JCJC SVSE 3 - JCJC - SVSE 3 - Microbiologie, immunologie, infectiologie

Temporal and spatial modulation of antiviral MAVS signaling – Viropero

Flavivirus sensing and signalling

Our project focuses on the cellular mechanisms that trigger interferons (IFNs) induction and subversion upon infection by Flavivirus, which are important causes of human diseases worldwide. For instance, Dengue Virus affects an estimated 50-100 million people per year. Vaccine and antiviral therapies are missing. On the other hand, Yellow Fever vaccine is one of the most successful ever. However, the molecular basis for the attenuation of YFV virulence is not known.

Understand the mechanisms that lead to induction of Interferon upon Flavivirus infection

By looking at the kinetics of IFN induction, by characterizing the signaling cascades involved, the nature of the genes induced and the function of the corresponding proteins, new scientific knowledge will be gained in the field of virology, cell biology and innate immunity. We are likely to identify new signaling molecules and new signaling cascades, as well as new anti-viral proteins, the function of which will be characterized.

We are comparing and characterizing innate immune responses that are induced by Flaviviruses in relevant cell lines. We are using techniques that allow us to follow the induction of interferon and interferon-induced-genes overtime, as well as viral growth and dissemination.

The results obtained so far show that =
- our viruses of interest replicate well in relevant cell lines, such as human liver cells
- the innate immune response kicks in late in infection, a time at which the viruses have already completed their cycle.
This suggests that the viruses are able to escape imune detection by the cells. We are trying to understand the mechanism behing this evasion.

The final product will be a detailed characterization of an arm of the innate immune response that represents a profoundly important host defence mechanism against viruses.
Clarifying this mechanism is extremely important with regard to our general understanding of viral pathogenesis and the development of disease. The better we understand this defence mechanism, the better we can develop strategies to fight viruses and the better we stand prepare for the next emerging viral diseases. Moreover, the project could lead to the discovery of the molecular basis behind the most successful ever anti-viral vaccine and such knowledge could be used for developing new successful vaccines.

The project is still in an early phase. However, we are planning to submit a publication around the end of this year/beginning of next year.
We are also planning to submit an abstract to present our data at the keystone meeting '‘Innate immunity to viral infections’, which will take place in Colorado, USA, in January 2014.

Viruses are of great importance for global public health. The first line of cellular defenses against viral infection begins with the recognition of viral components by pathogen recognition receptors (PRRs). The binding of viral RNA to intracellular PRRs, such as the RNA helicase retinoic acid-inducible gene I (RIG-I) and Melanoma differentiation associated gene 5 (Mda-5), triggers their conformational changes, which allows interaction with the adaptor molecule MAVS. Once activated, MAVS recruits a signaling complex able to activate transcription factors that induce the direct expression of ‘viral stress-inducible genes’ (VSIGs), also referred as ‘early IFN stimulated genes’ (ISGs), since they are also induced in response to interferons (IFN) treatment. The activated transcription factors also induced the production of IFNs, which will amplify the anti-viral state via their secretion, subsequent binding to IFN receptors and induction of several ISGs, including VSIGs. A number of ISGs have direct anti-viral effect and block viral replication, assembly or budding.

Until very recently, the adaptor molecule MAVS, which plays an essential role in this innate immune response, 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. Signaling through the mitochondrial MAVS can be amplified upon IFN treatment and is therefore conveniently referred to as IFN-dependent signaling pathway for easy discrimination from the peroxisomal MAVS pathway. Therefore, MAVS localization (mitochondrial versus peroxisomal) 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 MAVS and mitochondrial MAVS signaling in the context of infection by a variety of medically important viruses, such as Hepatitis C Virus, Dengue Virus, Yellow Fever Virus, Chikungunya virus and Hepatitis B Virus. The overall goal of this project is to understand innate immunity mechanisms that are taking places very early upon infection by a variety of viruses. 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.


Project coordinator

Madame NOLWENN JOUVENET (Centre National de la Recherche Scientifique) – nolwenn.jouvenet@gmail.com

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

IP Centre National de la Recherche Scientifique

Help of the ANR 309,442 euros
Beginning and duration of the scientific project: September 2012 - 48 Months

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