Centre de Recherche du CHUM (CRCHUM)
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.
- 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
- 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.
- 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.
- 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.