Overview of our projects

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, a broad range of interferon-stimulated genes (ISGs), along with inflammatory cytokines. These host responses suppress viral spread and jump-start the adaptive immunity.

While virtually all viruses have evolved mechanisms to inhibit host-sensing pathways within cells they invade, the expression of type I/III interferons and ISG is readily detected in humans upon infection with many viruses. These paradoxical observations suggest the existence of alternative sensing pathways.

MAINS QUESTIONS:

Our studies focus on the interferon signaling pathways/responses, and aims at understanding:

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

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

Our studies range from in vitro study of the molecular basis of the activation of interferon responses and viral counteraction to in vivo study allowing to grasp an 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 (such as Dengue, Zika virus, West Nile virus) and hepatitis C virus. The main findings are extended to other viruses of distinct families (e.g., chikungunya virus, and Human T-lymphotropic virus) to define the broad versus virus-specific regulations, related to the distinct PAMP-carriers involved and/or specific viral determinant(s). More recently we have launched a new research program on SARS-Cov2, focusing on the understanding of the innate immune responses from the molecular level to a clinical study in COVID-19 patients with different disease severities. 

OUR EXPERIMENTAL APPROACHES:

– Subcellular imaging by cutting-edge technologies including live-imaging by BSL3 based-spinning-disk confocal microscopy analysis, flow cytometry combined with imaging by ImageStream X Technology and super-resolution.

– Imaging on infected tissues/organs by multiplexed RNA-FISH and imunodetection analyzed using multicolor confocal microscopy.

– Basic methodologies to track the viral growth and the levels of ISG, interferon, and various other cytokines (e.g., RT-qPCR, flow cytometry, WB, ELISA, etc…).

– Functional analysis of the regulation by host and viral factors using recombinant virus, mutagenesis, lentiviral-transduction and CRISPR-Cas9 in cell culture, including primary cells.

–  In vivo studies using transgenic mouse models for invalidation of the innate responses.