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Generative model of SARS-CoV-2 variants under immune pressure unveils viral escape potential
No full textPosted June 25, 2025 on bioRxiv.International audienceThe evolutionary trajectory of SARS-CoV-2 is shaped by competing pressures for ACE2 binding, structural viability, and escape from neutralizing antibodies targeting its receptor-binding domain (RBD). Here, we present EscapeMap, a modular framework that quantifies immune selection and predicts which antibodies are more or less likely to be escaped by future viral evolution. EscapeMap integrates deep mutational scanning data for ACE2 and 31 monoclonal antibodies with a generative sequence model trained on pre-pandemic Coronaviridae. To probe escape potential, we designed RBD variants under pressure from four clinically relevant antibodies (SA55, S2E12, S309, VIR-7229). Among these designs, bearing up to 21 mutations from wildtype, 50% expressed as stable proteins. Binding assays confirm that S309 and VIR-7229 retain recognition across diverse mutation combinations. EscapeMap accurately forecasts which antibodies are vulnerable to escape by our designed sequences. Finally, by identifying negatively correlated escape routes, we prioritize antibody combinations less prone to simultaneous escape, offering a quantitative basis for guiding therapeutic strategies
DMEM and EMEM are suitable surrogate media to mimic host environment and expand leptospiral pathogenesis studies using <i>in vitro</i> tools
No full textInternational audiencePathogenic Leptospira species can survive and thrive in a wide range of environments. Distinct environments expose the bacteria to different temperatures, osmolarities, and amounts and sources of nutrition. However, leptospires are mostly cultured, in a laboratory setting under in vitro conditions that do not reflect natural environments. This constraint on laboratory cultures limits the applicability of in vitro studies to the understanding of even simple pathogenic processes. Here we report, investigate, and identify a medium and conditions that mimic the host environment during leptospirosis infection, expanding the available in vitro tools to evaluate leptospiral pathogenesis. We quantified genome-wide gene expression of pathogenic Leptospira interrogans cultured in different in vitro media compositions (EMJH, DMEM, EMEM, and HAN). Using EMJH as standard, we compared gene expression in these compositions to genome-wide gene expression gathered in a host environment: whole blood (WB) of hamsters after infection with pathogenic leptospires. Leptospires cultured in DMEM and EMEM media shared 40% and 47% of all differentially expressed genes (DEGs) of leptospires present within WB (FDR<0.01), while leptospires cultured in HAN media only shared 20% of DEGs with those from WB. Furthermore, gene and pathway expression of leptospires cultured on DMEM and EMEM media exhibited a better correlation with leptospires grown in WB, including promoting expression of a similar leptospiral lipid A profile to the one identified directly in host tissues. Taken together, these results indicate that commercial cell-culture media EMEM or DMEM are better surrogates for in vivo pathogenic studies than EMJH or HAN media in Leptospira. These alternative culture conditions, using media that are a standard supply worldwide, provide a reproducible and cost-effective approach that can accelerate research investigation and reduce the number of animal infections necessary for basic research of leptospirosis
Transcriptomic profiling reveals similarities between equine IVF and ICSI embryos
No full textInternational audienceIn vitro production of equine embryos has been performed using intracytoplasmic sperm injection (ICSI) for the last two decades. Since 2022, a repeatable protocol for conventional in vitro fertilization (IVF) provides a successful alternative. However, little is known about the influence of the fertilization method on embryo quality and the transcriptomic profile. In this study, we aimed to examine differentially expressed genes (DEGs) between ICSI and IVF embryos in the horse. Therefore, ten equine sibling blastocysts, produced in vitro by either ICSI or IVF from three different mares, were subjected to Full-Length Single-Cell RNA-Sequencing (FLASH-sequencing). As such, 11,518 genes were identified, with no DEGs between ICSI and IVF embryos. Cleavage rates, calculated on collected COCs, of IVF zygotes (55.0 %) were similar to those of ICSI zygotes (51.9 %; P = 0.74), but blastocyst rates were higher following ICSI (37.0 % vs 22.5 % calculated on collected COCs and 71.4 % vs 40.9 % calculated on cleaved zygotes; P = 0.04 and 0.004, respectively). The average day of blastocyst development did not differ (P = 0.55). In conclusion, gene expression was similar for the two fertilization techniques, supporting the safety of equine IVF for further clinical studies. Overall, the horse provides a valuable model to study longterm effects of assisted reproductive technologies with potential extrapolation to human medicine
Anopheles resistance to deltamethrin can be caused by the increased abundance of an enteric Aeromonas taxon
No full textThe enteric bacteriome of Anopheles mosquito vector has been linked with its vectorial competence, however, its influence on insecticide resistance is poorly understood. We found that the depletion of the bacterial microbiome in susceptible Anopheles strains, resulting from antibiotic treatment, led to greater than 50% insecticide deltamethrin tolerance compared to untreated mosquitoes. Simultaneous inhibition of cytochrome P450 activity reverted the antibiotic-induced tolerance phenotype, indicating that the antibiotic-induced deltamethrin tolerance is P450-dependent. We found that the antibiotic treatment, while suppressing most enteric bacterial taxa, allowed proliferation of a particular antibiotic-tolerant Aeromonas taxon, most closely related to Aeromonas hydrophila. Increasing the abundance of this taxon in mosquitoes not treated with antibiotics phenocopied the tolerance phenotype, converting deltamethrin-susceptible Anopheles to deltamethrin-tolerant mosquitoes. Collectively, these results highlight a mechanistic interplay in Anopheles mosquitoes between antibiotic-induced enteric dysbiosis and cytochrome P450-mediated detoxification that promotes insecticide tolerance. This effect could influence mosquito vectorial capacity, especially in Africa, where auto-medication with antibiotics is highly prevalent
EMBO Workshop Host–Parasite Relationship 2025: Cutting-edge science from the shores of Les Embiez
No full textInternational audienceThe EMBO-funded workshop 'Host–Parasite Relationship: from mechanism to control strategies' took place in Les Embiez, France, on 5–8 October 2025. It was supported by the LabEx ParaFrap community and organized by Lucy Glover and Benoit Gamain. After a hiatus of 3 years, this biannual conference series is consolidating its role as the flagship parasitology meeting within Europe, where scientists meet to share their breakthroughs and to discuss new ideas in the beautiful shores of Les Embiez Island. The workshop had an outstanding line-up of invited speakers, exciting reports from selected speakers, flash talk presenters, a panel discussion for Young Investigators in Parasitology (YIP), and two vibrant poster sessions. In this TrendsTalk, we invited early career researchers to summarize the highlights of the meeting
Dual AAV gene therapy achieves recovery of hearing and auditory processing in a DFNB16 mouse model
No full textInternational audienceBackgroundDFNB16, the second most common genetic cause of hearing loss, is caused by mutations of the STRC gene encoding stereocilin, a protein essential for the effective functioning of outer hair cells (OHCs) as cochlear amplifiers. Strc−/− mice, which lack stereocilin, display severe to profound deafness and constitute a relevant preclinical model for DFNB16.MethodsUsing Strc−/− mice, we developed a gene therapy strategy based on the use of dual AAV9-PHP.eB vectors to deliver the full-length Strc cDNA. Therapeutic efficacy was assessed by evaluating stereocilin expression, OHC bundle architecture, and their attachment to the tectorial membrane, together with functional recovery using distortion product otoacoustic emissions (DPOAEs), auditory brainstem responses (ABR) measurements and Go/No-Go behavioral testing with psychometric analysis.ResultsDual-AAV–mediated Strc gene delivery restored stereocilin expression, OHC bundle architecture and their attachment to the tectorial membrane, leading to the recovery of cochlear amplification and hearing to near normal thresholds, as confirmed by distortion product otoacoustic emission (DPOAE) and auditory brainstem response measurements. Behavioural assessment showed that treated Strc−/− mice regained normal frequency discrimination, indicating a restoration of higher-order auditory processing, up to 100 days post-treatment.ConclusionThese findings provide the first proof-of-principle that peripheral gene therapy can restore OHC function, cochlear amplification and central auditory perception in a DFNB16 model
Tunneling Nanotube–like Connections in the Developing Cerebellum: Distinct from Cytokinetic and Intercellular Bridges
No full textIntercellular communication is essential for brain development. While classical communication modes—such as paracrine, juxtacrine and synaptic signaling—are well characterized, emerging evidence suggests that tunneling nanotubes (TNTs), membranous bridges primarily observed in vitro, may also contribute. However, their presence and function in vivo remain unclear, partly due to the challenge of distinguishing them from other types of intercellular connections (ICs). Building on prior evidence of ICs in the external granule layer (EGL) of the developing cerebellum, we investigated their nature in postnatal day 7 (P7) mice. Using immunofluorescence and genetically sparse labeling, we distinguished cytokinetic bridges (CBs), transient connections formed between daughter cells during the final stage of cell division, and intercellular bridges (IBs), more stable connections that persist after division, from TNT-like structures, which form independently of cell division. We observed CBs but not IBs in the EGL. We also observed TNT-like connections throughout the EGL, which appeared to connect both clonally and non-clonally related cells. The presence of these TNT-like structures in the developing EGL suggests that TNT-like connections may contribute to intercellular communication, paving the way for further study of a previously unrecognized mechanism that could influence neuronal fate, migration, and network formation during cerebellar development
7-year trend of timely hepatitis B birth dose vaccination coverage in The Gambia: a retrospective, population-based analysis
No full textInternational audienceBackgroundAccording to WHO and UNICEF, Africa has the lowest coverage (18%) of timely (within the first 24 h) hepatitis B birth dose (HepB-BD) vaccination worldwide. To eliminate hepatitis B by 2030, 90% vaccination coverage is required. Experiences from The Gambia, the first African country to adopt HepB-BD vaccination in 1990, could guide HepB-BD implementation and scale-up in Africa. We aimed to assess the trend of, and barriers to, timely HepB-BD vaccination coverage over a 7-year period in The Gambia.MethodsIn this retrospective analysis, 2015–21 data were extracted from population-based Health and Demographic Surveillance Systems in three rural areas (Basse, Bansang, and Farafenni) in The Gambia. Fluctuation tests and Bayesian analysis using Markov chain Monte Carlo methods assessed the rate of timely (within days 0–1 of birth) and delayed HepB-BD vaccination coverage, change points (abrupt variation between two stable periods) in the average coverage of timely HepB-BD vaccination, and the factors associated with delayed HepB-BD vaccination during the first 7 years following the WHO recommendations on hepatitis B elimination.FindingsBetween Jan 1, 2015, and Dec 31, 2021, 4560 of 71 088 livebirths (6·4%, 95% CI 6·2–6·6) received a timely HepB-BD. Timely HepB-BD vaccination coverage increased from 1·7% (95% CI 1·3–2·0) in the first half of 2015 (ie, January to June) to 22·4% (21·3–23·6) in the second half of 2021 (ie, July to December; p<0·0001). Delayed HepB-BD administration was associated with being born on Friday (odds ratio [OR] 3·51 [95% CI 3·03–4·08]; p<0·0001) or Saturday (5·93 [4·96–7·13]; p<0·0001) compared with Tuesday; being born in Basse (2·03 [95% CI 1·83–2·25]; p<0·0001) or Farafenni (1·84 [1·63–2·08]; p<0·0001); and being born during the rainy season (1·16 [1·08–1·25]; p<0·0001). Average timely HepB-BD vaccination coverage significantly decreased from 10·1% (95% CI 9·5–10·6) pre-COVID-19 pandemic to 5·4% (4·5–6·3) during the first COVID-19 wave (p<0·0001). After adjusting for all other factors, being born during the first COVID-19 wave was associated with delayed HepB-BD vaccination (OR 1·41 [1·22–1·64]; p<0·0001).Interpretation30 years after the adoption of HepB-BD in The Gambia, the rate of vaccination coverage remains low and was significantly affected by the COVID-19 pandemic, highlighting the challenges for its implementation
Stage-resolved metabolomics reveals the methionine cycle as a key regulator of Aedes aegypti development and dengue virus susceptibility
No full textPosted December 29, 2025 on bioRxiv.International audienceDevelopmental transitions in the mosquito Aedes aegypti are central to vector competence and disease transmission, yet the underlying metabolic programs remain poorly defined. Here, we use untargeted metabolomics, gene expression analysis, and functional assays to delineate stage-specific metabolic fingerprints across the mosquito life cycle, from egg and larva to pupa and adult. Our profiling of the larval diet reveals comprehensive provisioning of essential nutrients, including B vitamins critical for development. Metabolomic analyses uncover distinct, stage-specific signatures, with the larval stage exhibiting a pronounced enrichment of methionine cycle metabolites and maximal methylation capacity. Notably, while S-adenosylmethionine (SAM) and related metabolites peak in larvae, the transcription of the methionine cycle and histone methyltransferase genes is highest in adults. Functional disruption of the methionine cycle in mosquito cells reveals network-level robustness and regulatory crosstalk within the pathway. However, we also identify a specific vulnerability: silencing the gene adenosylhomocysteinase ( ahcy ) enhances dengue virus 1 replication and infectious particle production. Collectively, our findings identify the methionine cycle as a metabolic–epigenetic hub that integrates nutrition, development, and viral susceptibility, and highlight the larval stage as a strategic target for novel mosquito-control strategies
N-Cadherin/α-Catenin Drive Adhesion and Actin Regulation to Orchestrate Tunneling Nanotube Formation
No full textAbstract Cell-to-cell communication is essential for maintaining homeostasis in multicellular organisms. Tunneling nanotubes (TNTs)—actin-based membranous connections—mediate the exchange of diverse cargoes between distant cells. Unlike other cellular protrusions, TNTs exhibit unique ultrastructural features and are enriched in the adhesion molecule N-Cadherin. Here, we dissect the role of N-Cadherin in the formation and function of TNTs in SH-SY5Y human neuronal-like cells. We show that N-Cadherin, via its effectors α-Catenin and p120-Catenin, is a central regulator of TNT architecture and their cargo transfer capability. Regulators of cortical tension p120-Catenin, ROCK, and non-muscle myosin II also emerge as critical for TNT functionality, highlighting a mechanosensitive component to TNT regulation. Moreover, we reveal that NMIIA can be processive inside TNTs and transfer through them using actin’s retrograde flow. Finally, we identify the Cdc42–IRSp53–N-WASP pathway as a downstream effector axis enhancing intercellular transfer downstream of N-Cadherin. Together, our findings uncover a structural and functional link between N-Cadherin signaling and TNT-mediated intercellular communication