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IL-23 tunes inflammatory functions of human mucosal-associated invariant T cells
No full textInternational audienceIL-23 signaling plays a key role in the pathogenesis of chronic inflammatory and infectious diseases, yet the cellular targets and signaling pathways affected by this cytokine remain poorly understood. We show that IL-23 receptors are expressed on the large majority of human mucosal-associated invariant T (MAIT), but not of conventional T cells. Protein and transcriptional profiling at the population and single cell level demonstrates that stimulation with IL-23 or the structurally related cytokine IL-12 drives distinct functional profiles, revealing a high level of plasticity of MAIT cells. IL-23, in particular, affects key molecules and pathways related to autoimmunity and cytotoxic functions. Integrated analysis of transcriptomes and chromatin accessibility, supported by CRISPR-Cas9 mediated deletion, shows that AP-1 transcription factors constitute a key regulatory node of the IL-23 pathway in MAIT cells. In conclusion, our findings indicate that MAIT cells are key mediators of IL-23 functions in immunity to infections and chronic inflammatory diseases
Monitoring molecular markers associated with antimalarial drug resistance in south-east Senegal from 2021 to 2023
No full textInternational audienceBackground Since 2006, artemisinin-based combination therapies (ACTs) have been introduced in Senegal in response to chloroquine resistance (CQ-R) and have shown high efficacy against Plasmodium falciparum. However, the detection of the PfKelch13R515K mutation in Kaolack, which confers artemisinin resistance in vitro, highlights the urgency of strengthening antimalarial drug surveillance to achieve malaria elimination by 2030. Objective To assess the proportion of P. falciparum parasites carrying molecular signatures associated with antimalarial resistance (PfKelch13, Pfmdr1, Pfcrt, dhfr and dhps) in isolates collected at Kédougou using multiplex amplicon deep sequencing. Methods Venous blood samples were collected from patients diagnosed with P. falciparum infection over a 3-year period (2021, 2022 and 2023). Parasite DNA was extracted, and multiplex amplicon sequencing was used to investigate gene polymorphisms. Results Analysis of PfKelch13 did not reveal any non-synonymous mutations. Pfcrt mutations were present in 45% of the samples, mainly K76T (44%) and I356T (36%). The dominant Pfmdr-1 allele was Y184F (62%). The sextuple mutant 51I/59R/108N + 436A/437G/613S dhfr/dhps was observed in 10% of the samples. Conclusion The absence of PfKelch13 mutants suggests that ACT efficacy remains uncompromised, although clinical outcome studies are required to confirm this. Analysis of Pfcrt and Pfmdr-1 shows that CQ-R alleles, probably from previous CQ use, are slowly decreasing. Likewise, the detection of the dhfr/dhps sextuple mutant highlights the need to monitor sulfadoxine-pyrimethamine resistance and the emergence of 581G. There is therefore a need for continued antimalarial resistance surveillance in Senegal
Liver Enzyme Elevation After Hepatitis C Virus Cure: Is There a Sex Effect? (ANRS CO13 HEPAVIH Cohort)
No full textInternational audienceWe read with great interest Zhang et al.'s work on liver enzyme elevation (LEE) after hepatitis C virus (HCV) cure [1]. While the authors found no evidence of an effect of HIV status on post-cure LEE, they showed that female sex, pretreatment alanine aminotransferase (ALT) and pretreatment cirrhosis were positively associated with this outcome. Their study limitations included its single-centre nature, the lack of data on alcohol use and the relatively small number of HIV-HCV co-infected individuals. We thus further explored the potential impact of HIV-related markers and alcohol use on post-HCV cure LEE in a larger sample of HIV-HCV co-infected adults enrolled in the French, prospective, multicentre cohort ANRS CO13 HEPAVIH [2]. Participants provided written informed consent. We selected participants cured from HCV thanks to direct-acting antiviral treatment (DAA), who had completed at least one clinical follow-up visit after HCV cure, and with available pretreatment data on age, sex, place of birth, body mass index, ALT and aspartate transaminase (AST) levels, CD4 cell count, HIV viral load, history or current cirrhosis or hepatocellular carcinoma and alcohol use (AUDIT-C [3]). We conducted a multivariable mixed-effects logistic regression model over the post-HCV cure follow-up period, with LEE as the outcome
New results on implementation of neuroscience methods in the study of bear brain
No full textInternational audienceRésumés des journées 202
Une nouvelle aventure: la section Jeunes prend vie !
No full textInternational audienceBonjour à tous ! La section Jeunes de la Société française de virologie se présente à vous ! Notre aventure a débuté pendant les Journées francophones de virologie (JFV 2024) à Bruxelles [1]. Il faut dire que les jeunes chercheurs (masters, doctorants, jeunes post-doc) représentent classiquement près de la moitié des participants des JFV – nombreux sont ceux qui partagent leurs travaux [...
A single-cell atlas of the Culex tarsalis midgut during West Nile virus infection
No full textInternational audienceThe mosquito midgut functions as a key interface between pathogen and vector. However, studies of midgut physiology and virus infection dynamics are scarce, and in Culex tarsalis— an extremely efficient vector of West Nile virus (WNV) — nonexistent. We performed single-cell RNA sequencing on Cx. tarsalis midguts, defined multiple cell types, and determined whether specific cell types are more permissive to WNV infection. We identified 20 cell states comprising 8 distinct cell types, consistent with existing descriptions of Drosophila and Aedes aegypti midgut physiology. Most midgut cell populations were permissive to WNV infection. However, there were higher levels of WNV RNA (vRNA) in enteroendocrine cells (EE), suggesting enhanced replication in this population. In contrast, proliferating intestinal stem cells (ISC) had the lowest levels of vRNA, a finding consistent with studies suggesting ISC proliferation in the midgut is involved in infection control. ISCs were also found to have a strong transcriptional response to WNV infection; genes involved in ribosome structure and biogenesis, and translation were significantly downregulated in WNV-infected ISC populations. Notably, we did not detect significant WNV-infection induced upregulation of canonical mosquito antiviral immune genes (e.g., AGO2 , R2D2 , etc.) at the whole-midgut level. Rather, we observed a significant positive correlation between immune gene expression levels and vRNA load in individual cells, suggesting that within midgut cells, high levels of vRNA may trigger antiviral responses. Our findings establish a Cx. tarsalis midgut cell atlas, and provide insight into midgut infection dynamics of WNV by characterizing cell-type specific enhancement/restriction of, and immune response to, infection at the single-cell level
Glucagon-Like Peptide-1 Receptor Agonists in Hidradenitis Suppurativa
No full textInternational audienceThis cohort study investigates the potential therapeutic benefits of glucagon-like peptide-1 receptor agonists in patients with hidradenitis suppurativa
Rational Design and Synthesis of Highly Stable Haloflavanone DNA Methyltransferase Inhibitors Inducing Tumor Suppressor Gene Re-expression in Cancer Cells
No full textInternational audienceDNA methylation is an epigenetic modification involved in cancer. The clinically approved nucleoside DNA methyltransferase (DNMT) inhibitors 5-azacytidine and 5-aza-2'-deoxycytidine lack selectivity and stability, resulting in high toxicity. Previously, we discovered 3-halo-3-nitroflavanones as non-nucleoside DNMT inhibitors. Here, we designed and synthesized a new series of 2-substituted haloflavanones to increase compound chemical stability. Moreover, replacement of the nitro by an additional halogen enhanced compound potency. Indeed, compound 34b (anti-3-bromo-3-chloro-2-methoxyflavanone) exhibited submicromolar DNMT3A inhibitory activity, upregulated the expression of DNMT-targeted genes, and impaired cell proliferation. Importantly, 34b triggered a critical cell cycle arrest in the G1/S transition, notably in p53-depleted HCT-116 colorectal cancer cells, which paves the way for novel therapeutic opportunities. 34b competes for the same DNMT catalytic pocket as confirmed by saturation transfer difference-nuclear magnetic resonance, but assuming different docking poses as shown by computational studies. Overall, the high stability and activity of 34b make it a promising DNMT inhibitor for anticancer research and therapy
Multitrait Analysis to Decipher the Intertwined Genetic Architecture of Neuroanatomical Phenotypes and Psychiatric Disorders
No full textInternational audienceBACKGROUND: There is increasing evidence of shared genetic factors between psychiatric disorders and brain magnetic resonance imaging (MRI) phenotypes. However, deciphering the joint genetic architecture of these outcomes has proven to be challenging, and new approaches are needed to infer the genetic structures that may underlie those phenotypes. Multivariate analyses are a meaningful approach to reveal links between MRI phenotypes and psychiatric disorders missed by univariate approaches. METHODS: First, we conducted univariate and multivariate genome-wide association studies for 9 MRI-derived brain volume phenotypes in 20,000 UK Biobank participants. Next, we performed various complementary enrichment analyses to assess whether and how univariate and multitrait approaches could distinguish disorder-associated and non-disorder-associated variants from 6 psychiatric disorders: bipolar disorder, attention-deficit/hyperactivity disorder, autism, schizophrenia, obsessive-compulsive disorder, and major depressive disorder. Finally, we conducted a clustering analysis of top associated variants based on their MRI multitrait association using an optimized k-medoids approach. RESULTS: A univariate MRI genome-wide association study revealed only negligible genetic correlations with psychiatric disorders, while a multitrait genome-wide association study identified multiple new associations and showed significant enrichment for variants related to both attention-deficit/hyperactivity disorder and schizophrenia. Clustering analyses also detected 2 clusters that showed not only enrichment for association with attention-deficit/hyperactivity disorder and schizophrenia but also a consistent direction of effects. Functional annotation analyses of those clusters pointed to multiple potential mechanisms, suggesting in particular a role of neurotrophin pathways in both MRI phenotypes and schizophrenia. CONCLUSIONS: Our results show that multitrait association signature can be used to infer genetically driven latent MRI variables associated with psychiatric disorders, thereby opening paths for future biomarker development.</div
Optimized lentiviral backbone induces robust and diverse T cell immunity against neoantigens to counteract tumor heterogeneity
No full textInternational audienceTargeting personalized tumor neoantigens is a promising strategy in immuno-oncotherapy, tumor heterogeneity requires that adaptive immunity be effectively induced against a broad spectrum of neoantigens for a significant anti-tumor effect. We developed several non-integrative lentiviral vectors encoding optimized immunogen that induce robust T cell responses against neoepitopes derived from murine colorectal tumors. Incorporating proteasome-targeting sequences and 4-alanine spacers between neoepitopes enhanced responses to both dominant and subdominant neoepitopes. Using longer natural sequences encompassing minimal epitopes further improved immunogenicity. These vectors drove complete regression of MC38 tumors expressing the selected neoepitopes and sustained immune memory to prevent relapse. Additionally, these vectors synergized with anti-programmed cell death protein 1 (PD1) therapy to inhibit wild-type MC38 tumor growth. Variant allele frequency tracking demonstrated T cells eradicated neoantigen-positive cells without affecting negative ones. Our results validate lentiviral vectors for personalized neoepitope therapy and underscore the need for diverse neoantigens in immunotherapy against tumor mosaicism