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