The cytoplasmic tail of the rabies virus G protein is an essential domain controlling death/survival in human neuronal cells

Poster presentation

Toll-Like Receptor 3 (TLR3) Plays a Major Role in the Formation of Rabies Virus Negri Bodies

Human neurons express the innate immune response receptor, Toll-like receptor 3 (TLR3). TLR3 levels are increased in pathological conditions such as brain virus infection. Here, we further investigated the production, cellular localisation, and function of neuronal TLR3 during neuronotropic rabies virus (RABV) infection in human neuronal cells. Following RABV infection, TLR3 is not only present in endosomes, as observed in the absence of infection, but also in detergent-resistant perinuclear inclusion bodies. As well as TLR3, these inclusion bodies contain the viral genome and viral proteins (N and P, but not G). The size and composition of inclusion bodies and the absence of a surrounding membrane, as shown by electron microscopy, suggest they correspond to the previously described Negri Bodies (NBs). NBs are not formed in the absence of TLR3, and TLR3−/− mice—in which brain tissue was less severely infected—had a better survival rate than WT mice. These observations demonstrate that TLR3 is a major molecule involved in the spatial arrangement of RABV–induced NBs and viral replication. This study shows how viruses can exploit cellular proteins and compartmentalisation for their own benefit

Sciences de l'éducation et formation des enseignants, à quand un mariage heureux ?

International audienc

Perte de stabilité induite par des solutions canards au travers d'une bifurcation homocline

his article deals with slow-fast systems and is, in some sense, a first approach to a general problem, namely to investigate the possibility of bifurcations which display a dramatic change in the phase portrait in a very small (on the order of 10−7 in the example presented here) change of a parameter. We provide evidence of existence of such a very rapid loss of stability on a specific example of a singular perturbation setting. This example is strongly inspired of the explosion of canard cycles first discovered and studied by E Benoît, J.-L. Callot, F. Diener and M. Diener. After some presentation of the integrable case to be perturbed, we present the numerical evidences for this rapid loss of stability using numerical continuation. We discuss then the possibility to estimate accurately the value of the parameter for which this bifurcation occurs.Cet article traite de systèmes lents-rapides et constitue en quelque sorte une première approche pour étudier un problème général, celui d'explorer les possibilités de bifurcations qui présentent un changement brutal au niveau du portrait de phase pour un très petit changement de paramètre (de l'ordre de 10−7 dans l'exemple présenté ici). Nous présentons des preuves de l'existence d'une perte brutale de stabilité de ce type sur un exemple spécifique dans un cadre de perturbations singulières. Cet exemple est fortement inspiré de l'explosion de cycles canards initialement découverte par E. Benoît, J.-L. Callot, F. Diener et M. Diener. Après une présentation du cas intégrable que l'on souhaite perturber, nous apportons une preuve numériques de cette perte brutale de stabilité obtenue en utilisant la continuation numérique. Nous discutons ensuite la possibilité d'estimer précisément la valeur de paramètre pour laquelle cette bifurcation se produit

Perte de stabilité induite par des solutions canards au travers d'une bifurcation homocline

International audiencehis article deals with slow-fast systems and is, in some sense, a first approach to a general problem, namely to investigate the possibility of bifurcations which display a dramatic change in the phase portrait in a very small (on the order of 10−7 in the example presented here) change of a parameter. We provide evidence of existence of such a very rapid loss of stability on a specific example of a singular perturbation setting. This example is strongly inspired of the explosion of canard cycles first discovered and studied by E Benoît, J.-L. Callot, F. Diener and M. Diener. After some presentation of the integrable case to be perturbed, we present the numerical evidences for this rapid loss of stability using numerical continuation. We discuss then the possibility to estimate accurately the value of the parameter for which this bifurcation occurs.Cet article traite de systèmes lents-rapides et constitue en quelque sorte une première approche pour étudier un problème général, celui d'explorer les possibilités de bifurcations qui présentent un changement brutal au niveau du portrait de phase pour un très petit changement de paramètre (de l'ordre de 10−7 dans l'exemple présenté ici). Nous présentons des preuves de l'existence d'une perte brutale de stabilité de ce type sur un exemple spécifique dans un cadre de perturbations singulières. Cet exemple est fortement inspiré de l'explosion de cycles canards initialement découverte par E. Benoît, J.-L. Callot, F. Diener et M. Diener. Après une présentation du cas intégrable que l'on souhaite perturber, nous apportons une preuve numériques de cette perte brutale de stabilité obtenue en utilisant la continuation numérique. Nous discutons ensuite la possibilité d'estimer précisément la valeur de paramètre pour laquelle cette bifurcation se produit

Virus Infection Switches TLR-3-Positive Human Neurons To Become Strong Producers of Beta Interferon

To study the capacity of human neurons to mount innate immunity responses to viral infections, we infected cells of a human postmitotic neuron-derivative cell line, NT2-N, with rabies virus (RABV) and herpes simplex type 1 (HSV-1). Changes in neuronal gene expression were analyzed by use of Affymetrix microarrays. Applying a twofold cutoff, RABV increased the transcription of 228 genes, and HSV-1 increased the transcription of 263 genes. The most striking difference between the two infections concerns genes involved in immunity. These genes represent 24% of the RABV-upregulated genes and only 4.9% of the HSV-1-upregulated genes. Following RABV infection, the most upregulated genes belong to the immunity cluster and included almost exclusively genes for beta interferon (IFN-β) primary and secondary responses as well as genes for chemokines (CCL-5, CXCL-10) and inflammatory cytokines (interleukin 6 [IL-6], tumor necrosis factor alpha, interleukin 1 alpha). In contrast, HSV-1 infection did not increase IFN-β gene transcripts and triggered the production of only IL-6 and interferon regulatory factor 1 mRNAs. The microarray results were confirmed by real-time PCR, immunocytochemistry, and enzyme-linked immunosorbent assay. Human neurons were found to express Toll-like receptor 3. They produced IFN-β after treatment with poly(I:C) but not with lipopolysaccharide. Thus, human neurons can mount an innate immunity response to double-stranded RNA. These observations firmly establish that human neurons, in absence of glia, have the intrinsic machinery to sense virus infection

Detrimental contribution of the immuno-inhibitor b7-h1 to rabies virus encephalitis.

International audienceRabies virus is the etiological agent of an acute encephalitis, which in absence of post exposure treatment is fatal in almost all cases. Virus lethality rests on its ability to evade the immune response. In this study, we analyzed the role of the immuno-inhibitory molecule B7-H1 in this virus strategy. We showed that in the brain and spinal cord of mice, rabies virus infection resulted in significant up-regulation of B7-H1 expression, which is specifically expressed in infected neurons. Correlatively, clinical rabies in B7-H1(-/-) mice is markedly less severe than in wild-type mice. B7-H1(-/-) mice display resistance to rabies. Virus invasion is reduced and the level of migratory CD8 T cells increases into the nervous system, while CD4/CD8 ratio remains unchanged in the periphery. In vivo, neuronal B7-H1 expression is critically depending on TLR3 signaling and IFN-beta, because TLR3(-/-) mice--in which IFN-beta production is reduced--showed only a limited increase of B7-H1 transcripts after infection. These data provide evidence that neurons can express the B7-H1 molecule after viral stress or exposure to a particular cytokine environment. They show that the B7-H1/PD-1 pathway can be exploited locally and in an organ specific manner--here the nervous system--by a neurotropic virus to promote successful host invasion