Flavivirus-Host Molecular Interactions

  HEADDr DESPRES Philippe / pdespres@pasteur.fr
  MEMBERSBRAULT Jean-Baptiste / BREHIN Anne-Claire / Dr COFFEY Lark / DEJEAN DE LA BATIE Caroline

  Annual Report

The FHMI lab is mainly dedicated to the understanding of molecular interactions between viral and host factors that contribute to the pathogenicity of arboviruses such as dengue (DEN), West Nile (WN), and Chikungunya (CHIK) viruses. The knowledge of such mechanisms has important implications for medical vaccine design and will yield crucial information to guide diagnostic development and therapeutic strategies against emerging arboviruses of global public health interest.

The cellular and viral factors involved in pathogenicity of arboviruses. The flaviviral M proteins have pro-apoptotic properties. The yeast two-hybrid technique using a human spleen cDNA library as prey and the M ectodomains as baits allowed the identification of a cellular partner able to interact with most of flaviviral M proteins. We are currently investigating the function of this candidate interactor of M in flavivirus virulence. Alphavirus such as Chikungunya virus could also induce apoptosis. The severity of CHIK disease may depend on the efficiency of virus replication and the ability of the virus to induce apoptosis. We are currently studying alphaviral factors that contribute to virus virulence among clinical isolates from La Réunion Island.

Innate immunity to flaviviruses.The C-lectin DC-SIGN (CD209) plays an essential role as attachment receptor for DEN virus on human dermal dendritic cells (DC). We reported a strong association between a promoter variant of CD209, DC-SIGN1-336, and the risk of DEN disease. The-336G variant down-regulates DC-SIGN expression on human myeloid cells. Although dermal DCs and their CD14+ precursors carry DC-SIGN, CD14+CD209+ cells are refractory to DEN virus infection. We are currently investigating the underlying mechanisms of resistance of CD14+CD209+ cells to DEN virus. Suppression of WN virus infection has been observed in murine cells expressing IFN-dependent 2’-5’ Oligo-Adenylate Synthetase 1b (Oas1b) gene by restricting WN virus replication. Escape of a WN virus variant via the Oas1b antiviral pathway was successfully achieved by a series of passages on Oas1b-expressing cells. Through genomic analysis, we are currently identifying viral determinants that contribute to WN virus resistance to the action of Oas1b. The importance of human OAS genes in DEN disease has been investigated. A significant association has been recently identified between a single nucleotide polymorphism in one of the OAS isoforms and the severity of DEN disease. We have developed an in vitro model that is now used to study the impact of this variant on the functional activity of candidate OAS gene.

Measles virus (MV)-based vaccine against dengue. A recombinant MV-WN vaccine has been shown to elicit protective immunity in a monkey model of WN virus infection. We are investigating whether a MV-based DEN vaccine could be protective. A candidate pediatric MV-DEN vaccine, generated by inserting a sub-domain from the E-glycoprotein fused to the M ectodomain for each DEN serotype into the infectious cDNA clone from the live MV vaccine, is currently tested.


Virus de la dengue par microscopie électronique (coll. MC. Prévost)

Electron microscopy of Dengue virus (courtesy MC Prevost)

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Publications 2006 of the unit on Pasteur's references database

Activity Reports 2006 - Institut Pasteur
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