Pathogenesis - Michèle Bouloy
Rift Valley fever is an emerging zoonosis caused by a virus of the Bunyaviridae family (genus Phlebovirus) and affecting mostly ruminants (ovines, caprines and cattle). In humans, infection often leads to hepatitis or encephalitis and may be associated with hemorrhagic fevers. Before 2000, this virus (RVFV) was confined to Egypt and subsaharian Africa but since, it has spread to Saudi Arabia and Yemen and caused frequent and serious outbreaks in the horn of Africa (Kenya, Somalia, Tanzania, Sudan) and Madagascar. In 2008, for the first time, the virus circulated in Comoros Islands.
Rift valley fever : an emergent disease
The NSs protein of almost all the RVFV strains (ZH548, in particular that we are studying) is mostly located in the nucleus, forming a ribbon-like filament. This is unexpected for a virus replicating in the cytoplasm, Through the characterization of the avirulent clone 13 isolate of RVFV which has a large deletion in the NSs open reading frame and appears as a good vaccine candidate, we identified NSs as a major virulence factor which blocks the host antiviral response by antagonizing the production of interferon ß. The molecular mechanism was recently deciphered: NSs interacts with SAP30, a subunit of the Sin3A repression complex which binds to the promoter through the transcription factor YY1 and maintains the Interferon ß promoter in a repressed state. To ascertain the role of the interaction between SAP30 and NSs we produced by reverse genetics, a RVFV in which NSs was mutated to abrogate the interaction with SAP30. This recombinant virus induces expression of interferon and is avirulent. Altogether, these data highlight the role of the cellular partners in pathogenesis and indicate that RVFV vaccines can be rationally designed.
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