Cytosolic Sensing of Viruses

Immunobiology Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
Immunity (Impact Factor: 21.56). 05/2013; 38(5):855-869. DOI: 10.1016/j.immuni.2013.05.007
Source: PubMed


Cells are equipped with mechanisms that allow them to rapidly detect and respond to viruses. These defense mechanisms rely partly on receptors that monitor the cytosol for the presence of atypical nucleic acids associated with virus infection. RIG-I-like receptors detect RNA molecules that are absent from the uninfected host. DNA receptors alert the cell to the abnormal presence of that nucleic acid in the cytosol. Signaling by RNA and DNA receptors results in the induction of restriction factors that prevent virus replication and establish cell-intrinsic antiviral immunity. In light of these formidable obstacles, viruses have evolved mechanisms of evasion, masking nucleic acid structures recognized by the host, sequestering themselves away from the cytosol or targeting host sensors, and signaling adaptors for deactivation or degradation. Here, we detail recent advances in the molecular understanding of cytosolic nucleic acid detection and its evasion by viruses.

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    • "During pathogen infection, these PRRs confer the recognition of PAMPs and then trigger the downstream signaling cascade to alert the immune system to take necessary countermeasures. RLRs, a pivotal cytosolic antiviral immune PRR family, contains three members: retinoic acid-inducible gene I (RIG-I), melanoma differentiation-associated gene 5 (MDA5) and laboratory of genetics and physiology 2 (LGP2) [2]. MDA5 and RIG-I have homologous core structural domains including two tandem caspase activation recruitment domains (CARD), a central DExD/H box RNA helicase domain and a C-terminal repressor domain (RD) [3] [4]. "
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    ABSTRACT: Melanoma differentiation-associated gene 5 (MDA5) is a member of retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) family which can initiate type I IFN expression in response to RNA virus infection. In this study, we constructed six mutants of Ctenopharyngodon idella MDA5 (CiMAD5) overexpression plasmids and generated stable transfected Ctenopharyngodon idella kidney (CIK) cell lines to study the function of different domains of CiMAD5. After ploy(I:C) stimulation, the downstream genes of CiMDA5 in transfected cells was repressed. Overexpression of CiMDA5 or its variant repressed the replication of grass carp reovirus (GCRV) in CIK cells and decreased the viral titer of GCRV more or less compared to that in control cells. After GCRV or bacterial pathogen-associated molecular patterns (PAMPs) stimulation, overexpression of CiMDA5 or CARD domain significantly induced the expression of CiIFN-I, CiIL-1β and CiMx1. The deletion of Helicase or RD domain reduced the inductive effect of CiMDA5 on CiIFN-I, CiIL-1β and CiMx1 expression. RD overexpression resulted in an enhanced expression of CiIFN-I, CiIL-1β and CiMx1. These observations collectively demonstrate that, in CIK cells, after GCRV or bacterial PAMPs stimulation, CARD domain alone can mediate signaling; Helicase or RD domain alone is negatively regulates CARD function by intramolecular interaction with CARD. However, RD domain acts as an enhancer by intermolecular interaction. These results enlarge the response spectrum of MDA5 and contribute to a further understanding of the functions of MDA5 and its domains in evolution. Copyright © 2015. Published by Elsevier Ltd.
    Fish &amp Shellfish Immunology 08/2015; 46(2). DOI:10.1016/j.fsi.2015.08.005 · 2.67 Impact Factor
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    • "RLRs initiate signaling through IFNb-promoter stimulator-1 (IPS-1, also named Cardif, MAVS or VISA), leading to the activation of IFN regulatory factor (IRF) and nuclear factor-jB (NF-jB) pathways. Activation of the transcription factors IRF3, IRF7 and NF-jB is responsible for the transcription of genes coding for type I IFNs (IFNa and IFNb) and pro-inflammatory cytokines like IL-6 or TNFa, respectively [5]. These processes constitute the first steps of the innate response giving rise to an anti-viral defense within infected tissues, prior the intervention of the adaptive immune system. "
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    ABSTRACT: Viral triggering of the innate immune response in infected cells aims at delaying viral replication and prevents tissue spreading. Viral replication is delayed by host protein synthesis inhibition and infected cell apoptosis on one hand, while infection spreading is controlled by the synthesis of specific proteins like type-I interferons (IFNs) and pro-inflammatory cytokines on the other hand. How do these two apparent conflicting responses cooperate within the same infected cells to mount effective defenses against pathogens? What are the molecules or the complexes resolving this contradiction over time? Some recent studies reveal unanticipated connections between innate immunity and stress pathways, giving important clues on how the cellular responses are orchestrated to limit infection efficiently. Copyright © 2015. Published by Elsevier B.V.
    FEBS letters 05/2015; 11(14). DOI:10.1016/j.febslet.2015.05.006 · 3.17 Impact Factor
    • " - I , MDA5 , or their variants and challenged with the viruses engineered to express a reporter gene , GFP , or with wild - type non - reporter IAV . Effi - ciency of virus spread , as measured by the number of GFP - or anti - IAV - NP - positive cells , was assessed ( Figure 4A ) . Consistent with their reported divergence in viral specificity ( Goubau et al . , 2013 ; Kato et al . , 2011 ) , full - length RIG - I and MDA5 suppressed different families of RNA viruses ( Figure 4A"
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    ABSTRACT: The vertebrate antiviral innate immune system is often considered to consist of two distinct groups of proteins: pattern recognition receptors (PRRs) that detect viral infection and induce the interferon (IFN) signaling, and effectors that directly act against viral replication. Accordingly, previous studies on PRRs, such as RIG-I and MDA5, have primarily focused on their functions in viral double-stranded RNA (dsRNA) detection and consequent antiviral signaling. We report here that both RIG-I and MDA5 efficiently displace viral proteins pre-bound to dsRNA in a manner dependent on their ATP hydrolysis, and that this activity assists a dsRNA-dependent antiviral effector protein, PKR, and allows RIG-I to promote MDA5 signaling. Furthermore, truncated RIG-I/MDA5 lacking the signaling domain, and hence the IFN stimulatory activity, displaces viral proteins and suppresses replication of certain viruses in an ATP-dependent manner. Thus, this study reveals novel "effector-like" functions of RIG-I and MDA5 that challenge the conventional view of PRRs. Copyright © 2015 Elsevier Inc. All rights reserved.
    Molecular cell 04/2015; 58(3). DOI:10.1016/j.molcel.2015.03.014 · 14.02 Impact Factor
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