|Hepacivirus and Innate Immunity - CNRS URA 3015|
|HEAD||Meurs Eliane / email@example.com|
|MEMBERS||Meurs Eliane, PhD, Lab Head, Unit Head, HDR, Institut Pasteur/ Budkowska Agata, PhD, Lab Head, HDR, Institut Pasteur/ Roohvand Farzin, PhD, senior scientist, Institut Pasteur Teheran (Iran), ANRS grant / Grubisha Olivera, PhD, Pasteur Fondation grant/ Maillard Patrick, PhD, Engineer Institut Pasteur/ Dabo Stéphanie, Engineer CNAM, techn. Institut Pasteur/ Ahmadi Pour Malek, PhD student Univ Paris VI 3rd year, lab grant / Arnaud Noëlla, PhD student Univ Paris VI, 1st year, MRT grant / Cerutti Andrea, PhD student Université de Piemonte Orientale (Avogadro), Novara, Italy, 2nd year, Italian Ministry or Research grant/ Walic Marine, PhD student 3rd year, Univ Paris VII, ANRS grant
We investigate the interaction of hepatitis C virus (HCV) with its target cell and with the host immune response with a view of developing new approaches to inhibit its replication and propagation. For this, we are currently characterizing the mechanisms of HCV cellular entry, morphogenesis, and interactions with components of the Interferon inducing pathway and of the cytoskeleton.
Mechanisms of HCV cellular entry and egress: role of lipoproteins, lipoprotein receptors and the microtubule network (A. Budkowska).
HCV is remarkably efficient in establishing a chronic infection and evading the host immune response. A unique feature of HCV is the dependence of the virus cell cycle on host lipid metabolism. We have shown that the human “scavenger receptor” SR-BI/Cla1 mediates the cellular uptake of natural virus from patients’ sera, not directly by the viral envelope glycoproteins, but due to an interaction of the virus-associated VLDL with the receptor. Apo-B containing lipoproteins incorporated into virus particles promote virus entry and ensure protection against neutralising antibodies (FASEB J. 2006). We have provided the first evidence that HCV can use a lipoprotein lipase (LPL)-dependent alternative pathway for cell entry, through the formation of a bridge between virus-associated triglyceride-rich lipoproteins and cell surface heparan sulfate. LPL has a potent inhibitory effect on HCV infection, probably leading the virus to an abortive infection, and as such can have anti-viral activity in vivo (Cell. Microb. 2007). These findings demonstrate an essential role for lipoproteins in the HCV life-cycle thereby providing new targets for the treatment of HCV infection. We have shown that the microtubule network is required for HCV cell entry, early transport and release of the progeny virus from infected cells. We have provided evidence that the HCV core protein directly binds to α/β tubulin, enhances tubulin polymerization and incorporates itself into the microtubule lattice in vitro. These observations suggest that HCV can exploit the microtubule network and polymerization-related mechanisms to promote virus transport and assembly. Microtubules could thus represent a potential new target for therapeutic intervention against HCV infection (Traffic 2008; Roohvand et al, in revision)
The Interferon (IFN) inducing pathway and the control of HCV infection (E.Meurs)
HCV infection provokes activation of the cellular innate immune response, including the production of IFN, through the RNA helicase RIG-I, the mitochondria-bound adapter MAVS and the TBK1/IKKε kinases. Using an HCV full- length replicon system, we have shown showed that this RIG-I pathway is inhibited by the HCV NS3/4A protease but can be restored by the overexpression of IKKε (J Virol, 2005). HCV NS3/4A is now known to interrupt IFN induction by cleaving the mitochondria-bound adapter MAVS. We have shown that IKKε, but not TBK1, associates preferentially with MAVS at the mitochondria (Lin et al, JV, 2006). We then demonstrated that the RNA expression levels of IKKε and of some IFN-induced genes, including RIG-I, were down-regulated in liver biopsies from HCV-infected patients who were non-responders to IFN treatment, confirming that HCV preferentially replicates in cells in which the IFN-inducing pathway is impaired (Hepatology, 2006). We recently characterized the mode of interaction of IKKε with MAVS and showed the importance of IKKε in regulating the ability of MAVS to activate the NF-κB pathway (Paz et al, in revision). HCV chronic infection and inflammation favour cell transformation and progression towards liver tumorigenesis. Through a yeast two-hybrid search, we identified a cell cycle-related kinase as a partner for both MAVS and IKKε that is a previously unknown cellular regulator of the IFN inducing pathway when overexpressed (Vitour et al, submitted). We are in the process of characterizing the interactions between this kinase and MAVS at the protein level, to generate inhibitors aimed at restoring IFN-induction and inhibiting cell proliferation .
Breiman, A., N. Grandvaux, R. Lin, C. Ottone, S. Akira, M. Yoneyama, T. Fujita, J. Hiscott, and E. F. Meurs. 2005. Inhibition of RIG-I-dependent signaling to the interferon pathway during hepatitis C virus expression and restoration of signaling by IKKepsilon. J Virol 79:3969-7 (PMID: 15767399)
Maillard, P., T. Huby, U. Andreo, M. Moreau, J. Chapman, and A. Budkowska. 2006. The interaction of natural hepatitis C virus with human scavenger receptor SR-BI/Cla1 is mediated by ApoB-containing lipoproteins. Faseb J 20:735-7. (PMID: 16476701)
Vilasco, M., E. Larrea, D. Vitour, S. Dabo, A. Breiman, B. Regnault, J. I. Riezu, P. Eid, J. Prieto, and E. F. Meurs. 2006. The protein kinase IKKepsilon can inhibit HCV expression independently of IFN and its own expression is downregulated in HCV-infected livers. Hepatology 44:1635-47. (PMID: 17133498)
Andreo, U., P. Maillard, O. Kalinina, M. Walic, E.F. Meurs, M. Martinot, P. Marcellin, P., and A. Budkowska. 2007. Lipoprotein lipase mediates hepatitis C virus (HCV) cell entry and inhibits HCV infection. Cellular Microbiology 9, 2445-2456. (PMID: 17517063)
Boulant, S., M. W. Douglas, L. Moody, A. Budkowska, P. Targett-Adams, and J. McLauchlan. 2008. Hepatitis C virus core protein induces lipid droplet redistribution in a microtubule- and Dynein-dependent manner. Traffic 9:1268-82
Activity Reports 2009 - Institut Pasteur
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