Hepatitis-C-virus-induced microRNAs dampen interferon-mediated antiviral signaling

Jarret, Abigail; McFarland, Adelle P.; Horner, Stacy M.; Kell, Alison; Schwerk, Johannes; Hong, MeeAe; Badil, Samantha; Joslyn, Rochelle C; Baker, Darren P.; Carrington, Mary; Hagedorn, Curt H.; Gale, Michael; Savan, Ram

doi:10.1038/nm.4211

Cited by 41 publications

(30 citation statements)

References 42 publications

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“…In support of this finding, miR‐146a expression is decreased in SLE patients compared to healthy controls . miR‐29a, miR‐208b, and miR‐499a‐5p are reported to target the IFNAR1 3′UTR, leading to a substantial decrease in IFNAR1 protein expression . miR‐221 and miR‐222 have also been identified as negative regulator of STAT1 and STAT2 .…”

Section: Type I Ifn Response and Its Regulationmentioning

confidence: 64%

Negative regulation of type I IFN signaling

Arimoto

Miyauchi

Stoner

et al. 2018

Journal of Leukocyte Biology

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Type I IFNs (α, β, and others) are a family of cytokines that are produced in physiological conditions as well as in response to the activation of pattern recognition receptors. They are critically important in controlling the host innate and adaptive immune response to viral and some bacterial infections, cancer, and other inflammatory stimuli. However, dysregulation of type I IFN production or response can contribute to immune pathologies termed "interferonopathies", pointing to the importance of balanced activating signals with tightly regulated mechanisms of tuning this signaling. Here, we summarize the recent advances of how type I IFN production and response are controlled at multiple levels of the type I IFN signaling cascade.

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Section: Type I Ifn Response and Its Regulationmentioning

confidence: 64%

Negative regulation of type I IFN signaling

Arimoto

Miyauchi

Stoner

et al. 2018

Journal of Leukocyte Biology

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“…HCV also enhances hepatic expression of miR-208b and miR-499a-5p, two “myomiRs” encoded in the introns of myosin-encoding genes 40 . These “myomiRs” depress both type I and III IFNs 40 , 41 . Nevertheless, the induction of miR-208b or miR-499a-5p by HCV was not observed in our transcriptome analyses.…”

Section: Discussionmentioning

confidence: 99%

Cellular microRNA networks regulate host dependency of hepatitis C virus infection

Lowey

Sodroski

et al. 2017

Nat Commun

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Cellular microRNAs (miRNAs) have been shown to regulate hepatitis C virus (HCV) replication, yet a systematic interrogation of the repertoire of miRNAs impacting HCV life cycle is lacking. Here we apply integrative functional genomics strategies to elucidate global HCV–miRNA interactions. Through genome-wide miRNA mimic and hairpin inhibitor phenotypic screens, and miRNA–mRNA transcriptomics analyses, we identify three proviral and nine antiviral miRNAs that interact with HCV. These miRNAs are functionally linked to particular steps of HCV life cycle and related viral host dependencies. Further mechanistic studies demonstrate that miR-25, let-7, and miR-130 families repress essential HCV co-factors, thus restricting viral infection at multiple stages. HCV subverts the antiviral actions of these miRNAs by dampening their expression in cell culture models and HCV-infected human livers. This comprehensive HCV–miRNA interaction map provides fundamental insights into HCV-mediated pathogenesis and unveils molecular pathways linking RNA biology to viral infections.

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“…The T allele leads to changes in the 3′ UTR allowing for enhanced binding of these HCV-induced microRNAs and AU-rich element-mediated decay of IFNL3 , impacting expression of the cytokine and the outcome of HCV infection. Intriguingly, these same microRNAs also dampen type I IFN signaling in HCV-infected hepatocytes by downregulating expression of IFNAR1, a mechanism distinct from miR-208b and miR-499a-5p regulation of type III IFN ( 104 ).…”

Section: Genetic Association Of Ifn Lambda Locus To Viral Susceptibilmentioning

confidence: 99%

Interferon Lambda Genetics and Biology in Regulation of Viral Control

2017

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Type III interferons, also known as interferon lambdas (IFNλs), are the most recent addition to the IFN family following their discovery in 2003. Initially, IFNλ was demonstrated to induce expression of interferon-stimulated genes and exert antiviral properties in a similar manner to type I IFNs. However, while IFNλ has been described to have largely overlapping expression and function with type I IFNs, it has become increasingly clear that type III IFNs also have distinct functions from type I IFNs. In contrast to type I IFNs, whose receptor is ubiquitously expressed, type III IFNs signal and function largely at barrier epithelial surfaces, such as the respiratory and gastrointestinal tracts, as well as the blood–brain barrier. In further support of unique functions for type III IFNs, single nucleotide polymorphisms in IFNL genes in humans are strongly associated with outcomes to viral infection. These biological linkages have also been more directly supported by studies in mice highlighting roles of IFNλ in promoting antiviral immune responses. In this review, we discuss the current understanding of type III IFNs, and how their functions are similar to, and different from, type I IFN in various immune cell subtypes and viral infections.

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Hepatitis-C-virus-induced microRNAs dampen interferon-mediated antiviral signaling

Cited by 41 publications

References 42 publications

Negative regulation of type I IFN signaling

Negative regulation of type I IFN signaling

Cellular microRNA networks regulate host dependency of hepatitis C virus infection

Interferon Lambda Genetics and Biology in Regulation of Viral Control

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