Nathalie Grandvaux

Contact Information

Centre de Recherche du CHUM (CRCHUM)
900, rue Saint-Denis
Tour Viger, 10e étage, room R10.470
Montréal (Québec)
H2X 0A9

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P 514 890-8000, ext. 35292
nathalie.grandvaux@umontreal.ca
WWW

Themes

• Cell signaling
• Control of gene expression
• Cancer

Signaling pathways involved in the cell autonomous response to invading pathogens.

Host cells express multiple Pathogen Recognition Receptors that allow them to sense invading pathogens (virus, bacteria, parasites). These PRRs recognize Pathogen Associated Molecular Patterns (PAMPs) to trigger the expression of hundreds of genes encoding proteins with activities aimed at defending the infected cell and alert the immune system of the invasion. Following virus infection, the autonomous antiviral response relies on multiple signaling pathways (IRF, NF-kB, AP-1) that are regulated in a strictly coordinated fashion to ultimately trigger the expression of genes encoding antiviral and proinflammatory cytokines (type I and III Interferons, TNF, etc…) and chemokines (CCL5, G-CSF etc…). Cytokines act in an autocrine/paracrine manner. Interferons establish a robust antiviral state through the activation of the JAK/STAT signaling cascade to induce hundreds of interferon-stimulated genes (ISGs), which restrict virus replication and spreading. Most viruses have evolved mechanisms to counteract the antiviral response at multiple levels.

To reach the ideal duration for efficient fighting of the infection without generation of side effects, the antiviral signaling pathways are subjected to stringent regulation by both positive and negative regulators. The inability of the host to sustain an antiviral response leads to failure in eradicating the infection. Conversely, uncontrolled duration (due to polymorphisms generating gain-of-function of signaling molecules; activation by endogenous ligands) of antiviral response is associated with the development of various autoimmune diseases (lupus, Aicardi-Goutière syndrome…). Some of these pathways are also deregulated in a number of cancers, such as breast cancer.

Our laboratory studies several aspects of the autonomous antiviral response in order to understand the molecular mechanisms that fine-tuned the intensity and duration of the response.

• Redox regulation of the antiviral signaling pathways. We recently identified two reactive oxygen species producing enzymes, NOX2 and DUOX2, which control at different levels the expression of antiviral and proinflammatory cytokines and chemokines. Our current research is aimed at studying the redox post-translational modifications of the signaling proteins involved in this process.
• Detection of RNA viruses by RIG-I and MDA5 PRRs. We are studying the respective role of RIG-I and MDA5 during infection by RNA viruses.
• Viral evasion mechanisms. We study the mechanisms evolved by the Respiratory Syncytial Virus (RSV) to counteract the Interferon-mediated antiviral response.
• Synergism between Interferon b and TNF. We recently identified a new signaling cascade that acts downstream of the costimulation with IFNb and TNF. We are characterizing this novel pathway and the induced antiviral and immunoregulatory transcriptional program.