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TEMPORAL AND SPATIAL MODULATION OF ANTIVIRAL MAVS SIGNALING

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Mechanism of viral infection

Old and emerging viruses pose a great socioeconomic impact throughout the globe. The development of novel anti-viral strategies requires an in depth understanding of the viral mechanisms of infectivity.

Fundamental Research icon Fundamental Research
Health icon Health

The first line of cellular defence against viral infection begins with the binding of viral RNA to intracellular pathogen recognition receptors (PRRs). These in turn undergo a conformational change, interact with and activate the adaptor molecule MAVS. Once activated, MAVS initiates a signalling cascade that culminates with the expression of interferon (IFN) genes. IFNs are key immune system signalling molecules that are secreted upon infection and help modulate immune responses. Recent evidence indicates that MAVS is located in the mitochondria and peroxisomes. In the former, it induces interferon-stimulated gene expression, while peroxisomal MAVS induces a direct and transient, IFN-independent expression of IFN-stimulated genes. In addition, the gene targets of peroxisomal MAVS and mitochondrial MAVS differ, suggesting that signalling from both organelles may be coordinated to ensure maximal antiviral gene expression. Scientists of the EU-funded VIROPERO (Temporal and spatial modulation of antiviral MAVS signalling) project investigated innate immune mechanisms that take place early upon virus infection, especially virus recognition. In this context, they studied medically relevant viruses such as yellow fever virus (YFV), Dengue virus and the Zika virus. Although these viruses differ in tissue tropism and disease outcome, they demonstrate an ability to modulate the innate immune response. Researchers employed plasmacytoid dendritic cells (pDCs), the most important source of IFNs in response to virus infection. Results showed that YFV is able to stimulate pDCs to produce antiviral cytokines through two distinct signalling pathways. Interestingly, the magnitude of cytokine-mediated antiviral responses was dictated by the viral entry mechanisms. Overall, the findings of the study provide fundamental knowledge on the level of plasticity and complexity of pDC-mediated viral sensing. Importantly, the results have great socioeconomic implications as they could form the basis for the design of future anti-viral interventions.

Keywords

Pathogen recognition receptors, MAVS, VIROPERO, yellow fever virus, plasmacytoid dendritic cells

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