Theme 1 : Duration of the RLR-mediated antiviral/proinflammatory responses

 

Intrinsic cellular antiviral response is the first line of defense against invading viruses. It relies mainly on the production of antiviral type I/III interferons (IFNs). Through autocrine/paracrine actions, IFNs establish a robust antiviral state through the induction of hundreds of interferon-stimulated genes (ISGs), which restrict virus replication and spreading. The inflammatory arm of the response mediated by production of proinflammatory cytokines and chemokines, such as Tumor Necrosis Factor a (TNFa) and RANTES, orchestrate the development of an appropriated adaptive immune response. The inability of the host to sustain an antiviral response leads to failure in eradicating the infection. Conversely, uncontrolled duration of the innate immune response is associated with the development of various autoimmune and chronic inflammatory diseases. To reach the ideal duration for efficient fighting of the infection without generation of side effects, the innate immune response is subject to stringent regulation by both positive and negative regulators. Major breakthroughs have been made in the understanding of how the innate antiviral response is initiated. However, the positive and negative mechanisms allowing the host to achieve the most appropriate duration for efficient fighting of the infection without generation of side effects have been understudied.

During the past ten years, an intensive research effort led to the characterization of intra- and extracellular Pathogen Recognition Receptors that allow innate recognition of ssRNA viruses. Cytosolic sensing relies on the retinoic acid-inducible gene I (RIG-I) and its structural homologue melanoma-differentiation-associated gene 5 (MDA5). Our work in progress has unveiled a specific role of the cytoplasmic sentinel MDA5 in the initiation of yet to be defined signal(s) resulting in the sustained activation of IRF-3, thereby sustaining the antiviral response. Our current work is aimed at further identifying positive and negative mechanisms modulating antiviral and proinflammatory signaling cascades to control the duration of the innate immune response to ssRNA virus infection. Knowledge of these mechanisms is essential to pave the way for the development of novel compounds or strategies directed at preventing or enhancing the activity of these regulators to promote transient activation of an optimal innate immune response to fight infectious diseases. Additionally, this knowledge is expected to impact a broad range of human health conditions given the importance of aberrant innate immune response in the development of autoimmune and chronic diseases.