Transcriptome Signature of Nipah Virus Infected Endothelial Cells

International audienc

Genetic bases of nitrogen requirement in wine yeast assessed trhrough QTL analysis

In grape must, nitrogen content is ofteninsufficient for the completion of alcoholic fermentation by yeast. For Saccharomyces cerevisiae, response to nitrogen deficiency is strain-dependent, some strains being able to complete fermentation despite nitrogen deficiency whereas others are not and result in sluggish or stuck fermentation. Thus, it is of high interest to study the mechanisms behind those different responses and exploit them to improve yeast strain for wine fermentation when nitrogen content is low. Previous study highlighted different genomic regions involved in nitrogen requirement through BSA (Bulk Segregant Analysis), and the contributions of three genes: MDS3, GCN1, and ARG81 have been shown (1). However, many other large genomic regions were also defined for which we could not find evident candidate genes. In addition, BSA did not provide any information on possible interactions between loci. In order to explore further the genetic bases of nitrogen requirement, we applied a QTL analysis to the fermentation rate in nitrogen deficient medium, on a population of 131 individually genotyped segregants obtained from the same cross as (1). The dense genetic map available for the segregant population (3727 markers) enabled us to perform single and multiple map QTL and thus define genomic regions which could be implied in low nitrogen requirement. In order to further validate the impact of candidate genes on the phenotype, alleles were “swapped” by CRISPR-Cas9 technique and phenotype was evaluated in comparison with haploid parent strains.Several regions with high LOD scores were identified, some above the significance threshold, and others below, among which the regions containing the genes identified by (1), probably in relation with the multigenic character of the trait. In the region with the highest LOD score, two candidate genes in relation with nitrogen metabolism (namely, Target of Rapamycin (TOR) pathwayand lifespan regulation) were identified. In addition, in order to reveal possible interaction between genes, strains carrying different combinations of GCN1 and MDS3 parental alleles (implied in TOR pathway) have been evaluated. These constructions confirm their role on the fermentation rate in low-nitrogen conditions and indicate dependence on the genetic background. These results confirm the complexity of mechanisms involved in nitrogen requirement during alcoholic fermentation and will permit to optimise wine yeast strain selection in response to winemaking industry demands

Cloned HTLV-1+CD4+, but not CD8+, T-cells display an oncogenic miRNome

HTLV-1 persistence in vivo relies on the persistent clonal expansion of its host cells. These are CD4+ and CD8+ T cells, yet ATL is regularly CD4+. Accordingly, untransformed HTLV-1+CD4+ but not CD8+ T cells cloned from carriers cumulate the features of preleukemic cells, including multinuclearity, chromatin bridges, increased cell cycling and inappropriate telomerase activity. MicroRNAs (miR) modify the maturation of a plethora of T-cells RNA and their deregulation would therefore constitute an appropriate explanation for the Tax-dependent or -independent pleiotropic changes in the phenotype of HTLV-1+CD4+ T cells. As the miRNome of naturally infected untransformed cells has not been investigated to date, we assessed the miR expression profiling of T cells cloned from carriers. Microarray results, confirmed by quantitative RTPCR, showed that, upon infection, CD4+ and CD8+ clones yielded aberrant expression of 15 distinct miRs including miR-34b and miR-494 that were respectively over- and underexpressed in both compartments. The more prominent effect of the infection consisted in the CD4+-restricted overexpression of the cancer-related miRs miR-21, -27b and -23b associated with the CD4+-restricted downregulation of the proapoptotic miR-15 and -16. Data were extended by the analysis of 40 additional CD4+ clones (20 infected). Crossing the miRNome against the whole transcriptome data identified putative miR-targeted genes. In silico, those targeted by miR-23b and -27b defined 2 hitherto unknown pathways involving the cell cycle and genetic disorders. Therefore HTLV-1 triggers a phenotype-specific miR signature consistent with the preleukemic HTLV-1+CD4+ phenoty

Lethal Nipah Virus Infection Induces Rapid Overexpression of CXCL10

Nipah virus (NiV) is a recently emerged zoonotic Paramyxovirus that causes regular outbreaks in East Asia with mortality rate exceeding 75%. Major cellular targets of NiV infection are endothelial cells and neurons. To better understand virus-host interaction, we analyzed the transcriptome profile of NiV infection in primary human umbilical vein endothelial cells. We further assessed some of the obtained results by in vitro and in vivo methods in a hamster model and in brain samples from NiV-infected patients. We found that NiV infection strongly induces genes involved in interferon response in endothelial cells. Among the top ten upregulated genes, we identified the chemokine CXCL10 (interferon-induced protein 10, IP-10), an important chemoattractant involved in the generation of inflammatory immune response and neurotoxicity. In NiV-infected hamsters, which develop pathology similar to what is seen in humans, expression of CXCL10 mRNA was induced in different organs with kinetics that followed NiV replication. Finally, we showed intense staining for CXCL10 in the brain of patients who succumbed to lethal NiV infection during the outbreak in Malaysia, confirming induction of this chemokine in fatal human infections. This study sheds new light on NiV pathogenesis, indicating the role of CXCL10 during the course of infection and suggests that this chemokine may serve as a potential new marker for lethal NiV encephalitis

Increasing importance of Bunyaviridae in public and veterinary health illustrated by hantaviruses, and the Schmallenberg and Rift Valley fever viruses

The virus family of Bunyaviridae is very important in terms of public health and veterinary medicine. With over 350 viruses identified to date, it includes viruses mainly transmitted by arthropods (arboviruses) or rodents (roboviruses), infecting mammals and plants for the genus Tospovirus. Humans can be infected by around 60 bunyaviruses sometime with very serious or even fatal consequences. The examples of Schmallenberg and Rift Valley fever viruses and hantavirus genus illustrate perfectly the many questions surrounding the Bunyaviridae family’s capacity to emerge, widely variable pathogenicity for different hosts, and capacity to persist in different vectors such as arthropods or rodents and more recently the soricomorph species (insectivores)La famille des Bunyaviridae est très importante en santé publique et vétérinaire. Avec plus de 350 virus identifiés à ce jour, elle regroupe des virus transmis principalement par des arthropodes (arbovirus) ou des rongeurs (robovirus), responsables d’infections chez les mammifères et chez les plantes pour le genre Tospovirus. L’homme peut être infecté par une soixantaine de ces Bunyaviridae, parfois avec des conséquences très graves, voire fatales. Les exemples du virus de Schmallenberg, du virus de la fièvre de la Vallée du Rift et du genre viral hantavirus illustrent parfaitement les nombreuses incertitudes concernant cette famille virale quant à leur potentiel d’émergence, leur pouvoir pathogène très varié pour des hôtes divers, et leur capacité à persister chez différents vecteurs appartenant aux arthropodes ou aux rongeurs et, plus récemment, aux soricomorphes (insectivores

Defective Retroviral Endogenous RNA Is Efficiently Transmitted by Infectious Particles Produced on an Avian Retroviral Vector Packaging Cell Line

AbstractThis report describes the contamination of "helper-free" stocks of defective retroviral vector with particles bearing retroviral endogenous RNA. An avian leukosis virus-based packaging cell line was developed from LMH cells that bear the ev1, ev3, and ev6 retroviral endogenous loci. The results show that an endogenous retroviral transcript (ev3) was packaged into virions produced by this packaging cell line and was efficiently transferred along with the vector to target cells. The titer of the ev contaminant particles was estimated at 50 - 100 CA-p27gag-expressing units/ml of supernatant

Repurposing of Drugs as Novel Influenza Inhibitors From Clinical Gene Expression Infection Signatures

Influenza virus infections remain a major and recurrent public health burden. The intrinsic ever-evolving nature of this virus, the suboptimal efficacy of current influenza inactivated vaccines, as well as the emergence of resistance against a limited antiviral arsenal, highlight the critical need for novel therapeutic approaches. In this context, the aim of this study was to develop and validate an innovative strategy for drug repurposing as host-targeted inhibitors of influenza viruses and the rapid evaluation of the most promising candidates in Phase II clinical trials. We exploited in vivo global transcriptomic signatures of infection directly obtained from a patient cohort to determine a shortlist of already marketed drugs with newly identified, host-targeted inhibitory properties against influenza virus. The antiviral potential of selected repurposing candidates was further evaluated in vitro, in vivo, and ex vivo. Our strategy allowed the selection of a shortlist of 35 high potential candidates out of a rationalized computational screening of 1,309 FDA-approved bioactive molecules, 31 of which were validated for their significant in vitro antiviral activity. Our in vivo and ex vivo results highlight diltiazem, a calcium channel blocker currently used in the treatment of hypertension, as a promising option for the treatment of influenza infections. Additionally, transcriptomic signature analysis further revealed the so far undescribed capacity of diltiazem to modulate the expression of specific genes related to the host antiviral response and cholesterol metabolism. Finally, combination treatment with diltiazem and virus-targeted oseltamivir neuraminidase inhibitor further increased antiviral efficacy, prompting rapid authorization for the initiation of a Phase II clinical trial. This original, host-targeted, drug repurposing strategy constitutes an effective and highly reactive process for the rapid identification of novel anti-infectious drugs, with potential major implications for the management of antimicrobial resistance and the rapid response to future epidemic or pandemic (re)emerging diseases for which we are still disarmed

Puces à ADN

National audienc

Organisation dynamique d'équipes d'engins autonomes par écoute flottante

Dans le domaine des systèmes multiagents (SMA), la communication est très souvent considérée selon une approche dyadique et abstraite assez rigide. Cette thèse fait l'hypothèse qu en s inspirant de la communication humaine, il est pro table d utiliser le phénomène de l'écoute ottante dans des systèmes multiagents a n de donner souplesse et robustesse à leur structure. Pour aller dans ce sens, nous proposons le modèle en étoile. Il permet aux membres d un SMA d utiliser l écoute ottante pour se structurer en groupes centrés sur des leaders a n de s adapter aux conditions de communication limitées et dynamiques dont ils disposent. Ce modèle fournit un cadre dans lequel les agents peuvent évoluer et assure que si leurs décisions respectent certaines contraintes (notamment de cohérence) ils pourront tirer parti de tous les messages qu ils pourront recevoir (même s ils ne leur sont pas destinés) a n de se forger les croyances les plus cohérentes possibles sur l'organisation de l équipe et ainsi faciliter son activité. D une part, nous développons plusieurs éléments utiles pour exploiter ce modèle en étoile (langage à la sémantique dé nie formellement, mécanisme de mise à jour et algorithme associé). D autre part, deux séries d expérimentations (OTTO et LOTTO) nous permettent d'étudier le comportement du modèle face aux variations de divers paramètres.TOULOUSE-ISAE (315552318) / SudocSudocFranceF

Lire les auteurs traduits

Comment aborder une œuvre littéraire traduite, diversifier les approches, apprécier le souci du traducteur de rendre la littérarité du texte ? Comment appréhender la littérarité des œuvres traduites ? Un constat s’impose en effet : les nouveaux programmes de français au collège et au lycée accordent une place croissante à la littérature étrangère. Les piliers 1 et 4, sans oublier le pilier 5 du socle commun, soulignent la nécessité de construire une réflexion sur des œuvres issues d’autres cu..