Mitochondrial dysfunction in the spinal cord is a hallmark of amyotrophic lateral sclerosis (ALS), but the neurometabolic alterations during early stages of the disease remain unknown. Here, we ...investigated the bioenergetic and proteomic changes in ALS mouse motor neurons and patients' skin fibroblasts. We first observed that SODG93A mice presymptomatic motor neurons display alterations in the coupling efficiency of oxidative phosphorylation, along with fragmentation of the mitochondrial network. The proteome of presymptomatic ALS mice motor neurons also revealed a peculiar metabolic signature with upregulation of most energy-transducing enzymes, including the fatty acid oxidation (FAO) and the ketogenic components HADHA and ACAT2, respectively. Accordingly, FAO inhibition altered cell viability specifically in ALS mice motor neurons, while uncoupling protein 2 (UCP2) inhibition recovered cellular ATP levels and mitochondrial network morphology. These findings suggest a novel hypothesis of ALS bioenergetics linking FAO and UCP2. Lastly, we provide a unique set of data comparing the molecular alterations found in human ALS patients' skin fibroblasts and SODG93A mouse motor neurons, revealing conserved changes in protein translation, folding and assembly, tRNA aminoacylation and cell adhesion processes.
Adenovirus based vectors are very attractive candidates for vaccination purposes as they induce in mammalian hosts potent humoral, mucosal and cellular immune responses to antigens encoded by the ...inserted genes. We have generated E1-deleted and replication-competent recombinant canine type-2 adenoviruses expressing the rabies virus glycoprotein (G). The effectiveness of both vectors to express a native G protein has been characterized in vitro in permissive cell lines. We compared the humoral and cellular immune responses induced in mice by intramuscular injection of the recombinant canine adenovirus vectors with those induced by a human (Ad5) E1-deleted virus expressing the same rabies G protein. Humoral responses specific to the adenoviruses or the rabies glycoprotein antigens were studied. The influence of the mouse strain was observed using replication-competent canine adenovirus. A high level of rabies neutralizing antibody was observed upon i.m. inoculation, and 100% of mice survived lethal challenge. These results are very promising in the perspective of oral vaccine for dog rabies control.
Understanding the modalities of interaction of neurotropic viruses with their target cells represents a major challenge that may improve our knowledge of many human neurological disorders for which ...viral origin is suspected. Borna disease virus (BDV) represents an ideal model to analyze the molecular mechanisms of viral persistence in neurons and its consequences for neuronal homeostasis. It is now established that BDV ensures its long-term maintenance in infected cells through a stable interaction of viral components with the host cell chromatin, in particular, with core histones. This has led to our hypothesis that such an interaction may trigger epigenetic changes in the host cell. Here, we focused on histone acetylation, which plays key roles in epigenetic regulation of gene expression, notably for neurons. We performed a comparative analysis of histone acetylation patterns of neurons infected or not infected by BDV, which revealed that infection decreases histone acetylation on selected lysine residues. We showed that the BDV phosphoprotein (P) is responsible for these perturbations, even when it is expressed alone independently of the viral context, and that this action depends on its phosphorylation by protein kinase C. We also demonstrated that BDV P inhibits cellular histone acetyltransferase activities. Finally, by pharmacologically manipulating cellular acetylation levels, we observed that inhibiting cellular acetyl transferases reduces viral replication in cell culture. Our findings reveal that manipulation of cellular epigenetics by BDV could be a means to modulate viral replication and thus illustrate a fascinating example of virus-host cell interaction.
Persistent DNA viruses often subvert the mechanisms that regulate cellular chromatin dynamics, thereby benefitting from the resulting epigenetic changes to create a favorable milieu for their latent and persistent states. Here, we reasoned that Borna disease virus (BDV), the only RNA virus known to durably persist in the nucleus of infected cells, notably neurons, might employ a similar mechanism. In this study, we uncovered a novel modality of virus-cell interaction in which BDV phosphoprotein inhibits cellular histone acetylation by interfering with histone acetyltransferase activities. Manipulation of cellular histone acetylation is accompanied by a modulation of viral replication, revealing a perfect adaptation of this "ancient" virus to its host that may favor neuronal persistence and limit cellular damage.
The analysis of the biology of neurotropic viruses, notably of their interference with cellular signaling, provides a useful tool to get further insight into the role of specific pathways in the ...control of behavioral functions. Here, we exploited the natural property of a viral protein identified as a major effector of behavioral disorders during infection. We used the phosphoprotein (P) of Borna disease virus, which acts as a decoy substrate for protein kinase C (PKC) when expressed in neurons and disrupts synaptic plasticity. By a lentiviral-based strategy, we directed the singled-out expression of P in the dentate gyrus of the hippocampus and we examined its impact on mouse behavior. Mice expressing the P protein displayed increased anxiety and impaired long-term memory in contextual and spatial memory tasks. Interestingly, these effects were dependent on P protein phosphorylation by PKC, as expression of a mutant form of P devoid of its PKC phosphorylation sites had no effect on these behaviors. We also revealed features of behavioral impairment induced by P protein expression but that were independent of its phosphorylation by PKC. Altogether, our findings provide insight into the behavioral correlates of viral infection, as well as into the impact of virus-mediated alterations of the PKC pathway on behavioral functions.
Invasive pneumococcal disease is presently a leading cause of mortality due to bacterial infectious diseases in French children less than 2 years of age, and only the pneumococcal conjugate vaccines ...induce a protective immune response for those within this vulnerable age group.
The safety and immunogenicity of a heptavalent pneumococcal polysaccharide conjugate vaccine (PREVENAR was tested in French infants immunized with the 2, 3 and 4 month French schedule as part of an open, randomized, comparative clinical study, in association with a whole-cell pertussis-based pediatric combination vaccine.
In the PREVENAR plus DTP-IPV/Hib association group, 90.6-100% of children achieved a post-dose three threshold IgG concentration of >0.15 microg/ml against each of the seven pneumococcal serotypes. Regarding immunogenicity, no interference with the antibody response to the various antigenic components of the DTP-IPV/Hib vaccine was observed. Local reactions were significantly less frequent at the PREVENAR injection site than at the DTP-IPV/Hib injection site; there was no increase in systemic adverse events in the vaccine association group compared to the DTP-IPV/Hib alone group, further exception of fever >38 degrees C which was more frequently reported in the PREVENAR + PENTACOQ group following the second dose of vaccines (56% vs. 35%); no serious adverse event could be considered to be related to the PREVENAR immunization in this study.
The heptavalent pneumococcal conjugate vaccine is immunogenic when administered at 2, 3 and 4 months. PREVENAR can be administered simultaneously with the DTP-IPV/Hib combination vaccine.
La réduction de la consommation énergétique est actuellement un point important lors de la conception d'un véhicule qu'il soit à moteur thermique (réduction de la consommation d'essence), électrique ...(augmenter la distance parcourue sans recharger les batteries) ou hybride. C'est dans cette optique que nous chercherons à réduire les forces de traînée aérodynamique qui s'opposent au mouvement de tout véhicule et qui sont donc à l'origine d'une consommation supplémentaire d'énergie. Grâce au développement des outils de calcul, il est aujourd’hui possible de tester sans fabriquer. En effet, grâce à l’essor de la CFD (Computational Fluid Dynamics) il est désormais possible de reproduire tous nos bancs de tests et nos optimisations de façon numérique. Cependant, ces outils ne sont pas encore parfaits et ils nécessitent des ajustements obtenus grâce à la mise en place de tests expérimentaux. C’est ainsi que les caractérisations et optimisations effectuées sur le tricycle hybride étudié et ses sous-systèmes seront réalisées. L'étude portera principalement sur l'aérodynamique externe du tricycle ainsi que sur ses échangeurs thermiques.
Les affections invasives à pneumocoque représentent actuellement une cause majeure de mortalité par maladie infectieuse bactérienne chez les enfants de moins de deux ans en France, et seul le vaccin ...pneumococcique conjugué permet d’induire une réponse immunitaire protectrice dans cette tranche d’âge vulnérable.
Matériel et méthodes. –
La tolérance et l’immunogénicité d’un vaccin pneumococcique conjugué heptavalent (Prevenar
®) ont été évaluées en France chez 157 nourrissons vaccinés selon le schéma vaccinal français administré en trois injections à deux, trois et quatre mois dans le cadre d’une étude clinique ouverte, randomisée, comparative, en association avec une combinaison vaccinale comprenant la valence coquelucheuse à germe entier.
Résultats. –
Dans le groupe d’enfants ayant reçu les vaccins Prevenar
® et DTCoq-Polio/Hib, 90,6 à 100 % des nourrissons ont présenté, après la troisième dose, une concentration d’IgG ≥ 0,15 μg/mL vis-à-vis de chacun des sept sérotypes pneumococciques. En ce qui concerne l’immunogénicité, aucune interférence avec la réponse anticorps aux différents composants du vaccin DTCoq-Polio/Hib n’a été observée. Les réactions locales étaient significativement moins fréquentes au site d’injection de Prevenar
® qu’à celui du vaccin DTCoq-Polio/Hib ; il n’a pas été observé d’augmentation des évènements indésirables systémiques dans le groupe d’enfants ayant reçu l’association des deux vaccins par rapport au groupe d’enfants ayant reçu le vaccin DTCoq-Polio/Hib seul, à l’exception de la fièvre supérieure à 38 °C qui était plus fréquente dans le groupe Prevenar + Pentacoq après la deuxième dose de vaccins (56 vs 35 %). Aucun évènement indésirable grave n’a été associé à la vaccination par Prevenar
® dans cette étude.
Conclusion. –
Le vaccin pneumococcique conjugué heptavalent est immunogène lorsqu’il est administré à deux, trois et quatre mois. Prevenar
® peut être administré simultanément avec la combinaison vaccinale DTCoq Polio/Hib.
Invasive pneumococcal disease is presently a leading cause of mortality due to bacterial infectious diseases in French children less than 2 years of age, and only the pneumococcal conjugate vaccines induce a protective immune response for those within this vulnerable age group.
Material and methods. –
The safety and immunogenicity of a heptavalent pneumococcal polysaccharide conjugate vaccine (PREVENAR
®) was tested in French infants immunized with the 2, 3 and 4 month French schedule as part of an open, randomized, comparative clinical study, in association with a whole-cell pertussis-based pediatric combination vaccine.
Results. –
In the PREVENAR
® plus DTP-IPV/Hib association group, 90.6–100% of children achieved a post-dose three threshold IgG concentration of >0.15 μg/ml against each of the seven pneumococcal serotypes. Regarding immunogenicity, no interference with the antibody response to the various antigenic components of the DTP-IPV/Hib vaccine was observed. Local reactions were significantly less frequent at the PREVENAR
® injection site than at the DTP-IPV/Hib injection site; there was no increase in systemic adverse events in the vaccine association group compared to the DTP-IPV/Hib alone group, further exception of fever >38 °C which was more frequently reported in the PREVENAR + PENTACOQ group following the second dose of vaccines (56% vs. 35%); no serious adverse event could be considered to be related to the PREVENAR
® immunization in this study.
Conclusion. –
The heptavalent pneumococcal conjugate vaccine is immunogenic when administered at 2, 3 and 4 months. PREVENAR
® can be administered simultaneously with the DTP-IPV/Hib combination vaccine.
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