"Viruses are of great importance for global public health. The first line of cellular defenses against viral infection begins with the binding of viral RNA to intracellular pathogen recognition receptors. Such interaction triggers the conformational change of these receptors and allows subsequent interaction with the adaptor molecule MAVS. Once activated, MAVS recruits a signaling complex able to activate transcription factors that induce the direct expression of ‘early IFN stimulated genes’ (ISGs), which have direct anti-viral effect.
Until recently, the key adaptor molecule MAVS, was thought to localize exclusively at the mitochondrial membrane, therefore establishing mitochondria as a unique platform for antiviral signaling. Recent work has revealed that MAVS is also found on peroxisomes, organelles that are best known for lipids oxidation. Interestingly, peroxisomal MAVS induces a direct, rapid and transient, IFN-independent expression of ISGs, whereas mitochondrial MAVS induces both IFN and ISGs with delayed kinetics. Therefore, MAVS localization determines the type of signaling pathway activated during viral infection. The set of genes that are induced by peroxisomal MAVS and mitochondrial MAVS differ, suggesting that signaling from both organelles may be coordinated to ensure maximal antiviral gene expression.
We propose to characterize the molecular basis for the regulation and coordination between peroxisomal and mitochondrial MAVS signaling in the context of infection by a variety of medically important viruses. The overall goal of this project is to understand innate immunity mechanisms that are taking places very early after virus infection. A better understanding of this arm of the innate immune response should shed some light on important mechanisms such as the control of virus replication by the host cell, the cell tropism of the virus and the development of disease. Such understanding is key to the development of strategies to fight viruses."
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