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IS-AUR-Samarb.progr. Norge Frankrike


Awarded: NOK 60,000

The impact of the spread of arboviruses in terms of public health has been particularly underscored by the recent epidemics of the Alphavirus Chikungunya (CHIKV) in the Indian Ocean regions (2005) and in the Caribbean islands (2013). In humans, CHIKV is responsible for an acute syndrome of varying intensity that can progress towards long-term disabling joint pathologies as well as neurological complications. The recent spread of the Flavivirus Zika (ZIKV) from the Pacific Ocean (2007-2013) to South America (2015) and the increased incidence of birth defects related to brain development abnormalities are additional examples of the health risk of these mosquito-transmitted viruses against which there is no vaccination or treatment. In this project we will investigate the mechanism underlying neuronal tropism of CHIKV and ZIKV, focusing initially on entry factors, by exploring the role of TAM-receptors in recognizing exposed phosphatidylserines on the viral envelope. We will then investigate how the viruses can manipulate the host cell epitranscriptome to allow viral replication. One of the mechanisms cells mount to combat viruses, is the shut-down of mRNA translation and translocation of mRNAs to stress granules (SGs) and processing bodies. This hostile environment can be manipulated by viruses so that they can attenuate host antiviral responses and subvert SGs to facilitate viral RNA translation. Recent evidence also indicates that the cellular mRNA methylation machinery can strongly influence viral replication. Here, knockdown of the m6A methyltransferases METTL3 and 4 enhanced production of Zika virions, whereas knockdown of the m6A demethylase had the opposite effect. To what extent the arboviruses are able to manipulate the host cell epitranscriptome and epigenome, remains, however, unknown. Quantification and eventually positional identification of such modifications subsequent to infection will be major goals of the project.

Funding scheme:

IS-AUR-Samarb.progr. Norge Frankrike