К вопросу о психолингвистической концепции перевода

Dengue virus (DENV) is the leading cause of mosquito-borne viral illness and death in humans. Like many viruses, DENV has evolved potent mechanisms that abolish the antiviral response within infected cells. Nevertheless, several in vivo studies have demonstrated a key role of the innate immune response in controlling DENV infection and disease progression. Here, we report that sensing of DENV infected cells by plasmacytoid dendritic cells (pDCs) triggers a robust TLR7-dependent production of IFNα, concomitant with additional antiviral responses, including inflammatory cytokine secretion and pDC maturation. We demonstrate that unlike the efficient cell-free transmission of viral infectivity, pDC activation depends on cell-to-cell contact, a feature observed for various cell types and primary cells infected by DENV, as well as West Nile virus, another member of the Flavivirus genus. We show that the sensing of DENV infected cells by pDCs requires viral envelope protein-dependent secretion and transmission of viral RNA. Consistently with the cell-to-cell sensing-dependent pDC activation, we found that DENV structural components are clustered at the interface between pDCs and infected cells. The actin cytoskeleton is pivotal for both this clustering at the contacts and pDC activation, suggesting that this structural network likely contributes to the transmission of viral components to the pDCs. Due to an evolutionarily conserved suboptimal cleavage of the precursor membrane protein (prM), DENV infected cells release uncleaved prM containing-immature particles, which are deficient for membrane fusion function. We demonstrate that cells releasing immature particles trigger pDC IFN response more potently than cells producing fusion-competent mature virus. Altogether, our results imply that immature particles, as a carrier to endolysosome-localized TLR7 sensor, may contribute to regulate the progression of dengue disease by eliciting a strong innate response

Mécanisme de transmission de signal viral immunostimulateur des cellules infectés aux cellules dendritiques plasmacytoïdes par contacts cellulaires

Les cellules dendritiques plasmacytoides (pDCs), spécialisées dans la réponse antivirale, produisent de fortes quantités d’interféron (IFN) lorsqu’elles sont en contact avec des cellules infectées par des virus. Pourtant, les pDCs sont réfractaires à l’infection. Ce mécanisme d’activation de la réponse antivirale par le contact physique avec les cellules infectées, nouvellement découvert, constituerait un aspect général des voies de défense de l’hôte contre les virus.En utilisant le virus de l’Hépatite C et de la Dengue comme modèle viral, nous avons observé une réorganisation moléculaire au niveau des contacts entre les pDCs et les cellules infectées. La polarisation d’éléments cellulaires, notamment de régulateurs du cytosquelette d’actine et de molécules de la machinerie d’endocytose en direction du contact favoriserait son établissement et/ou sa stabilisation ainsi qu’une transmission efficace d’éléments viraux, ensuite reconnus par les pDCs. Nous avons également démontré que les pDCs effectuent des contacts plus stables et présentent une polarisation plus importante d’éléments cellulaires aux contacts avec des cellules infectées qu’avec des cellules non infectées. Ces interactions présentent des similarités avec les synapses, contacts cellulaires organisés impliqués dans la communication cellulaire. Notamment, les synapses immunologiques jouent un rôle important dans l’activation de la réponse immunitaire adaptative. Nous proposons donc de nommer ces contacts activateurs de pDCs des « synapses immunologiques innées ». Ce mécanisme représenterait un processus de reconnaissance des infections par les pDCs généralisable à différents types de virus, par « scan » du statut infectieux des cellules par contact. Nos résultats suggèrent également que des éléments viraux s’accumulent au niveau de ces contacts. Ces éléments diffèrent en fonction du type d’infection. Notamment, nous avons mis en évidence dans un contexte d’infection par le virus de la Dengue que des structures virales non canoniques et non infectieuses, différentes des particules virales infectieuses dites « classiques », jouent un rôle important dans l’activation de la réponse antivirale. Notre travail apporte un nouvel angle d’analyse de l’activation des pDCs et des stratégies de détection des infections virales par l’hôte.Plasmacytoid dendritic cells (pDCs), specialized in the antiviral response, are important producers of interferons (IFN) after cell-cell contacts with virally infected cells. Nonetheless, they are poorly permissive to the majority of viral infections. This newly uncovered mechanism of the activation of an antiviral response by physical cell-cell contacts with infected cells could constitute a general aspect of the host defense against viral infections.Using Hepatitis C virus and Dengue virus as models, we observed a molecular reorganization of the contacts between pDCs and infected cells. The polarization toward contacts of cellular elements, such as regulators of the actin cytoskeleton and components of the endocytic machinery could favor their establishment and/or their stabilization, as well as the efficient transmission of viral elements that are recognized by pDCs. We also demonstrated that pDCs contacts with infected cells are more stable and present a higher polarization of cellular components than contacts with uninfected cells. These interactions present similarities with synapses, a type of organized contact involved in cell-to-cell communication. Notably, immunological synapses are known to play an important role in the activation of the adaptive immune response. We thus propose to call these pDC-activating contacts « innate immunological synapses ». This mechanism could represent a general process of recognition of viral infections by pDCs, by « scanning » the infectious status of the cells by cell-cell contacts. Our results also suggest that viral elements cluster at the level of contacts. These elements differ depending on the type of viral infection. Notably, we observed in the context of Dengue virus infection that non-infectious non-canonical viral structures, that differ from the « classical » viral infectious particles, play an important role in the activation of the antiviral response. Our work brings a new light in the mechanisms of pDC activation and in the host defense strategies against viral infection

Regulation of the Host Antiviral State by Intercellular Communications

Viruses usually induce a profound remodeling of host cells, including the usurpation of host machinery to support their replication and production of virions to invade new cells. Nonetheless, recognition of viruses by the host often triggers innate immune signaling, preventing viral spread and modulating the function of immune cells. It conventionally occurs through production of antiviral factors and cytokines by infected cells. Virtually all viruses have evolved mechanisms to blunt such responses. Importantly, it is becoming increasingly recognized that infected cells also transmit signals to regulate innate immunity in uninfected neighboring cells. These alternative pathways are notably mediated by vesicular secretion of various virus- and host-derived products (miRNAs, RNAs, and proteins) and non-infectious viral particles. In this review, we focus on these newly-described modes of cell-to-cell communications and their impact on neighboring cell functions. The reception of these signals can have anti- and pro-viral impacts, as well as more complex effects in the host such as oncogenesis and inflammation. Therefore, these “broadcasting” functions, which might be tuned by an arms race involving selective evolution driven by either the host or the virus, constitute novel and original regulations of viral infection, either highly localized or systemic

La susceptibilité à l’infection par le virus de l’hépatite C et la réponse antivirale sont modulées par le polymorphisme associé à l’interféron lambda

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[Modulation of permissiveness and antiviral response against hepatitis C virus by interferon lambda-associated polymorphism].

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Regulation of the Host Antiviral State by Intercellular Communications

International audienceViruses usually induce a profound remodeling of host cells, including the usurpation of host machinery to support their replication and production of virions to invade new cells. Nonetheless, recognition of viruses by the host often triggers innate immune signaling, preventing viral spread and modulating the function of immune cells. It conventionally occurs through production of antiviral factors and cytokines by infected cells. Virtually all viruses have evolved mechanisms to blunt such responses. Importantly, it is becoming increasingly recognized that infected cells also transmit signals to regulate innate immunity in uninfected neighboring cells. These alternative pathways are notably mediated by vesicular secretion of various virus- and host-derived products (miRNAs, RNAs, and proteins) and non-infectious viral particles. In this review, we focus on these newly-described modes of cell-to-cell communications and their impact on neighboring cell functions. The reception of these signals can have anti- and pro-viral impacts, as well as more complex effects in the host such as oncogenesis and inflammation. Therefore, these "broadcasting" functions, which might be tuned by an arms race involving selective evolution driven by either the host or the virus, constitute novel and original regulations of viral infection, either highly localized or systemic

Plasmacytoid Dendritic Cells and Infected Cells Form an Interferogenic Synapse Required for Antiviral Responses

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Sensing of cell-associated HTLV by plasmacytoid dendritic cells is regulated by dense β-galactoside glycosylation.

Human T Lymphotropic virus (HTLV) infection can persist in individuals resulting, at least in part, from viral escape of the innate immunity, including inhibition of type I interferon response in infected T-cells. Plasmacytoid dendritic cells (pDCs) are known to bypass viral escape by their robust type I interferon production. Here, we demonstrated that pDCs produce type I interferons upon physical cell contact with HTLV-infected cells, yet pDC activation inversely correlates with the ability of the HTLV-producing cells to transmit infection. We show that pDCs sense surface associated-HTLV present with glycan-rich structure referred to as biofilm-like structure, which thus represents a newly described viral structure triggering the antiviral response by pDCs. Consistently, heparan sulfate proteoglycans and especially the cell surface pattern of terminal β-galactoside glycosylation, modulate the transmission of the immunostimulatory RNA to pDCs. Altogether, our results uncover a function of virus-containing cell surface-associated glycosylated structures in the activation of innate immunity

A multi-colour/multi-affinity marker set to visualize phosphoinositide dynamics in Arabidopsis

International audiencePhosphatidylinositolphosphates (PIPs) are phospholipids that contain a phosphorylated inositol head group. PIPs represent a minor fraction of total phospholipids, but are involved in many regulatory processes, such as cell signalling and intracellular trafficking. Membrane compartments are enriched or depleted in specific PIPs, providing a unique composition for these compartments and contributing to their identity. The precise subcellular localization and dynamics of most PIP species is not fully understood in plants. Here, we designed genetically encoded biosensors with distinct relative affinities and expressed them stably in Arabidopsis thaliana. Analysis of this multi-affinity PIPline' marker set revealed previously unrecognized localization of various PIPs in root epidermis. Notably, we found that PI(4,5)P2 is able to localize PIP2-interacting protein domains to the plasma membrane in non-stressed root epidermal cells. Our analysis further revealed that there is a gradient of PI4P, with the highest concentration at the plasma membrane, intermediate concentration in post-Golgi/endosomal compartments, and the lowest concentration in the Golgi. Finally, we also found a similar gradient of PI3P from high in late endosomes to low in the tonoplast. Our library extends the range of available PIP biosensors, and will allow rapid progress in our understanding of PIP dynamics in plants