Vesicular trafficking, Innate response and Viruses

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Research themes

Virtually all types of cells can sense invading viruses. This detection triggers signaling events leading to the induction of antiviral responses. This first line of defense is initiated by the recognition of viral elements (called pathogen-associated molecular patterns; PAMPs) by cellular receptors, including the toll-like receptors (TLRs). This sensing leads to the production of antiviral molecules including type I and III interferons (IFNs), a broad range of interferon-stimulated genes (ISGs), along with inflammatory cytokines. These host responses suppress viral spread and jump-starts the adaptive immune response.

Nonetheless, virtually all viruses have evolved mechanisms to inhibit host-sensing pathways within cells they invade. Despite of this, the expression of ISG is readily detected in humans upon infection with many viruses. These paradoxical observations suggest the existence of alternative sensing pathways.

 

Main questions:
Our study focuses on the IFN signaling pathways/responses and aims at understanding:

  • How do viruses escape/circumvent the host antiviral response within infected cells?
  • Alternative pathways: how do cell types specialized for IFN production (g., plasmacytoid dendritic cells; pDCs) recognize the infected state of the neighboring cells?

 

Our research program gathers aspects of virology, immuno-virology and cell biology areas.

Our studies range from in vitro study of the molecular basis of the activation of IFN responses and viral counteraction to in vivo study allowing to grasp integrated view of the cross-talks between antiviral pathways.

Our viral models are viruses highly pathogenic to humans. Capitalizing on our expertise, we focus primarily on the Flaviviruses (Dengue, Zika virus, West Nile) and hepatitis C virus. The main findings are extended to other viruses of different families (e.g., chikungunya virus, and Human T-lymphotropic virus) to define the broad vs virus-specific regulations, related to the distinct PAMP-carriers involved and/or specific viral determinant(s).

Our experimental approaches:
– Cutting-edge technologies for imaging, including live-imaging by BSL3 based-spinning-disk confocal microscopy analysis, flow cytometry combined with imaging by Image stream X Technology and super-resolution, and on infected tissues/organs by multiplexed RNA-FISH and IF anlyzed by confocal microscopy.
– Basic methodologies to follow the viral growth and the IFN/ISG/cytokines responses (RT-qPCR, WB, ELISA, IF, etc…).
– Functional analysis of the regulation by host and viral factors using mutagenesis, lentiviral-transduction, CRISPR-Cas9 in cell culture, including primary cells.
– In vivo studies using transgenic mouse models.

Video: my thesis in 180 secondes by Sonia Assil
https://www.youtube.com/watch?v=ILxZajB9Hag

Press release by INSERM for Webster et al. 2018 eLIFE
https://www.inserm.fr/actualites-et-evenements/actualites/dengue-et-chikungunya-cellules-minoritaires-cle-controle-infection

Twitter: @DreuxMarlene

Recent achievements:

  • We showed that the contact site between plasmocytoid dendritic cells (pDC) and virally infected cells reorganizes into a specialized platform with the polarization of cellular machineries for the transfer of viral immunostimulatory-RNA to pDCs, which leads to an antiviral response. We named this newly discovered pivotal structure for type I IFN production: the interferogenic synapse (Figure 1).

  •  We uncovered that the sensing of immature non-infectious particles produced by cells infected by dengue virus induces an antiviral response by pDCs (Figure 2).
  • We revealed a previously unsuspected mechanism of innate immunity in which exosomal export of viral RNA from infected cells serves as a host strategy to induce an innate response by pDCs (Figure 2).

Sponsors:

• Agence Nationale de la Recherche (ANR-JCJC)
• European Community (H2020 – Horizon)
• Fondation pour la Recherche Médicale (FRM)
• EMBO Long-Term fellowship program
• Labex Ecofect
• Ligue Nationale Contre le Cancer (LNCC)
• Agence Nationale pour la Recherche contre le SIDA et les Hépatites Virales (ANRS)
• FINOVI foundation
• CIRI transversal Projects

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