PACT- and RIG-I-Dependent Activation of Type I Interferon Production by a Defective Interfering RNA Derived from Measles Virus Vaccine

Ho, Ting‐Hin; Kew, Chun; Lui, Pak-Yin; Chan, Chi-Ping; Satoh, Takashi; Akira, Shizuo; Jin, Dong Yan; Kok, Kin‐Hang

doi:10.1128/jvi.02161-15

Cited by 40 publications

(47 citation statements)

References 72 publications

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“…RIG-I is triggered by binding of 5′ di-or triphosphates present on uncapped RNA or short regions of double-stranded (ds)RNA. Phosphatase treatment suppresses the ability of in vitro-transcribed copy-back DVGs to trigger IFN production following transfection supporting the role of RIG-I in DVG sensing 91,94,96 . SeV DVGs can also associate with melanoma differentiation-associated protein 5 (MDA5) 88,94 , but the role for MDA5 in sensing other DVGs is less clear 99,100 .…”

Section: Moi Multiplicity Of Infection Ratio Of Infectious Virus Tomentioning

confidence: 79%

“…Immunostimulatory DVGs can be recognized by pattern recognition receptors (PRRs), including Toll-like receptors (TLRs) and RIG-I-like receptors (RLRs). While TLR signalling is not essential for production of type I IFNs in vitro in response to DVGs, RLR signalling is required 55,88,[94][95][96][97][98] . SeV copy-back DVGs are stronger immunostimulators than deletion DVGs 89 and are among the strongest known inducers of the antiviral response.…”

Section: Moi Multiplicity Of Infection Ratio Of Infectious Virus Tomentioning

confidence: 99%

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Defective viral genomes are key drivers of the virus–host interaction

2019

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Viruses survive often harsh host environments, yet we know little about the strategies they utilize to adapt and subsist given their limited genomic resources. We are beginning to appreciate the surprising versatility of viral genomes and how replicationcompetent and -defective virus variants can provide means for adaptation, immune escape and virus perpetuation. This Review summarizes current knowledge of the types of defective viral genomes generated during the replication of RNA viruses and the functions that they carry out. We highlight the universality and diversity of defective viral genomes during infections and discuss their predicted role in maintaining a fit virus population, their impact on human and animal health, and their potential to be harnessed as antiviral tools. Review ARticleNATuRe MicRoBiology extinction interfere with replication of a wild-type viral genome 29,30 . Hypermutations and mutations leading to frame shifts also result in defective viruses 31 (Fig. 1a). One example is mutations introduced by the cellular protein APOBEC3G into pro-retroviruses 32 . APOBEC3G deaminates deoxycytidine nucleotides in the viral DNA, leading to hypermutations that interfere with the ability of the viral genome to integrate into the host genome and replicate. Interestingly, in opposition to an interfering activity for these mutated pro-viruses, it has been proposed that defective proviruses enhance fitness and that complementation among them drives viral persistence and pathogenesis 33,34 .Deletions. The genomic viral species most commonly referred to as DVGs are truncated viral genomes resulting from large internal deletions occurring during viral replication. Deletion DVGs tend to bear single large truncations that remove several or all essential genes required for self-propagation while retaining 5′ and 3′ ends as well as other RNA structural elements required for polymerase binding, replication and/or packaging [35][36][37] . Multiple variants also exist, including DVGs that can be described as 'mosaic' in that they appear to be the result of multiple recombination and rearrangement events, including deletions, insertions, duplications and even inversions of parts of the genome [38][39][40] (Fig. 1b). Copy-backs.Copy-back and snap-back DVGs are rearranged genomes in which a sequence is duplicated in reverse complement to create theoretical stem-like structures (panhandle structures for copy-back DVGs or hairpin structures for snap-back DVGs) 41-43 . Copy-back DVGs have been reported in many negative-sense (ns) RNA viruses and are generated from the 5′ end of the genome in a process that produces DVGs with complementary 3′ and 5′ termini 44,45 . If the complementary region of the DVG comprises almost the entire sequence, the DVG can be further characterized as a snap-back DVG 43 (Fig. 1c). Copy-back DVGs are predicted to be generated when the viral RNA-dependent RNA polymerase (RdRP) detaches from the template and reattaches to the nascent strand, copying back the end of the genome 42,46 .

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Section: Moi Multiplicity Of Infection Ratio Of Infectious Virus Tomentioning

confidence: 79%

Section: Moi Multiplicity Of Infection Ratio Of Infectious Virus Tomentioning

confidence: 99%

Defective viral genomes are key drivers of the virus–host interaction

2019

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“…It has been demonstrated that PACT-dependent activation of IFNβ production was inhibited by all three subunits of IAV polymerase 57,58 . In an RNP reconstitution assay, knocking down PACT in IAV-infected A549 cells enhanced vRNA production and the subsequent IFN response 59 . Of interest, there might be interplay between PACT and other viral molecules, such as the herpes simplex virus type 1 (HSV-1) Us11 protein, Middle East respiratory syndrome coronavirus (MERS-CoV) 4a and the nucleocapsid of the Ebola virus (EBOV) VP35, mouse hepatitis virus (MHV) N proteins and influenza A virus NS1 [60][61][62][63] .…”

Section: Discussionmentioning

confidence: 96%

Antiviral activity of iridoid glycosides extracted from Fructus Gardeniae against influenza A virus by PACT-dependent suppression of viral RNA replication

Guo

Bao

et al. 2020

Sci Rep

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Epidemic and pandemic influenza A virus (IAV) poses a significant threat to human populations worldwide. Iridoid glycosides are principal bioactive components from the Gardenia jasminoides J. Ellis fruit that exhibit antiviral activity against several strains of IAV. In the present study, we evaluated the protective effect of Fructus Gardeniae iridoid glycoside extracts (IGEs) against IAV by cytopathogenic effect(CPE), MTT and a plaque formation assay in vitro and examined the reduction in the pulmonary index (PI), restoration of body weight, reduction in mortality and increases in survival time in vivo.As a host factor, PACT provides protection against the pathogenic influenza A virus by interacting with IAV polymerase and activating the IFN-I response. To verify the whether IGEs suppress IAV replication in a PACT-dependent manner, IAV RNA replication, expression of PACT and the phosphorylation of eIF2α in A549 cells were detected; the levels of IFNβ, PACT and PKR in mouse lung tissues were determined; and the activity of IAV polymerase was evaluated in PACT-compromised cells. The results indicated that IGEs sufficiently alleviated cell damage and suppressed IAV replication in vitro, protecting mice from IAV-induced injury and lethal IAV infection. These anti-IAV effects might be related to disrupted interplay between IVA polymerase and PACT and/or prevention of a PACT-dependent overactivated IFN-I antiviral response. Taken together, our findings reveal a new facet of the mechanisms by which IGEs fight the influenza A virus in a PACT-dependent manner.

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“…For a wide range of human-pathogenic viruses, such as Ebola virus (EBOV), influenza A virus (IAV), Middle East respiratory syndrome coronavirus (MERS-CoV), human T-cell leukemia virus 1 (HTLV-1), mouse hepatitis virus (MHV), measles virus (MeV), and herpes simplex virus 1 (HSV-1), their viral proteins or defective interfering (DI) RNAs have been shown to modulate the PACT-mediated enhancement of the function of RIG-I to drive the expression of type I IFNs (24,(26)(27)(28)(29)(30)(31)(32). Specifically, the EBOV VP35, IAV NS1, HSV-1 Us11, MERS-CoV 4a and nucleocapsid (N), as well as MHV N proteins have been shown to directly abolish the interaction between RIG-I and PACT and, hence, block the ability of PACT to activate RIG-I (24,(26)(27)(28)(29)32).…”

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confidence: 99%

Arenaviral Nucleoproteins Suppress PACT-Induced Augmentation of RIG-I Function To Inhibit Type I Interferon Production

Shao

Huang

et al. 2018

J Virol

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RIG-I is a major cytoplasmic sensor of viral pathogen-associated molecular pattern (PAMP) RNA and induces type I interferon (IFN) production upon viral infection. A double-stranded RNA (dsRNA)-binding protein, PACT, plays an important role in potentiating RIG-I function. We have shown previously that arenaviral nucleoproteins (NPs) suppress type I IFN production via their RNase activity to degrade PAMP RNA. We report here that NPs of arenaviruses block the PACT-induced enhancement of RIG-I function to mediate type I IFN production and that this inhibition is dependent on the RNase function of NPs, which is different from that of a known mechanism of other viral proteins to abolish the interaction between PACT and RIG-I. To understand the biological roles of PACT and RIG-I in authentic arenavirus infection, we analyze growth kinetics of recombinant Pichinde virus (PICV), a prototypical arenavirus, in RIG-I knockout (KO) and PACT KO mouse embryonic fibroblast (MEF) cells. Wild-type (WT) PICV grew at higher titers in both KO MEF lines than in normal MEFs, suggesting the important roles of these cellular proteins in restricting virus replication. PICV carrying the NP RNase catalytically inactive mutation could not grow in normal MEFs but could replicate to some extent in both KO MEF lines. The level of virus growth was inversely correlated with the amount of type I IFNs produced. These results suggest that PACT plays an important role in potentiating RIG-I function to produce type I IFNs in order to restrict arenavirus replication and that viral NP RNase activity is essential for optimal viral replication by suppressing PACT-induced RIG-I activation. We report here a new role of the nucleoproteins of arenaviruses that can block type I IFN production via their specific inhibition of the cellular protein sensors of virus infection (RIG-I and PACT). Our results suggest that PACT plays an important role in potentiating RIG-I function to produce type I IFNs in order to restrict arenavirus replication. This new knowledge can be exploited for the development of novel antiviral treatments and/or vaccines against some arenaviruses that can cause severe and lethal hemorrhagic fever diseases in humans.

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PACT- and RIG-I-Dependent Activation of Type I Interferon Production by a Defective Interfering RNA Derived from Measles Virus Vaccine

Cited by 40 publications

References 72 publications

Defective viral genomes are key drivers of the virus–host interaction

Defective viral genomes are key drivers of the virus–host interaction

Antiviral activity of iridoid glycosides extracted from Fructus Gardeniae against influenza A virus by PACT-dependent suppression of viral RNA replication

Arenaviral Nucleoproteins Suppress PACT-Induced Augmentation of RIG-I Function To Inhibit Type I Interferon Production

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