DUSP1 regulates apoptosis and cell migration, but not the JIP1-protected cytokine response, during Respiratory Syncytial Virus and Sendai Virus infection

Alexa C. Robitaille; Elise Caron; Nicolas Zucchini; Espérance Mukawera; Damien Adam; Mélissa K. Mariani; Anaïs Gélinas; Audray Fortin; Emmanuelle Brochiero; Nathalie Grandvaux

Respiratory syncytial virus (RSV) belongs to the Pneumoviridae family of large enveloped negative-sense ssRNA viruses that includes important human pathogens 1, 2 . RSV is a leading cause of acute lower respiratory tract infections associated with morbidity and mortality in infants, children and elderly, but also adults of all-age with a compromised immune system, cardiopulmonary diseases or following transplantation 3, 4 . The capacity of the host to mount an appropriate antiviral defense aimed at limiting virus replication and spreading is critical to determine the outcome of the infection. As a consequence, the inability of the host to sustain an antiviral response leads to failure in eradicating the infection. Conversely, uncontrolled duration or intensity of the response is harmful to the host and is associated with the development of virus-associated pathogenesis, chronic inflammatory diseases and various autoimmune diseases 5, 6 . Therefore, these responses need to reach the ideal intensity and duration for efficient fighting of the infection while limiting tissue damage and promote tissue repair 7 . To this aim, the various components of the host antiviral defense, including the transcriptional induction of interferons (IFNs) and proinflammatory cytokines and chemokines, but also the activation of cell death pathways, such as apoptosis, are subjected to stringent regulation by both positive and negative mechanisms 8,9 . Upon virus entry and sensing by the cytosolic pathogen recognition receptors (PRRs) retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated protein 5 (MDA-5), the mitochondrial membrane-associated adaptor (MAVS) coordinates multiple signalling pathways ultimately leading to the activation of the transcription factors IFN regulatory factors (IRF) 3/7, Nuclear Factor κB (NF-κB) and Activator Protein 1 (AP-1) [10] [11] [12] . Activation of IRF3