RNA viruses are responsible for important acute, chronic as well as emerging human infections. While some of these viruses like for instance the hepatitis C virus (HCV) are highly species-specific, others (e.g. Dengue Virus) infect different host species. These latter viruses cause zoonotic infections, i.e. infections of animal hosts that are transmitted to humans by unintentional contact. Why some RNA viruses are highly species-specific, whereas others have a broad species-tropism is poorly understood. Moreover, host-derived control mechanisms that prevent viruses to transmit across species barriers and viral evasion and adaptation strategies are only beginning to emerge. While climatic changes, augmented population density and mobility increase the risk for human exposure to novel RNA viruses, therapeutics preventing disease in humans or precluding transmission are lacking. In some cases, small animal models for drug discovery, vaccine research and pathogenesis studies are not available. The objective of the proposal is to define all factors that prevent HCV propagation in mouse liver cells. The inability of HCV to propagate in non-human cells may be due to lack or genetic incompatibility of essential viral replication co-factors and/or due to antiviral restriction mechanisms effectively suppressing viral replication in non-human host cells. Taking this into account, both rationale and unbiased genetic screening systems will be employed to derive a comprehensive profile of all factors relevant to the species barrier for HCV infection of mouse cells. Moreover, viral adaptation and evasion strategies to overcome these barriers will be explored. These pioneer studies will prepare the ground for development of urgently needed HCV small animal models and provide valuable insights into the mechanisms of pathogen control at species barriers. This should promote future development of strategies which prevent zoonotic transmission of emerging RNA viruses to humans.
Start date: 2012-02-01 End date: 2017-01-31 EU-Contribution: 1 444 515 Euro Total costs: 1 444 515 Euro