Université de Montréal
Dr. Nathalie Grandvaux was initially trained as an engineer in Biochemistry. In 1999, she obtained a PhD in Molecular and Cellular Biology from the University of Grenoble. In 2000, she joined the Lady Davis Institute for Medical Research at the Jewish General Hospital in Montreal as a post-doctoral fellow. In 2005, Dr. Grandvaux joined the Department of Biochemistry and Molecular Medicine at Université de Montréal as an assistant-professor and the Research Center of the Université de Montréal affiliated hospital (CHUM) as a principal investigator. She was promoted Associate-Professor in 2011.
- Associate Professor in Dept. of Biochemistry, Université de Montréal
- Canada Research Chair in signaling in virus infection and oncogenesis, 2005-2015
Signaling pathways involved in the cell autonomous response to invading pathogens.
Current Research in Dr. Grandvaux’s laboratory is focused on signaling mechanisms that regulates the cytokine responses that are involved in host-pathogen interaction, cancer and autoimmune diseases. 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.
Dr. Grandvaux’s research group studies several aspects of the this response in order to understand the molecular mechanisms that fine-tuned its intensity and duration:
- Redox regulation of the pathways controlling Interferon and proinflammatory cytokines expression. Dr. Grandvaux’ group 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. The 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. Current studies are aimed at characterizing the respective role of RIG-I and MDA5 during infection by RNA viruses.
- Viral evasion mechanisms evolved by the Respiratory Syncytial Virus (RSV) to counteract the Interferon-mediated antiviral response.
- Synergism between Interferon b and TNFa. After the identification of a new signaling cascade that acts downstream of the costimulation with IFNb and TNFa, the current research is focused on the characterization of this novel signaling pathway and the induced antiviral and immunoregulatory transcriptional program.
- E. Mukawera, S. Chartier, V. Williams, P. Pagano, R. Lapointe and N. Grandvaux (2015). Redox-modulating agents target NOX2-dependent IKK oncogenic kinase expression and proliferation in human breast cancer cell lines. Redox Biol. 6: 9-18
- N. Grandvaux, X. Guan, F. Yoboua, N. Zucchini, K. Fink, P. Doyon, L. Martin, M. Servant and S. Chartier (2014). Sustained activation of IRF-3 during infectino by paramyxoviruses requires MDA5. J. Innate Immun. 6:650-662.
- K. Fink, L. Martin, E. Mukawera, S. Chartier, X. De Deken, E. Brochiero, F. Miot and N. Grandvaux (2013). IFNβ/TNFα synergism induces a non-canonical STAT2/IRF9-dependent pathway triggering a novel DUOX2 NADPH Oxidase-mediated airway antiviral response. Cell Res. 23(5):673-690.
- A. Soucy-Faulkner, E. Mukawera, K. Fink, A. Martel, L. Jouan, Y. Nzengue, D. Lamarre, C. Vande Velde and N. Grandvaux (2010). Requirement of NOX2 and Reactive Oxygen Species for efficient RIG-I-mediated antiviral response through regulation of MAVS expression. PloS Pathogens 6(6):e1000930.