Flavivirus-Host Molecular Interactions  


  HEADDr. Philippe DESPRES / philippe.despres@pasteur.fr
  MEMBERSDr. Matthieu BLANCHET / Jean-Baptiste BRAULT / Hans Henrik GAD / Charlotte FORET / Marie-Pascale FRENKIEL/ Dr Marc GRANDADAM/ Eva MERTENS / Brigitte MILLIOT / Isabelle MOLTINI / Dr. Nathalie PARDIGON / Sylvie PAULOUS / Dr Charlotte RENAUDAT


  Annual Report

The FHMI lab has an internationally recognized science programme in the area of arbovirus-host interactions ranging from research at the molecular and cellular level to studies in natural hosts. The FHMI’s research programme is geared towards deciphering host-cell/virus interactions that define the pathogenicity of arboviruses. Several notable achievements have been recently obtained including molecular mechanisms of resistance of dermal macrophages to dengue virus infection, the unraveling of Chikungunya virus-related disease mechanisms, the role of interferon-inducible 2’,5’-Oligoadenyle Synthetases in antiviral innate immunity to arboviruses, the ability of flavivirus envelope proteins to interact with NK cell receptors, and the suitability of lentivirus and measles virus as vaccine vectors for arboviral antigens. The FHMI virology laboratory hosts the NRC Arbo which is involved in surveying and diagnosing arbovirus infections in France mainland and over-sea French territories and also contributes to the global surveillance of arboviroses throughout the world together with InVS, eCDC, WHO and OIE. The research and medical virology groups interact closely, allowing new emerging arboviruses to be studied both at the level of basic research in academic virology and medical virology.

Major achievements in 2009

Cellular interactors to flaviviral proteins. We have identified a cellular protein (Tctex-1) that interacts with the M membrane protein of flaviviruses, using the yeast two-hybrid technology. We defined amino-acids in the M protein that are mandatory for the interaction with Tctex1. siRNAs targetting the gene encoding Tctex1 were shown to decrease West Nile virus infectivity. We are currently investigating the mechanisms of this interaction and its role in the flaviviral life cycle in vitro and pathogenicity in vivo. Cellular interactors to non-structural proteins from neurotropic flaviviruses have also been identified, and we are now in the process of establishing a physiological role for these interactions (in collaboration with P.O. Vidalain and V. Deubel).

Innate immunity to arbovirus. Weshowed that triggering of Natural Killer cells by West Nile and dengue viruses is mediated by engagement of NK-activating receptor NKp44 by viral envelope proteins (coll. A.Porgador, BGU, Israel). Work from IFMH lab (1) demonstrated the important role of the large form of the human 2’,5’-Oligoadenylate Synthetase (OAS3) protein in protective innate immunity to Chikungunya virus infection (coll. A. Sakuntabhai, IP Paris) and (2) identified viral determinants in the NS3 ATPase/helicase domain and the C-terminal region of NS4A that promote West Nile virus resistance to antiviral action of Oas1b in mouse cells. (coll. A. Khromykh, Queensland University, Australia).

Keywords: arbovirus, flavivirus, alphavirus, dengue, West Nile fever, Chikungunya, viral pathogenicity, host-cell/virus interactions, innate immunity, antiviral immune mechanisms, virus evasion, vaccine development, medical virology, epidemiological surveying

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Visualization of recombinant West Nile NS4A protein in human cells (in yellow: NS4A, in red: ER resident calreticulin)



  Publications

Hershkovitz, O., Rosenberg L.A., Navarro-Sanchez, M.E., Jivov, S., Zilka, A., Gershoni-Yahalom, O., HO, J.W., Campbell, K.S., Rager-Zisman, B., Desprès, P., and Porgador, A. (2009). NKp44-Mediated Natural Killer cells interaction with envelope protein of dengue and West Nile viruses. J. Immunol. 83 : 2610-2621

Pagès F, Peyrefitte CN, Mve MT, Jarjaval F, Brisse S, Iteman I, Gravier P, Tolou H, Nkoghe D, Grandadam M. (2009). Aedes albopictus mosquito: the main vector of the 2007 Chikungunya outbreak in Gabon. PLoS One. 4(3):e4691.

Bréhin, A-C., Casadémont, I., Frenkiel, M-P., Julier, C., Sakuntabhai, A., and Desprès, P. (2009). The large form of human 2’,5’-Oligoadenylate Synthetase (OAS3) exerts antiviral activity against Chikungunya virus. Virology 384, 216-22

Wing, W-H., Navarro-Sanchez, E., Dumortier, H., Decossas, M., Barreto dos Santos, F., Fridman, H.W., Rey, F., Harris, E., Desprès, P., and Mueller, C.G. (2008). Dermal-type macrophages expressing CD209/DC-SIGN show inherent resistance to dengue virus growth. PLoS Negl. Trop. Dis. 2(10) :e311.

Kajaste-Rudnitski, A., Mashimo, T., Frenkiel, M-P., Guénet, J.-L., Lucas, M., and Desprès , P. (2006). The 2’-5’ Oligoadenylate Synthetase 1b is a potent inhibitor of West Nile replication inside infected cells. J.Biol.Chem. 281 : 4624-37



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Activity Reports 2009 - Institut Pasteur
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