Research & Publications

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

Africa cycle bio
Like all the bunyaviruses, RVFV has a tripartite RNA genome of negative polarity. The L and M segments code respectively, for the L RNA dependent RNA polymerase and the precursor to the envelope glycoproteins and the S segment utilizes an ambisense strategy and codes for two proteins in opposite orientations, the nucleoprotein N and a nonstructural protein NSs. In an effort to better understand RVFV pathogenesis, we focused our efforts on the nonstructural protein NSs.
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.

Publications

2009

  • LAGERQVIST N,  J. NASLUND, A. LUNDDKVIST, M. BOULOY, C. AHLM AND G. BUCHT. 2009. Characterization of immune responses and protective efficacy in mice after immunisation with Rift Valley fever virus cDNA constructs. Virology Journal. 6 :6 doi :10.1186/1743-422X-6.6
  • AHMED J. BOULOY M. EGONUL O, FOOKS T., PAWESKA J, CHEVALIER V, DROSTEN C, MORMANN R, TORDO N, VATANSEVER Z, CALISTRI P, ESTRADA A, MIRAZIMI A,UNGER H, YIN H AND SEITZER U. 2009. International network for capacity building for the control of emerging viral vector borne zoonotic diseases : Arbo-zoonet. Eurosurveillance 14  1-4.
  • CETRE-SOSSAH C., A. BILLECOCQ, R. LANCELOT, C. DEFERNEZ, J. FAVRE, M. BOULOY, D. MARTINEZ AND E. ALBINA. 2009. Evaluation of a commercial competitive ELISA for the detection of antibodies to Rift valley fever virus in sera of domestic ruminants in France. Preventive Veterinar Medecine.
  • ATTARZADEH-YAZDI G, FRAGKOUDIS R, CHI Y, SIU RW, ULPER L, BARRY G, RODRIGUEZ-ANDRES J, NASH AA, BOULOY M, MERITS A, FAZAKERLEY JK, KOHL A. 2009.  Cell to cell spread of the RNAi response suppresses Semliki Forest virus infection of mosquito cell cultures and cannot be antagonised by this virus. J. Virol. 83 5735-5748.
  • BOULOY M.AND R. FLICK. 2009. Reverse genetics technology for Rift Valley fever virus: Current and future applications for the development of therapeutics and vaccines. Antiviral research Ahead of print
  • PEYREFITTE C N, PERRET M, GARCIA S, RODRIGUES R, BAGNAUD A, LACOTE S, CRANCE JM, VERNET G, GARIN D, BOULOY M* AND PARANHOS-BACCALÀ  G. 2009. Differential activation profiles of Crimean-Congo hemorrhagic fever virus versus Dugbe virus infected antigen presenting cells. J . Gen Virol. Ahead of print

2008

  • LE MAY N, Z MANSUROGLU, P LÉGER, T JOSSE, G BLOT, A BILLECOCQ, R FLICK, Y JACOB, E BONNEFOY AND M BOULOY. 2008 A SAP30 Complex Inhibits IFN-b Expression in Rift Valley Fever Virus Infected Cells. Plos Path 4(1) e13 doc101371/journalppat 0040013
  • SUSPÈNE, R, RENARD, M, MICHEL, H, GUÉTARD D, PUYRAIMOND-ZEMMOUR, D, BILLECOCQ, A,  BOULOY, M, TANGY, F, VARTANIAN, J-P, WAIN-HOBSON S. 2008. Inversing the natural hydrogen bonding rule to selectively amplify GC-rich ADAR-edited RNAs. Nucl Ac. Res.
  • AUGOT D, SAUVAGE F, BOUE F, BOULOY M, ARTOIS M, DEMERSON JM, COMBES B, COUDRIER D, ZELLER H, CLIQUET F, PONTIER D. 2008 Spatial and temporal patterning of bank vole demography and the epidemiology of the Puumala hantavirus in northeastern France. Epidemiol Infect. 6:1-6.
  • BILLECOCQ A, N GAULIARD, N LE MAY, R M ELLIOTT, R FLICK AND M. BOULOY. 2008. RNA Polymerase I-mediated expression of viral RNA for the rescue of infectious virulent and avirulent Rift Valley fever viruses. Virology 378, 377-384
  • PEYREFITTE C. N., L. BOUBIS, D. COUDRIER, M. BOULOY, M. GRANDADAM, H. J. TOLOU, AND S. PLUMET. 2008. Real-time reverse transcription loop-mediated isothermal amplification for rapid detection of Rift Valley fever virus. J Clin Microbiol 11 3653-3659
  • PEPIN M, F GUIGUEN, V CHEVALIER ET M BOULOY. 2008. La fièvre de la vallée du Rift : prochaine maladie infectieuse émergente en France. Bulletin des GTV. Hors série 2008 p 21-28

2007

  • MOUTAILLER S., BOULOY M. AND A.-B. FAILLOUX. 2007. Efficient oral infection of Culex pipiens quinquefasciatus by Rift Valley fever virus using cotton stick support. American Journal of Tropical Medicine and Hygiene 76(5): 827-829.