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  Director : Philippe DESPRES (pdespres@pasteur.fr)


  abstract

 

Flavivirus is a genus of the Flaviviridae family that comprises positive-sense, single-stranded, and enveloped RNA viruses, most of which are arthropod-transmitted. Mosquito-borne flaviviruses can cause epidemic outbreaks in humans and patients infected may exhibit severe hemorragic manifestations or meningo-encephalitic syndromes. Research programs have been conducted in the Flavivirus-Host Molecular Interactions laboratory to improve the knowledge of the viral and cellular mechanisms that contribute to the pathogenicity of dengue, yellow fever and West Nile viruses.



  report

cale

1. Molecular basis of mosquito-flavivirus interactions (team leader : A. Delécluse)

Relationships between flavivirus and its mosquito vector are crucial in the maintenance and transmission of dengue, yellow fever and West Nile diseases. Understanding the mosquito-virus interactions will allow development of innovative control methods to prevent disease transmission. Mosquito populations display variable susceptibility to flavivirus development, termed " vector competence ". Competence reflects the different barriers encountered by the virus from its entry into the mosquito midgut to the release in the saliva. Various factors including specific mosquito receptors and/or differential viral replication in the mosquito may be critical in the competence. We are currently developing post-genomic approaches to identify the cellular factors and viral components responsible for vector competence to dengue and yellow fever viruses. Evolution studies of dengue virus have revealed that its genetic diversity is increasing. It is possible that evolution of the flavivirus genome occurs during its replication within the mosquito vector, Aedes aegypti. Mutations in a single genome or recombination events between separate genomes might account for this evolution. We are currently studying the mutation rate of the dengue virus during its replication in the mosquito and investigating the possibility of genome recombination. (team : V. Juárez-Pérez, V. Mayau, and M. Porcar).

2 . The gene encoding the 2'-5'-OAS 1b may play a crucial role in the determinism of susceptibility to West Nile virus in mice (team leader : P. Desprès)

West Nile virus is endemic in parts of Africa, Asia, Europe and Autralia. On the past 5 years, West Nile fever has been an emerging concern for public health in Europe, in the Middle East and more recently in the United States. A new highly neurovirulent variant of West Nile virus was frequently isolated during recent outbreaks. The main goal of the transverse research program 21 (leader : Philippe Desprès) is to investigate the influence of the host genetic constitution on the severity of West Nile virus infection. To improve our understanding of the genetic determinism of susceptibility to West Nile virus, we have established a mouse model for virus infection (coll. : Unité de Génétique des Mammifères and P-E. Ceccaldi). The genetic data demonstrated that the severity of WN virus infection is controlled by major genetic determinant, wnv, and the gene encoding the 1b isoform of 2'-5' Oligoadenylate synthetase (OAS)/L1 was considered candidate. Further investigation is necessary to determine whether OAS 1b plays a critical role in the established endogeneous antiviral pathway. Further studies will determine whether the genetic variability of the human OAS may explain part of the differential susceptibility to infection and pathological manifestations in individuals exposed to dengue virus (Team : M. Lucas and M-P. Frenkiel ; coll. : Cécile Julier [Unité des Maladies Infectieuses et Autoimmunes], and Mahidol University, Thailand).

3. Analysis of the biological properties of flavivirus nonstructural protein NS1 (team leader : M. Flamand)

NS1, the nonstructural glycoprotein of flaviviruses, is essential for virus viability. The cell-associated NS1 protein has been shown to participate in virus replication although no proper biological activity has been related to it. We found that NS1 may be also secreted as a major soluble form in a host-dependent fashion. Glycoprotein NS1 exists as an unique hexameric species into the culture fluids of dengue virus-infected primate cells. Interestingly, mosquito-derived infected with dengue virus do not secrete soluble NS1. Complete processing of the complex-type sugar appears to be required for its efficient release. To investigate the biological significance of NS1 secretion in vivo, the level of circulating NS1 was analyzed in the serum of patients infected with dengue virus using an ELISA-sandwich assay (developed in the partnership with BioRad). Soluble NS1 can be detected in most if not all patients, during the entire clinical phase of the disease, from Day 0 corresponding to the onset of fevers till Day 6. The fact that NS1 circulates during the acute phase of the disease in the human blood stream leads to the suggestion that the protein may be a soluble effector of biological relevance to the pathophysiology of dengue disease. (team : S. Alcon, M.T. Drouet, F. Coulibaly ; Coll. : M. Arborio, S. Darvetelle, J. Krinsje-Locker, F. Nato, F. Rey, and S. Kayal).

4. The membrane M protein comprises a proapoptotic sequence (team leader : P. Desprès)

Flaviviruses have been shown to induce apoptosis but it is unclear whether particular viral components play a crucial role in virus-mediated cell death. Intracellular production of the intraluminal ectodomain of the dengue membrane M protein triggers apoptosis in host cells of various origins. The M ectodomains of all four serotypes of dengue virus and the wild-type strains of Japanese encephalitis, yellow fever, and West Nile viruses have proapoptotic properties. The transport the M ectodomain through the secretory pathway appears to be essential for the induction of apoptosis. The M ectodomain may exert its cytotoxicity by activating a mitochondrial apoptotic pathway. The death-promoting activity of the M ectodomain reflects the proapoptotic properties of the last carboxy-terminal amino acids. The identification of an intrinsic sequence responsible for the proapoptotic activity of the M ectodomain may provide novel insight into the role of the M protein in flavivirus pathogenicity (A. Catteau ; Coll. : S. Susin [Apoptose et Systèmes Immunitaires], L. Cedillo [CINVESTAV, Mexico]).

Keywords: Virus-host molecular interactions, flaviviruses, hemorragic fevers, dengue, yellow fever, West Nile



  publications

puce Publications of the unit on Pasteur's references database


  personnel

  Office staff Researchers Scientific trainees Other personnel
  Milliot Brigitte , bmilliot@pasteur.fr Delécluse Armelle, senior researcher ,armdel@pasteur.fr

Desprès Philippe, senior researcher ,pdespres@pasteur.fr

Flamand Marie, senior researcher ,mflamand@pasteur.fr

Lucas Marianne post-doctmlucas@pasteur.fr

Porcar Manuel post-doctmporcar@pasteur.fr

Juàrez-Perez Victor , post-doct (< 10/02)

Alcon Sophie , PhD student, alcon@pasteur.fr

Catteau Adeline, PhD student, acatteau@pasteur.fr

Coulibaly Fasséli , PhD student ,fcoul@pasteur.fr

Navarro Erika, PhD student, enavarro@pasteur.fr

Davison Sophie, student (07-08/02)

Kajaste-Rudnitski Anna, student (07-08/02)

Drouet Marie-Thérèse, Technician , mtdrouet@pasteur.fr

Frenkiel Marie-Pascale, Technicianmpfrenk@pasteur.fr

Mayau Véronique, Technician, vmayau@pasteur.fr

Ollivier Noëlle

Palmyre Jocelyne


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