|Hepacivirus and Innate Immunity - CNRS URA 3015|
|HEAD||Meurs Eliane, PhD / 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, Pasteur-Weizman grant / Arnaud Noëlla, PhD student Univ Paris VI, 1st year, MRT grant / Cerutti Andrea, PhD student Univ. de Piemonte Orientale (Avogadro), Novara, Italy, 2nd year (Italian Ministry or Research Grant / Walic Marine, PhD student 3rd year, Univ Paris VII, ANRS and Pasteur-Weizman grants / Laurent Tosolini, D.U.T student, Univ. Bourgogne, lab support
We investigate the interaction of hepatitis C virus (HCV) with its target cell and with the innate 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 cell entry and its intracellular transport and interactions with components of the Interferon-inducing pathway.
Mechanisms of HCV cell entry: 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. Indeed, very low density lipoproteins (VLDL) are incorporated into virus particles during virus morphogenesis, and are essential for virus cell entry. We showed that the human "scavenger receptor" SR-BI/Cla1, one of the major HCV receptors, mediates the cellular uptake of HCV not directly, by the viral envelope glycoproteins, but interacting with the virus-associated VLDL, which also ensure the virus protection against neutralising antibodies (FASEB J. 2006). We provided evidence that due to its association with VLDL, HCV is a target for the lipoprotein lipase (LPL)- a lipolytic enzyme mediating cellular uptake of lipoproteins by the liver. We showed that dimeric form of LPL mediates virus internalisation by the mechanisms which involve formation of a bridge between the virus associated lipoproteins and heparan sulfate at the cell surface (Cell. Microb. 2007). Our studies showed that LPL is a potent inhibitor of cell infection with two virus strains produced either in vitro (Huh7.5 cells) or in vivo (chimeric mice with transplanted human hepatocytes). These data suggest that LPL mediates an alternative route of virus cell entry leading to abortive infection. Thus, virus associated lipoproteins can provide a new target for inhibition of virus cell entry (M. Walic et al, submitted). We also demonstrated that HCV requires an intact and dynamic microtubule network for the initiation of a productive infection. Moreover, HCV core protein directly binds to α/β tubulin chains, enhancing tubulin polymerization and incorporates into the microtubule lattice. Thus, HCV can exploit the microtubule network by polymerization-related mechanisms, to promote virus cell entry and transport. Microtubules could thus represent a new and promising target for therapeutic intervention against HCV infection. (J.Biol. Chem. 2009).
The Interferon (IFN) inducing pathway and the control of HCV infection (E.Meurs)
Cells can sense unusual DNA, ssRNA or dsRNA structures, such as those produced during viral infections, to trigger the innate immune response through the activation of the RIG-I/MAVS signalling pathway leading to the induction of IFN and pro-inflammatory cytokines. MAVS recruits the IKK complex and the TBK1/IKKε kinases, which are responsible for the activation of the transcription factors NF-κB and IRF3/IRF7, respectively. We 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 (Mol.Cell.Biol, 2009). Chronic HCV infection and inflammation favour cell transformation and progression towards liver tumorigenesis. Through a yeast two-hybrid search, we identified the cell cycle-related kinase PLK1 as a novel regulator of MAVS and IKKε, establishing a novel link between innate immunity and cell cycle (J.Biol.Chem, 2009). Previously, we 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, showing that HCV preferentially replicates in cells in which the IFN-inducing pathway is impaired (Hepatology, 2006). HCV is known to poorly induce IFN, a phenomenon that was explained, at least in part, by the ability of the NS3/4A protease to cleave MAVS. Recently, we have identified a novel way of control of IFN induction by HCV. This occurs at the translational level, through the activation of PKR, in addition to –and earlier than -the NS3/4A-mediated MAVS cleavage (Arnaud et al, submitted). These results provide a new insight in the interaction of HCV with the innate immune pathway and point out to PKR as a novel target to restore IFN induction during HCV infection.
Keywords: Hepatitis C virus, lipoproteins, microtubules, capsid, cell cycle, PLK1, MAVS, IKK, Interferon, translation, PKR
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)
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).
F. Roohvand, P.Maillard, JP Lavergne, S. Boulant, M. Walic, U. Andréo, L.Goueslain, F. Helle, A.Mallet, J. McLauchlan and A. Budkowska. 2009. Initiation of hepatitis C virus infection requires the dynamic microtubule network: role of the viral nucleocapsid protein. J Biol Chem 284(20):13778-91.
Paz, S., M. Vilasco, M. Arguello, S. Q, J. Lacoste, T. Nguyen, T. Zhao, S. Zaari, A. Bibeau-Poirier, M. J. Servant, R. Lin, E. F. Meurs, and J. Hiscott. (2009). Ubiquitin-regulated recruitment of IKKε to MAVS interferon signaling adapter. Mol Biol Cell. 29 : 3401-12,
Vitour, D., S. Dabo, M. Ahmadi Pour, M. Vilasco, P. O. Vidalain, Y. Jacob, M. Mezel-Lemoine, S. Paz, M. Arguello, R. Lin, F. Tangy, J. Hiscott, and E. F. Meurs. 2009. Polo-like kinase 1 (PLK1) regulates interferon (IFN) induction by MAVS. J Biol Chem 284:21797-809.
Activity Reports 2009 - Institut Pasteur
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