MD) simulations of DNA and PNA aptamers revealed similarities in their secondary structures, as well as distinctions in their propensity to adopt compact conformations. Overall, our findings not only provided a comprehensive framework for PNA design, surface functionalization, and cTnI biomarker detection using PNAbased bio-recognition scaffolds but also substantiated the biostability of PNAs, suggesting their high relevance for future PoC diagnostic applications.</div
Pre-therapeutic bone marrow-resident leukemic cells in acute myeloid leukemia exhibit a distinct dysregulated calcium signature and stem-like profile reflecting minimal residual disease precursors
No full textInternational audienceBackground: Acute myeloid leukemia (AML) remains a high-risk hematologic malignancy due to frequent relapse and therapeutic resistance. Although induction therapy can achieve cytological remission, a fraction of leukemic cells (minimal residual disease, MRD) persists within the protective bone marrow (BM) microenvironment. MRD is heterogeneous and may include subclones with intrinsic survival features present before therapy. Among these, rare BM-resident leukemic cells (BMresLC) may represent pre-adapted precursors of MRD, maintained in a low-proliferative (Ki67low) or quiescent state. We previously showed that calcium signaling through ORAI1-dependent store-operated calcium entry (SOCE) contributes not only to AML stemness and drug resistance but also to the regulation of the G0-G1 cell-cycle transition and the emergence of slow-cycling leukemic cells. With this study, we have characterized the stemness and calcium signature of BMresLC before any therapeutic intervention. Our results, beyond further characterizing a population of cells rarely studied, could thus pave the way to new therapeutic opportunities combining current treatments with the targeting of relevant pathways highlighted by our work.Methods: A patient-derived xenograft (PDX) model in NSG (NOD/SCID/IL2Rγnull) mice was used to localize, isolate, and characterize human BMresLC. Whole-bone clearing and 3D-Imaris imaging enabled spatial localization of rare leukemic cells. Flow cytometry and qPCR assessed cell-cycle status, immunophenotype (CD34, CD38, TIM-3, PD-L1, Ki67), stemness, and calcium-signaling components (ORAI1-3, STIM1-2, NFATc1-4). SOCE was measured using Indo-1 assays. Comparative analyses were performed against diagnostic AML cells, public MRD RNA-seq datasets, and prognosis-stratified patient cohorts.Results: BMresLC displayed an immune-evasive immunophenotype and contained a small fraction of Ki67neg quiescent cells, but were not enriched in fully quiescent cells. Instead, they predominantly exhibited a Ki67low slow-cycling profile, consistent with a low-proliferative persistent state. Transcriptional analysis revealed overexpression of stemness-associated genes and selective downregulation of calcium-signaling components ORAI1, ORAI2, STIM2, and NFATc1/c4, consistent with a SOCE-suppressed calcium signature. Functional assays confirmed reduced calcium influx. Compared with post-therapy MRD datasets, BMresLC showed some stemness and immune-evasion traits but displayed a distinct pre-therapeutic calcium signature, suggesting that it represents an early, persistent state preceding full MRD remodeling. Prognostic subgroup analysis further showed that BMresLC calcium and stemness profiles partially recapitulate features of adverse-risk AML, including differences in CD34, CD38, PD-L1, MMRN1, LAPTM4B, NFATc2, and STIM2 expression.Conclusions: Our findings identify a distinctive calcium- and stemness-based signature in BMresLC, representing a pre-MRD survival state characterized by slow cycling rather than enrichment in strict quiescence. This pre-therapeutic signature may contribute to MRD establishment and relapse risk in AML
A new family of TonB-dependent copper transporters linked to respiratory oxidase function
No full textInternational audienceCopper is an essential metal notably found in respiration complexes for its redox properties. It is also toxic hence its cellular trafficking is tightly controlled. Bacteria have developed a number of defense systems against copper excess, but its acquisition pathways remain poorly characterized. Ubiquitous in Gram-negative bacteria, TonB-dependent transporters (TBDTs) are outer membrane β-barrel proteins that mediate the proton motive force-dependent import of various nutrients to the periplasm. Here, we characterized a TBDT that imports copper in the whooping cough agent Bordetella pertussis, CrtA Bp (formerly BfrG), which is a prototype of a new subfamily of TBDTs. Our data indicate that CrtA Bp is dedicated to the import of copper for heme-copper respiratory oxidoreductases. We revealed that CrtA Bp imports chelated rather than free copper, solved the crystal structure of CrtA Bp and identified a conserved ligand binding site. By combining bacterial growth experiments, biophysical approaches and Alpha-Fold3 modeling we sketched out the features of copper-ligand complexes for CrtA Bp . In contrast with ferrisiderophorespecific TBDTs, no high-affinity chalkophore ligand of CrtA Bp could be identified, implying two nonmutually exclusive models. In the host, CrtA Bp might use a xenometallophore produced by another species present in the same niche to acquire copper. In vitro however, CrtA appears not to have high-affinity ligands but to import copper chelated by small molecules notably harboring carboxylate groups, which might represent a paradigm of 'scavenger' TBDTs with low ligand selectivity. We identified an essential, invariant histidine residue that might serve as a selectivity filter for copper-chelate complexes
Consequences of irradiation on blood-brain tumor barrier model of Diffuse Midline Glioma: characterization of physical and metabolic properties
No full textInternational audienceBackgroundDiffuse midline glioma (DMG) is a rare and aggressive pediatric brain tumor, with a median survival of less than 12 months. Due to its location in the pons, surgical resection is impossible, leaving radiation therapy as the only palliative treatment option. Unfortunately, radiation therapy yields minimal improvement in survival. Thus, characterization of the vascular component of the DMG microenvironment at the cellular and molecular levels following radiotherapy to improve therapeutic strategies.MethodsA human syngeneic blood-brain tumor barrier (BBTB) in vitro model, comprising endothelial cells, pericytes and DMG cells was submitted to a single dose of radiation (2 Gγ to 6 Gγ) and was characterized for its physical and metabolic properties over a period of 7 days post-exposure. The results were then compared to the effects of the same irradiation protocol on a physiologic blood-brain barrier (BBB) model.ResultsFollowing irradiation, the endothelial permeability of the BBB ECs and the BBTB ECs was preserved for up to 7 days but associated with Claudin-5 heterogeneous distribution at the ECs borders and decrease of expression after irradiation. Nevertheless, irradiation was found to potentiate the effect of TNFα on the physical integrity of the BBB, which was less important for the BBTB. The metabolic properties of the BBB and BBTB were modulated by radiation at the transcriptional level. Interestingly, different regulations were observed in endothelial cells and pericytes. Notably, pericytes have demonstrated compensatory effects. Immunoblots confirmed the decrease of BCRP, MRP4 and MFSD2A in BBTB endothelial cells after irradiation. Despite significant reduced efficiency, P-gp/BCRP efflux pump activity remains functional in endothelial cells and pericytes following irradiation.ConclusionsIrradiation sensitizes the BBB, but to a lesser extent the BBTB, to the effects of pro-inflammatory cytokines. The observed decrease in P-gp/BCRP activity, as well as the involvement of MFSD2A, MRP4 and Claudin-5 regulation, warrant further investigations