Innate immunity; PAMP ; PRR; Paramyxovirus; Arenavirus; IFN antagonists
Pourcelot Marie, Zemirli Naima, Silva Da Costa Leandro, Loyant Roxane, Garcin Dominique, Vitour Damien, Munitic Ivana, Vazquez Aimé, Arnoult Damien (2016), The Golgi apparatus acts as a platform for TBK1 activation after viral RNA sensing., in BMC biology
, 14, 69-69.
Anchisi Stéphanie, Guerra Jessica, Mottet-Osman Geneviève, Garcin Dominique (2015), Mismatches in the Influenza A Virus RNA Panhandle Prevent Retinoic Acid-Inducible Gene I (RIG-I) Sensing by Impairing RNA/RIG-I Complex Formation., in Journal of virology
, 90(1), 586-90.
Anchisi Stéphanie, Guerra Jessica, Garcin Dominique (2015), RIG-I ATPase activity and discrimination of self-RNA versus non-self-RNA., in mBio
, 6(2), 02349-02349.
Széles Lajos, Meissner Felix, Dunand-Sauthier Isabelle, Thelemann Christoph, Hersch Micha, Singovski Simon, Haller Sergio, Gobet Florian, Fuertes Marraco Silvia A, Mann Matthias, Garcin Dominique, Acha-Orbea Hans, Reith Walter (2015), TLR3-Mediated CD8+ Dendritic Cell Activation Is Coupled with Establishment of a Cell-Intrinsic Antiviral State., in Journal of immunology (Baltimore, Md. : 1950)
, J Immunol. 2015 Jun 22. pii: 1402033. [Epub ahead (J Immunol.), J Immunol.-J Immunol..
Kolakofsky Daniel, Garcin Dominique (2015), γHV68 vGAT: a viral pseudoenzyme pimping for PAMPs., in Molecular cell
, 58(1), 3-4.
Castanier Céline, Zemirli Naima, Portier Alain, Garcin Dominique, Bidère Nicolas, Vazquez Aimé, Arnoult Damien (2012), MAVS ubiquitination by the E3 ligase TRIM25 and degradation by the proteasome is involved in type I interferon production after activation of the antiviral RIG-I-like receptors., in BMC biology
, 10, 44-44.
Nishio Machiko, Tsurudome Masato, Garcin Dominique, Komada Hiroshi, Ito Morihiro, Le Mercier Philippe, Nosaka Tetsuya, Kolakofsky Daniel (2011), Human parainfluenza virus type 2 L protein regions required for interaction with other viral proteins and mRNA capping., in Journal of virology
, 85(2), 725-32.
Le Thuc-vy L, Mironova Elena, Garcin Dominique, Compans Richard W (2011), Induction of influenza-specific mucosal immunity by an attenuated recombinant Sendai virus., in PloS one
, 6(4), 18780-18780.
Rawling Joanna, Cano Olga, Garcin Dominique, Kolakofsky Daniel, Melero José A (2011), Recombinant Sendai viruses expressing fusion proteins with two furin cleavage sites mimic the syncytial and receptor-independent infection properties of respiratory syncytial virus., in Journal of virology
, 85(6), 2771-80.
Marq Jean-Baptiste, Hausmann Stéphane, Veillard Nicolas, Kolakofsky Daniel, Garcin Dominique (2011), Short double-stranded RNAs with an overhanging 5' ppp-nucleotide, as found in arenavirus genomes, act as RIG-I decoys., in The Journal of biological chemistry
, 286(8), 6108-16.
The molecular basis of ligand recognition by RIG-I and viral escape strategies1.Summary1.1BackgroundViral infections are responsible for extensive human and animal suffering and death, resulting in heavy human and economic cost. Very few antiviral molecules are available and more importantly escape mutants resistant to existing antiviral agents generally emerge rapidly for RNA viruses, due to their high mutation rate. On the other hand, one of the first line of defense against viral infection is innate immunity. Therefore detailed knowledge of how this first line of defense is established and how viruses escape these antiviral defenses, is critical to understand how to prevent viral infection. Recent developments in this field now hold the promise of fighting viral infections by enhancing the innate immune response. Innate immunity starts with the specific detection of a pathogen. Detection of specific “non-self” viral nucleic acid in the cytoplasm involves cytosolic pattern recognition receptors (PRRs) including the RNA-sensing RIG-like helicases (RLHs), RIG-I, MDA-5, LGP2.1.2Working hypothesesViral strategies to escape detection by RIG-I clearly represent an interesting approach. Viruses are probably the best molecular biologists; they are professionals in handling cellular metabolic pathways, either to escape or fight these pathways, or to divert them to their own benefit. They are thus an invaluable source of information on these cellular pathways. Work from our laboratory and others has led us to elaborate a working model in which RIG-I first binds dsRNA, then moves in an ATP dependent fashion to locate and interact with its end. A blunt 5’ppp-dsRNA-end leads to productive RIG-I conformational changes and full IFN-ß induction(at least for short dsRNAs). For long dsRNAs devoid of blunt 5’ppp-ends, the stabilization of the RIG-I/dsRNA (required for activation of RIG-I and IFN-ß induction), appears to be somehow related to the length of this dsRNA. We propose to test this model and also to study what exactly are the pathogen associated molecular patterns (PAMPs) of paramyxovirus and arenavirus infections.1.3Specific aims and experimental designWe will develop two important aspects of our work: i)Molecular basis of ligand recognition by RIG-I and escape viral strategies. In vitro and in vivo RNA binding experiments to RIG-I will be performed using either mutated bacterially purified RIG-I or transfected RIG-I. Arenavirus infection will be used to further characterize the ligand sensed by RIG-I and to study the Arenavirus decoy strategy in the context of a viral infection. In vivo and in vitro RNA binding assays will also be used to characterize the RNA ligand of viral proteins (such as vaccinia virus E3L, influenza virus NS1…) involved in blocking RIG-I activation and whose function clearly depends on the integrity of their dsRNA binding domain. ii)The “real” PAMP in paramyxovirus infection. The exact nature of the PAMP(s) generated during Paramyxovirus infection is still a subject of debate. Virus stocks of either non defective genomes or internal deletion defective interfering genomes (DI) or copy back DI genomes carrying mutations in the L terminal sequence will be generated and analyzed for their ability to induce IFN-ß. The nature of the PAMP bound to RIG-I will be further characterized in those infections.