HAL-Pasteur
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Selective eIF4E–eIF4G Pairing and Cap-4 Recognition Mechanisms in Trypanosomatids: Insights From EIF4E5–EIF4G1 and EIF4E6–EIF4G5 Complexes
No full textInternational audienceTargeting epigenetics is a new strategy to treat cancer and develop novel epigenetic drugs with anti-tumor activity. DNA methyltransferases transfer the methyl group from S-adenosyl-L-methionine (SAM) to the cytosine residue in a CpG island, leading to the transcription silencing of the gene. Hypermethylation can frequently be observed in several tumor types. Hence, the inhibition of DNMT1 has become a novel approach to cure cancer. In this study, virtual screening and molecular docking were performed for more than 11,000 ligands from the ZINC15 database to discover new hypomethylation agents. Four candidate compounds were further tested for their effects on DNMT1 in silico and in vitro. Compounds 2 and 4 showed the best DNMT1 inhibitory activity, but only compound 4 was able to inhibit the growth of several cancer cell lines. The hypomethylation of the luciferase gene by compound 4 was verified by a CMV- luciferase assay using KG-1 cells. Additionally, compound 4 suppressed cell migration in a dose- and time-dependent manner in the wound healing assay. Moreover, cell cycle analyses demonstrated that compound 4 arrested CCRF-CEM cells and MDA-MB-468 cells in the G0/G1 phase. Also, compound 4 significantly induced early and late apoptosis in a dose-dependent manner. In conclusion, we introduce compound 4 as a novel DNMT1 inhibitor with anticancer activity
Automated mapping of DNA replication fork progression in human cells with ForkML
No full textInternational audienceCurrent approaches to mapping fork progression in the human genome suffer from drastically low throughput. Here, we introduce ForkML, a nanopore sequencing-based method automatically positioning thousands of individual fork velocities by tracking BrdU incorporation into replicating DNA after double pulse-labelling of asynchronous cells. ForkML recovers known human fork speed, accurately detects replication stress, and, crucially, connects replication dynamics to genomic and chromatin contexts, exposing fork slowdown in early-replicating transcribed regions
MAPPING CHANGES OF MIRNA-MRNA NETWORKS IN LEISHMANIA-INFECTED MACROPHAGES PREDICTS REGULATORY MIRNA-TF LOOPS AS NOVEL TARGETS OF PARASITE IMMUNE SUBVERSION
No full textMicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression at the posttranscriptional level and play a crucial role in numerous disease processes, including infections.Although intracellular microbial pathogens are known to modulate host cell gene expression to establish permissive conditions for infection, the specific role of host-encoded miRNAs underlying such subversion remains poorly understood. In this study, we employed the protozoan parasite Leishmania amazonensis as a model system to investigate how infection of macrophages modifies the host cell miRNA profile to evade antimicrobial functions and to establish permissive conditions for intracellular proliferation. Dual RNA-seq analyses using matched mRNA and miRNA-enriched samples from uninfected and L. amazonensis-infected bone marrow-derived macrophages (BMDMs) revealed 102 differentially expressed miRNAs (padj <0.05), with 18 miRNAs showing reduced and 84 miRNAs showing increased abundance in infected BMDMs. Mapping putative networks of miRNA-mRNA interactions based on the observed expression changes, combined with Gene Ontology enrichment analyses, allowed us to identify potential miRNA target genes involved in key biological processes and metabolic pathways that permit parasite intracellular survival and proliferation. Our analyses predict the existence of a large miRNA-mRNA network affecting the expression level of numerous transcription factors that indicates inhibition of the NF-κB-dependent inflammatory response or the promotion of cholesterol biosynthesis during infection. In particular, the over 10e3-fold increase in the abundance of mmu-miR-686 in infected BMDMs was correlated with a reduced abundance of putative target transcripts implicated in miRNA biogenesis itself, in RNA binding, and in regulation of apoptosis, such as Caspase 12, the mRNA decay activator protein Zfp36l1 or Leukemia Inhibitory Factor Receptor Alpha. Likewise, the over 200-fold increase in abundance of mmu-miR-6546-3p was associated with a reduced abundance of putative target mRNAs implicated in cytokine-mediated signaling, positive regulation of apoptotic process and regulation of gene expression, affecting, for example, the MADS box transcription enhancer factor 2, the transformation related protein 53 inducible nuclear protein 1, or the G protein-coupled receptor 35. Interestingly, both miRNAs are predicted to simultaneously target 32 mRNAs that showed reduced abundance in infected BMDMs, including Maturin Neural Progenitor Differentiation Regulator (Mturn), a regulator of NF-κB transcription factor activity. In conclusion, our approach provides novel insight into molecular mechanisms that may govern macrophage subversion and intracellular Leishmania survival. Our results shed newlight on the complex relationship among miRNAs, macrophage gene expression and Leishmania infection, proposing regulatory feed-forward loops (FFLs) and feedback loops (FBLs) between miRNAs and TFs as a novel target of Leishmania immune subversion. These findings open exciting new avenues for the development of intervention strategies aimed at disrupting such crucial interactions, for example using an anti-miR (antagomir) approach against mmu-miR-686 and mmu-miR-6546-3p
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
Spatiotemporal regulation of energetic charge dictates T cell function
No full textInternational audienceImmune cell functions are dictated by their differentiation state and regulated by transcriptional and epigenetic changes. Immune cell differentiation also controls the preferential metabolic pathways used for energy production. However, whether the energy charge of individual immune cells itself varies across time and space and regulates cell function remains to be fully understood. Here, we show that T cells harbor distinct energetic resources and function in different anatomical locations and times of the day. To monitor ATP: ADP ratio, an indicator of cellular energetic resources, we rely on SPICE-Met, a method that dissects energy metabolism in complex cell populations in vivo. We find that cells with the highest glycolytic capacity, including effector T cells and NK cells, exhibit the highest ATP: ADP ratio. Importantly, effector T cells but not naïve T cells display higher energetic charge when present in the blood compared to lymph nodes due to differential glucose availability. Energetic resources are also regulated in a circadian manner, being highest at the early rest phase. Importantly, differences in energetic charge are directly translated at the level of T cell function, impacting IFN-γ production. Thus, modulation of energetic charge and nutrient availability dictates immune cell function across time and space
Interim vaccine effectiveness against influenza virus among outpatients, France, October 2025 to January 2026
No full textInternational audienceIn Europe, the 2025/26 seasonal influenza epidemic started in October 2025. Co-circulation of A(H3N2) and A(H1N1)pdm09 was observed in several countries including France. We estimated early vaccine effectiveness (VE) against influenza virus in French outpatients (5,451 positives/18,816 negatives). A significant VE across all age groups was measured: 28% (95% CI: 17–37) for those aged ≥ 65 years, 45% (95% CI: 36–53) for 18–64-year-olds and 57% (95% CIs: 29–74) for 0–17-year-olds. Reinforcing vaccination uptake is warranted
Burden of rodent-borne viruses in rodents and zoonotic risk in humans in Cambodia
No full textInternational audienceRodent-borne viruses, including orthohantaviruses, mammarenaviruses, and rat hepatitis virus (HEV-C), pose significant health threats to humans, causing severe diseases such as hemorrhagic fevers, respiratory illness, and hepatitis. In Cambodia, data on these viruses remain limited, and their burdens on human health are unknown. This study investigated the presence of these viruses in rodents and assessed potential human exposure across diverse environmental and socio-economic contexts in Cambodia. The study was conducted in urban, semi-urban, and rural areas of Cambodia during the rainy season of 2020 and dry season of 2022. Rodents were screened for viruses using RT-PCR. Human serum samples from the same sites were tested for IgG antibodies using ELISA. Factors associated with virus spillover into humans were analyzed. Among 750 rodents, 9.7% carried at least one virus: 5.2% mammarenavirus, 3.3% orthohantavirus, and 1.9% HEV-C. Infection rates were highest in urban (14.5%), followed by semi-urban (11.9%) and rural (2.1%) interfaces. Mammarenavirus was more prevalent in the rainy season, while orthohantavirus and HEV-C remained consistent across seasons. In humans, seroprevalence was 12.7% for mammarenavirus, 10.0% for orthohantavirus, and 24.2% for HEV. Higher mammarenavirus seroprevalence was associated with urban residency. Orthohantavirus seroprevalence was associated with urban residency, acute hepatitis history, and flood-prone living areas. HEV seroprevalence increased with urban residency, increasing age, and medical condition history. Our findings highlighted the need for rodent control, improved market infrastructure, enhanced waste management, and public awareness of hygiene practices and zoonotic risks, especially in urban high-risk areas. IMPORTANCE Rodents can carry viruses that may spread to humans, sometimes causing serious diseases. However, little was known about the presence of these viruses in Cambodia or their potential impact on human health. This study investigated rodent populations across urban, semi-urban, and rural areas and tested both rodents and humans for three key viruses: arenavirus, hantavirus, and hepatitis E virus. The findings confirm the presence of these viruses in rodents and indicate human exposure, particularly in urban areas. Factors such as urban residency and living in flood-prone areas were associated with an increased risk of exposure. These results emphasize the need for improved rodent control, waste management, and public awareness of zoonotic disease risks. A better understanding of virus transmission dynamics will help guide health officials in developing effective strategies to prevent infections and protect communities
Non-Aspergillus invasive mould infections in liver transplant recipients : a French national retrospective case-control study, 2007 to 2021
No full textInternational audienceBACKGROUND: Non-Aspergillus invasive mould infections (IMIs) are emerging in immunocompromised patients and liver is the second most commonly organ transplanted worldwide. METHODS: We conducted a multicenter retrospective case-control (1:1) study of liver transplant recipients diagnosed with non-Aspergillus IMIs in France between January 2007 and December 2021. RESULTS: We identified 27/14,332 (0.18%) LT recipients with non-Aspergillus IMIs. Mucorales spp. (48%) were the most common pathogens, followed by Scedosporium spp. (14%), Fusarium spp. (14%), and other IMIs (25%). Lungs were the primary infection site, followed by soft tissues, abdomen, brain, sinuses, heart, and bone. Multivariate analysis showed that a MELD score > 20 prior to transplantation and primary antifungal prophylaxis (with echinocandins or fluconazole) tended to increase the risk of non-Aspergillus IMIs by nearly threefold ((aOR: 3.73, 95% CI [0.90-15.45], p = 0.07) and (aOR: 3.93; 95% CI [0.94-16.42], p = 0.06) respectively). The 6-month mortality rate was 55%. In a Cox survival model, non-Aspergillus IMIs were associated with a threefold increase in mortality risk ((HR: 3.82 [2.01-7.26] p<0.001). CONCLUSION: Non-Aspergillus IMIs are rare but highly fatal infections whose early diagnosis in high-risk liver-transplanted patients is essential. Whether or not recently available molecular tools for diagnosing non-Aspergillus IMIs will improve their prognosis in the liver transplantation setting remains to be studied
IL-17-mediated antifungal immunity restricts Candida albicans pathogenicity in the oral cavity
No full textLe fichier joint est la révision 2 et n'a pas le même titreInternational audienceCandida albicans is a common resident of the microbiota that supports host homeostasis but can cause disease when immune defences are impaired. Mucocutaneous candidiasis in individuals with IL-17 immune defects provides insights into the immune system’s role in controlling C. albicans. Here, using a murine model of oral colonization, we show that IL-17 signalling maintains C. albicans in a non-pathogenic state. Loss of IL-17 leads to fungal filamentation and upregulation of hyphae-associated genes, which is accompanied by epithelial barrier disruption and inflammation, linked to aberrant IL-22 and IL-13 production. The emergence of pathogenic fungal traits was associated with impaired zinc chelation due to reduced calprotectin expression in the IL-17-deficient mice. Prolonged exposure to the immune-dysregulated tissue led to selection of stable, damage-inducing C. albicans variants, mirroring the evolution of isolates from a chronic mucocutaneous candidiasis patient. These findings reveal how IL-17 protects against fungal pathogenicity and how immune dysfunction fosters C. albicans adaptation and diversification within the host
“Tobaliviridae”, a new family of filamentous mycoviruses in the order Martellivirales
No full textInternational audienceThe order Martellivirales currently comprises seven families of positive-strand (+) RNA viruses, namely, Bromoviridae, Closteroviridae, Endornaviridae, Kitaviridae, Mayoviridae, Togaviridae, and Virgaviridae, that infect a range of animals, fungi, and plants. These viruses display remarkably diverse virions built from non-homologous capsid proteins but are unified through homologous alphavirus-like replication module. Here, we introduce an additional family in the order Martellivirales, with the proposed name "Tobaliviridae", to accommodate an emerging group of viruses reported from fungi. This family includes a single genus, "Tobalivirus", with nine species. Tobaliviruses share a capsid protein homologous to those of closteroviruses, potyviruses and alphaflexiviruses, and consistently, some members of the family have been demonstrated to form flexible filamentous virions. The formal taxonomic proposal for the establishment of the family "Tobaliviridae" is awaiting ratification by the International Committee for Taxonomy of Viruses (ICTV)