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RIG-I sensing of viral infections: beyond discrimination between self and non-self RNAs.

English title RIG-I sensing of viral infections: beyond discrimination between self and non-self RNAs.
Applicant Garcin Dominique
Number 163129
Funding scheme Project funding (Div. I-III)
Research institution Dépt Microbiologie et Médecine Moléculaire Faculté de Médecine Université de Genève
Institution of higher education University of Geneva - GE
Main discipline Molecular Biology
Start/End 01.10.2015 - 30.09.2018
Approved amount 525'000.00
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All Disciplines (2)

Discipline
Molecular Biology
Biochemistry

Keywords (9)

PRR; RLR ; UPR; IRE1 RNase; RNase L; Interferon; Innate immunity; LGP2; Rig-I

Lay Summary (French)

Lead
Dans le cadre du lien de dépendance absolue qu’entretient un virus avec son hôte, les deux organismes concernés se doivent de coévoluer au risque de leur extinction. Cette éternelle bataille met en jeu d’un côté les défenses immunes de l’hôte, et tout particulièrement la première d’entre elles, l’immunité innée, et de l’autre côté, un foisonnement de stratégies virales pour échapper ou lutter contre ces dernières. La connaissance intime des mécanismes mis en jeu ainsi que des stratégies virales pour y échapper sont primordiaux afin de lutter efficacement contre ces infections virales pour lesquelles il n’existe que très peu d’agents antiviraux en regard d’une capacité exceptionnelle des virus à générer des souches résistantes.
Lay summary

Les virus sont des parasites obligatoires dont la multiplication et la propagation dépendent exclusivement de la machinerie de la cellule hôte. La conséquence est que la totalité des composants viraux dérive de cette même cellule hôte rendant la détection de ces virus en tant qu’agent infectieux étranger par le système immun inné très difficile. Or cette détection est déterminante pour la mise en place de la réponse immune dans toutes ses composantes. Une partie essentielle de cette détection passe par la discrimination par des récepteurs cellulaires spécialisés entre des ARN viraux se référant au non-Soi et un océan d’ARN cellulaires constituant du Soi.

Notre projet scientifique s’articule autour de la discrimination entre les ARN viraux et les ARN cellulaires, de l’activation et la régulation des récepteurs cellulaires en charges de cette détection ainsi que de la formidable capacité des virus à évoluer pour s’adapter à ce déploiement de mesures antivirales lui même en constante évolution.  

 

Direct link to Lay Summary Last update: 12.10.2015

Responsible applicant and co-applicants

Employees

Publications

Publication
IFN-λ prevents influenza virus spread from the upper airways to the lungs and limits virus transmission
Klinkhammer Jonas, Schnepf Daniel, Ye Liang, Schwaderlapp Marilena, Gad Hans Henrik, Hartmann Rune, Garcin Dominique, Mahlakõiv Tanel, Staeheli Peter (2018), IFN-λ prevents influenza virus spread from the upper airways to the lungs and limits virus transmission, in eLife, 7, 1.
Severe viral respiratory infections in children with IFIH1 loss-of-function mutations
Asgari Samira, Schlapbach Luregn J., Anchisi Stéphanie, Hammer Christian, Bartha Istvan, Junier Thomas, Mottet-Osman Geneviève, Posfay-Barbe Klara M., Longchamp David, Stocker Martin, Cordey Samuel, Kaiser Laurent, Riedel Thomas, Kenna Tony, Long Deborah, Schibler Andreas, Telenti Amalio, Tapparel Caroline, McLaren Paul J., Garcin Dominique, Fellay Jacques (2017), Severe viral respiratory infections in children with IFIH1 loss-of-function mutations, in Proceedings of the National Academy of Sciences, 114(31), 8342-8347.
Loss of Sendai virus C protein leads to accumulation of RIG-I immunostimulatory defective interfering RNA
Sánchez-Aparicio Maria Teresa, Garcin Dominique, Rice Charles M., Kolakofsky Daniel, García-Sastre Adolfo, Baum Alina (2017), Loss of Sendai virus C protein leads to accumulation of RIG-I immunostimulatory defective interfering RNA, in Journal of General Virology, 98(6), 1282-1293.
Mismatches in the Influenza A Virus RNA Panhandle Prevent Retinoic Acid-Inducible Gene I (RIG-I) Sensing by Impairing RNA/RIG-I Complex Formation
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), 586-590.
RIG-I ATPase Activity and Discrimination of Self-RNA versus Non-Self-RNA
Anchisi Stéphanie, Guerra Jessica, Garcin Dominique (2015), RIG-I ATPase Activity and Discrimination of Self-RNA versus Non-Self-RNA, in mBio, 6(2), 1.

Collaboration

Group / person Country
Types of collaboration
Laboratory of Prof. Jacques Fellay, EPFL, Lausanne Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Laboratory of Prof. Walter Reith, Faculty of Medicine, Geneva Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Origène Nyanguile. Hes.so, Institute of Life Technologies, Sion Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Industry/business/other use-inspired collaboration

Scientific events



Self-organised

Title Date Place
Negative Strand Virus meeting 17.06.2018 Verona, Italy

Associated projects

Number Title Start Funding scheme
135467 The molecular basis of ligand recognition by RIG-I and viral escape strategies 01.04.2011 Project funding (Div. I-III)
182347 RIG-I-like receptors (RLRs) sensing of viral infections, beyond discrimination between self and non-self. 01.10.2018 Project funding (Div. I-III)

Abstract

RIG-I sensing of viral infections: beyond discrimination between self and non-self RNAs. 1. Summary of research plansViral infections are responsible for extensive human and animal suffering and death, resulting in heavy human and economic cost. Moreover, 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. One of the first lines of defense against viral infection is innate immunity. Detailed knowledge of how this first line of defense is established and how viruses escape these antiviral defenses is therefore critical to understand how to prevent viral infection. The crucial step that determines the entire immune response is the detection phase of the viral infection. It involves specific detection of nucleotidic molecular signatures inherent in viral infections. Because this step is crucial, it is the focus of a constant battle between the viruses and the infected host cells. In the past we have studied the mechanisms that trigger the innate immune response through its sensor RIG-I, as well as the viral strategies to escape RIG-I detection. This project represents a continuation of these studies.My research goals aim at: 1.The identification and characterization of the RNA PAMPs (pathogen-associated molecular pattern) that activates RIG-I in vivo during the course of a viral infection. One cellular strategy to overcome the ability of viruses to develop means to prevent formation of detectable viral RNA PAMPs, is to produce their own RNA PAMPs in response to infections. For that purpose, cells can use a number of cellular RNases such as RNaseL or RNases associated with the unfolded stress response (UPR) that is very often activated in response to viral infections. This project is focused on two major hinges: i) The importance of the cellular RNases involved in the UPR for the generation of RNAs sensed by RIG-I, and ii) the nature and origin (viral and/or cellular) of the RNA PAMPS generated by these RNases and how they activate RIG-I.2.The study of RIG-I ATPase activity: self vs non-self RNA discrimination and effector functions. LGP2 appears to regulate RIG-I activation and ability to discriminate between self and non-self PAMPs. We want to study at three levels the mechanisms by which LGP2 promotes ATPase dependent RIG-I recycling: i) at the level of the RNA (self vs non-self RNA discrimination), ii) at the level of the RIG-I ATPase activity, and iii) at the level of the RIG-I-LGP2 interface by the identification of the amino-acids on both proteins involved in this function. We also want to study the potential ATPase dependent remodelling activities of RIG-I and LGP2, and their respective contributions to direct antiviral effector functions. 3.The study of viral evolutionary potential triggered by the confrontation with host cell innate immunity. We want to use the evolutionary capacity of viruses to select for natural mutations in genes coding for cellular innate immune components. For that purpose we built a recombinant virus expressing a cellular gene involved in the antiviral innate response (coding for the mitochondrial protein MAVS), and will passage the virus several times in selective conditions (i.e. IFN competent cells). Escape mutations both in the cellular gene and in the viral genome will be identified and characterized.
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