Unit: Flavivirus-Host Molecular Interactions

Director: Desprès Philippe

The research group Flavivirus-Host Molecular Interactions is dedicated to the knowledge of the complex molecular interactions among viral factors, host genetics, and innate immunity that contribute to dengue hemorrhagic fever and encephalitis to West Nile virus. Understanding these mechanisms has important implications for vaccine development and will provide crucial informations to guide diagnosis and therapeutic strategies against flavivirus-induced diseases.

Host susceptibility to West Nile virus (WNV). The emergence of a virulent variant of WNV that causes recurrent enzoonosis in North America and Mediterranean regions, has been associated with a dramatic increase in the severity of infection in humans drawing the attention to viral encephalitis as a public health concern. The neuropathogenic properties of WNV have been studied in the mouse model. A single nucleotide polymorphism (SNP) in the mouse 2'-5' Oligo-Adenylate Synthetase 1b (Oas1b) gene was associated to the susceptibility of mice to WNV infection. We have investigated the role of alpha interferon (IFN)-inducible Oas1b in the antiviral innate immunity to WNV. The expression of Oas1b protein was capable of suppressing viral infection by restricting the ability of WNV to accumulate viral RNA inside infected cells (1). Improved knowledge of Oas1b antiviral action provides new insight into the IFN-induced genes that are responsible for establishment of an antiviral state against WNV opening new perspectives in therapeutic development against flavivirus infection.

Innate immunity to dengue virus (DV). Dengue fever has worldwide distribution in the tropics and the four serotypes of DV (types 1-4) each cause human disease. Epidemics with a high frequency of the severe, life-threatening forms -dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS)- continue to expand geographically in Asia and South America. To date, dengue illness is the most important arthropod-borne virosis in humans with an estimated 100 millions cases and over 500,000 cases of DHF/DSS occur each year, including about 25,000 fatal cases, mainly in children under the age of 15. Despite its increased health and economic impacts, there is as yet no specific prophylaxis or treatment of DV infection. One most important question in dengue pathogenesis is to identify the host factors that might play a crucial role in innate antiviral immunity. DV primarily targets immature myeloid dendritic cells (DCs) after the initial bite by the mosquito vector. The DC-SIGN (CD209), a cell surface mannose C-type lectin, has been shown to interact with DV grown in mosquito cells. DC-SIGN concentrates virus particles at the cell surface to allow efficient interaction with a yet-unidentified entry factor that would be responsible for WNV internalization into DCs (2). We reported strong association between a promoter variant of CD209 and risk of DF (3). The SNP has been shown to play a functional role in the transcriptional regulation of CD209. This may have consequences for therapeutic and preventive strategies against dengue disease.

Visualization of viral antigens (green) inside two DV-infected DCs (nuclei in blue) by immunofluorescence assay

Design of effective vaccines against flaviviroses. We have evaluated the applicability of live-attenuated Schwarz strain of measles virus and lentivirus-derived TRIP vectors as efficient replicating (measles vector) and non-replicating (lentiviral vectors) vaccines against flaviviruses for which neutralizing humoral responses is one active arm of the protective immunity. Immunization of mice with measles virus or defective lentivirus expressing the secreted form of the E-glycoprotein from WNV was efficient at eliciting a long-lasting and protective antiviral immunity against a lethal challenge with WNV (4, 5). Measles and lentiviral vectors appear to be promising tools for prevention of West Nile encephalitis and likely other flaviviroses. The measles vector is now used for the development of a candidate pediatric vaccine against dengue disease.

Partners at the Institut Pasteur: (1) Mammalian Genetics; (2) Viral Immunity; (3) Genetic of Infectious Diseases and Autoimmunity; (4) Molecular Virology and Vectorology; and (5) Slow Viruses.

Keywords: Flaviviridae, flavivirus, RNA virus, arbovirus, emerging disease, tropical disease, dengue, West Nile fever, viral immunopathogenesis, host genetics, innate immunity, antiviral immunity, virus virulence, vaccinology

Activity Reports 2005 - Institut Pasteur

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