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All cells possess signaling pathways designed to trigger antiviral responses against invading viruses. Importantly, infected cells also deploy stress response to cope with viral infection, including autophagy. Autophagy is a catabolic pathway by which cells break down damaged organelles and protein aggregates via sequestration in vesicles and degradation by lysosomes. Autophagy regulates cellular homeostasis and interconnects with various cellular pathways. While autophagy can contribute to the removal of viral protein aggregates from the cells, the same process can have a positive impact on viral replication via indirect regulations. For example, we demonstrated that HCV uses autophagy proteins for the translation of incoming viral genomes in newly infected cells. Interestingly, DENV also usurps autophagy pathway for its own benefit, by providing energy required for replication by ingestion of the lipid droplets. Our recent work suggests that, autophagy also regulates DENV replication in cells issued from its mosquito vector i.e., Aedes Aegypti. Intriguingly, as opposed to the proviral function of autophagy in human cells, autophagy restricts DENV propagation in the mosquito host.

Importantly, autophagy is emerging as a key regulator of viral propagation by regulating positively or negatively the production of antiviral molecule. Such response is triggered by recognition of viral nucleic acids and leads to the production of type I interferon (IFNs), inflammatory cytokines and IFN-stimulated genes (ISGs). This first line of host response suppresses viral spread and jump-starts the adaptive immune response. Not surprisingly, virtually all viruses have evolved mechanisms to inhibit host-sensing pathways within cells that they invade. For example, dengue virus (DENV) and hepatitis C virus (HCV) encodes viral proteases, which inactivate key adaptors of signaling induced by the cytosolic sensors (RIG-I) and the endolysosome-localized sensors, i.e., the Toll-like receptors (TLR). Nonetheless, these viruses strongly induce the expression of IFN and ISGs in infected patients, suggesting the existence of alternative pathogen-sensing mechanisms.

OBJECTIVES: We aim at better our understanding of the activation of innate immunity by virally-infected cells.

MAIN RESULTS: In the context of DENV infection, we uncovered an alternative sensing pathway mediated by the recognition of infected cells by the plasmacytoid dendritic cells (pDCs), which involves physical cell-cell contact between the pDCs and the infected cells. Such cell-cell contact is also required for the detection of evolutionarily divergent RNA viruses and is now increasingly recognized as a hallmark of the pDC-mediated antiviral state. Importantly, we recently showed that actin network concentrates at the cell-cell contact and constitutes a structural platform for the transmission of the activating signal from infected cells to the pDCs. Furthermore, we demonstrated that immunostimulatory viral RNA can be transferred by non-canonical carriers (i.e., independently of infectious virions) from infected cells to pDCs. In particular, in the context of HCV and DENV, we reported that infected cells produce non-infectious and/or non-canonical vesicle that efficiently transfer immunostimulatory RNAs to pDCs (HCV RNA-containing exosomes and DEN immature particles respectively). This leads to a potent antiviral response by pDCs, characterized by IFN production, and that are not subject to viral inhibition, because pDCs are non-permissive to HCV. Similarly, pDCs are non-permissive to most viral infections, hence emphasizing their essential role as IFN producers for the antiviral response of the host.

CONCLUSION: our work underscored that cell-cell contact is a newly ascribed feature of pDC biology that is required for many different modalities of pDC activation, therefore we anticipate that our results will serve as a conceptual framework for similar analysis for other viruses.

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