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RIG-I-like receptors (RLRs) sensing of viral infections, beyond discrimination between self and non-self.

English title RIG-I-like receptors (RLRs) sensing of viral infections, beyond discrimination between self and non-self.
Applicant Garcin Dominique
Number 182347
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 01.10.2018 - 30.09.2022
Approved amount 700'000.00
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All Disciplines (2)

Discipline
Molecular Biology
Biochemistry

Keywords (6)

IRE1; RIG-I-like-receptors; Escape viral strategies; UPR; self vs non-self discrimination; innate immunity

Lay Summary (French)

Lead
La réponse immune innée doit détecter de façon spécifique une infection virale. Pour partie, cette détection est sous la dépendance de sentinelles cytoplasmiques qui ont pour rôle de discriminer entre l’ARN viral et l’ARN cellulaire. Mais sous la pression des stratégies virales d’échappement à cette détection, la cellule a dû évoluer pour générer ses propres molécules d’ARN issues du soi pour activer la réponse innée et dépasser ainsi cette simple discrimination entre le soi et le non-soi.
Lay summary
  1. Une source potentielle d’ARNs issus du soi activateur de la réponse innée est représentée par une famille de protéines constitutives du réticulum endoplasmique. Notre projet s’articule autour du rôle respectif de ces protéines dans la génération de ces ARNs qui induisent une réponse innée mais également dans la caractérisation moléculaire des ARN générés qui font qu’ils sont dorénavant reconnus comme relevant du non-soi.
  2. Nous avons caractérisé des mutations qui inactivaient la fonction d’une de ces sentinelles cytoplasmiques chez des enfants qui présentaient une grande susceptibilité aux infections respiratoires virales. Notre projet vise à étudier les mécanismes moléculaires de la restriction des virus respiratoires.  
  3. Les virus se caractérisent par leur capacité à échapper aux défenses antivirales innées. Nous allons générer un virus de souris recombinant exprimant diverses fonctions virales et étudier la pathogénèse de ces infections dans la souris afin d’appréhender le rôle de la réponse innée dans la sévérité des symptômes.

 

 

La connaissance intime des mécanismes de défenses innés contre les infections virales mais également des stratégies virales pour échapper à ces défenses doit permettre de lutter plus efficacement contre ces infections qui représentent une réelle menace.

 

Direct link to Lay Summary Last update: 02.10.2018

Responsible applicant and co-applicants

Employees

Associated projects

Number Title Start Funding scheme
163129 RIG-I sensing of viral infections: beyond discrimination between self and non-self RNAs. 01.10.2015 Project funding (Div. I-III)

Abstract

1.Project summaryBackground: The innate response is the cornerstone of the immune response against viral infections. Its role is to detect viral infection and to immediately initiate antiviral defenses and inflammatory responses; the absolute prerequisite for induction of the adaptive immune response. Part of this detection is performed by cytoplasmic sensors of the RIG-I-like receptors family (RLRs) that discriminate between dsRNA structures of viral and cellular origin. Faced with this powerful and sophisticated defense system, viruses have developed a phenomenal capacity for adaptation, making this discrimination and detection difficult. In the relentless and endless confrontation in which viruses and their host are condemned to co-evolve, detection of viral infections goes beyond simple discrimination between self and non-self dsRNAs. As part of the host’s strategy to counteract viral strategies to escape detection, cells have evolved to produce RNAs endogenously that have lost self-attributes, and thus will activate RLRs. Moreover, beyond their function of specifically binding viral RNAs, these cytoplasmic sentinels have also developed the ability to directly restrict viral replication. Of course, in this endless tit-for-tat war, viruses evolved functions to counteract these host antiviral strategies.My research goals aim at:1.IRE1 a/b dependent generation of self RNA PAMPs sensed by RLRs. One host candidate for the generation of endogenous RNA PAMP sensed by RLRs is a protein of the endoplasmic reticulum: IRE1a/b. Using in vitro approaches, we want to characterize the nature of the RNAs generated by the nuclease activity of IRE1, as well as their capacity to activate RIG-I, compared to bona fide RIG-I ligands described so far. In this context, the role of LGP2 in the regulation of RIG-I activation by these endogenous RNA PAMPs, needs to be clarified. We also want to investigate the relevance of this pathway in the detection of respiratory virus infection in airway tissues that uniquely express IRE1b. Finally, we are interested in the viral strategies targeting this pathway.2.Molecular Characterization of the restriction of viral respiratory infections by MDA5. We have characterized mutations in the gene encoding for MDA5, one of the cytoplasmic sentinels belonging to the RLR family. These loss-of-function mutations are associated with increased susceptibility to respiratory virus infections (such as hRSV) in young children, raising the question of the role of MDA5 in these infections. Besides its role in virus detection, we want to investigate the role of MDA5 and RIG-I in the direct restriction of viral replication, using in vitro approaches. We also want to characterize this restriction in cells knocked-out for MAVS (incapable of downstream signaling), to study only the restriction potential of these RLRs in vivo, as well as the viral strategies to escape this restriction.3.Characterization of hRSV NS1 and NS2 proteins. hRSV is a leading cause of acute lower respiratory tract infections in children. It is at present not clear whether severe outcomes following hRSV infections result from excessive innate responses, or from innate immune evasion. To study this, we want to use a gain of function approach. We will generate recombinant Sendai viruses expressing RSV NS1 or NS2 and characterize their pathogenesis in a mouse model and how they affect the innate immune response in various tissues.The intimate knowledge of the mechanisms involved in innate immune response, as well as the viral strategies to counteract these defenses, will hopefully allow us to conceive strategies that reinforce the first and counteract the second.
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