Identification of key cellular pathways and genes involved in the pathogenicity and resistance to Rift Valley Fever virus. – GenRift
Does the susceptibility to Rift Valley fever depend on host genetic factors ?
Identification of key cellular pathways and genes involved in the pathogenicity and resistance to Rift Valley fever virus.
The identification of novel potential targets for antiviral drug treatment is an urgent aim.
The Rift Valley fever virus is transmitted by mosquitoes. It is responsible for a severe zoonosis both in terms of morbidity and mortality in humans and livestock. The virus was first identified in 1931 in the greater Rift Valley of Kenya. The Rift Valley fever virus has already demonstrated a real capacity to emerge in new territories, as exemplified by outbreaks in Egypt (1977), Saoudia Arabia and Yemen (2000), and in the Archipelago of Comores (2007). Humans generally develop a mild, self-limiting febrile disease. However, approximately 5% of exposed individuals suffer from a severe illness including hepatitis, meningoencephalitis and hemorrhagic manifestations. Death is associated with hepatorenal failure, shock and a severe anemia. There is neither safe vaccine nor antiviral agents for therapy. Treatment is essentially symptomatic and supportive. Novel antiviral drugs able to control the infection and its clinical consequences in human and animal populations are sorely needed. This current status fuels the argument that new targets for therapeutic intervention must be identified. These targets may be either viral or host proteins.
Host proteins involved in viral infection are encoded by a definable set of cellular genes designated the infectome. As for proteins able to confer resistance to infection and/or pathogenicity, they are encoded by a small fraction of the host genome, the resistome. The hypothesis of the GenRift project is that host factors that are major players in the pathogenesis of Rift Valley fever virus infection and provide effective containment of viral infection will be excellent targets for therapeutic intervention. These factors will be identified in the Mouse species, where it is possible to control most environmental parameters, including the virus strain and the inoculated dose. This research project relies on genetics of complex trait and virology, whole-genome analysis of gene expression and exome sequencing, and on methods for studying protein-DNA interactions on a genome-wide scale.
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Rift Valley Fever (RVF) virus is an arbovirus of the Bunyaviridae family (genus Phlebovirus) transmitted by mosquitoes that infect a wide range of vertebrate hosts and causes severe illness in humans, including retinitis, encephalitis and hepatitis which can be fatal when associated with hemorrhagic fever. RVF virus (RVFV) is also responsible for abortions among pregnant ruminants. Important advances have been made these last years concerning the genetic organization and the biology of the virus. RVFV is a segmented, single-stranded, negative/ambisense RNA virus. Upon infection by RVFV, the NSs protein, the major virulent gene product of RVFV, accumulates in the nucleus where it forms filamentous structures that subvert cellular processes through several mechanisms, including the inhibition of IFN ß gene expression. As it stands, other regulatory functions for the NSs virulent factor have yet to be defined. Following infection, host cells detect viral RNA through pathogen sensors and induce type I interferons and an active antiviral program. Little is known about the biology of the host-virus relationship and much remains to be done to determine the influence of the genetic background of the mammalian host on the capacity of the virus to subvert host defenses and induce RVFV-related clinical syndromes.
Our overall goal is to identify key cellular pathways and genes involved in the pathogenicity and resistance to Rift Valley Fever virus. We will accomplish our goals by implementing several strategies. First, we will identify proteins and cellular pathways of the target cells that are important for infection and pathogenesis. This part of the host genome is collectively called the infectome. In this project a special emphasis will be given to the functional importance of genes whose expression is regulated by the NSs filamentous protein. Indeed, our recent data has shown that although most cellular DNA is excluded from the NSs filament, a number of specific regions of the host genome closely interact with the NSs filamentous structure. These data raise the question of a possible link between the capacity of NSs to target specific cellular DNA sequences and RVF pathogenesis. There is strong evidence that genes targeted by the NSs filament play a crucial role during the development of RVFV pathogenicity in both infected animals and humans. Our hypothesis is that some of these target genes are also directly involved in conferring resistance in vivo to infection and/or counteracting the pathological effects of infection. Therefore, as a second strategy, we will use a phenotypic-driven approach to determine the set of host genes that confer natural resistance to infection with RVFV, referred to as the resistome. We have recently demonstrated, using mouse inbred lines derived from wild progenitors, that it is possible to identify individual genes whose expression confers resistance to RVF. The final goal will involve the integration of all described factors, allowing the characterization of cellular pathways and key determinants of the host directly responsible for the pathogenesis and resistance to Rift Valley Fever.
The present project relies on results obtained from ongoing collaborations carried out in the context of previous ANR programs. These include the use of reverse genetics as a tool to decipher the role of the proteins encoded by the different RNA segments of the virus, the study of the tissue tropism and the nature of the target cells in vivo, and the identification of promoter DNA regions of the host specifically interacting with NSs. We also used genetic mapping to identify loci in the mouse genome controlling resistance to RVFV infection.
Monsieur Jean-Jacques PANTHIER (CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE - DELEGATION REGIONALE ILE-DE-FRANCE SECTEUR OUEST ET NORD) – firstname.lastname@example.org
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.
IP INSTITUT PASTEUR
CNRS-FRE3235 CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE - DELEGATION REGIONALE ILE-DE-FRANCE SECTEUR PARIS A
CNRS CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE - DELEGATION REGIONALE ILE-DE-FRANCE SECTEUR OUEST ET NORD
Help of the ANR 520,000 euros
Beginning and duration of the scientific project: - 36 Months