Reduction of MicroRNA 122 Expression in
            <i>IFNL3</i>
            CT/TT Carriers and during Progression of Fibrosis in Patients with Chronic Hepatitis C

Estrabaud, Emilie; Lapalus, Martine; Broët, Philippe; Appourchaux, Kevin; Muynck, Simon De; Lada, Olivier; Martinot–Peignoux, Michelle; Bièche, Ivan; Valla, Dominique; Bédossa, Pierre; Marcellin, Patrick; Vidaud, Michel; Asselah, Tarik

doi:10.1128/jvi.00016-14

Cited by 30 publications

(39 citation statements)

References 45 publications

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“…MicroRNAs (miRNAs) are short (22–23 nucleotides) non‐coding RNAs that regulate gene expression and function through translation inhibition or degradation of target mRNA . Compelling evidence suggests that some miRNAs regulate HCV replication, immune functions and liver diseases directly by interacting with the HCV genome or indirectly via controlling virus‐associated host immune pathways . How HCV induces the expression of specific miRNAs in HCV‐infected individuals, particularly in MDSCs, to suppress immune responses and promotes viral persistence in vivo , is largely unknown.…”

Section: Introductionmentioning

confidence: 99%

Decline of miR‐124 in myeloid cells promotes regulatory T‐cell development in hepatitis C virus infection

et al. 2016

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Myeloid-derived suppressor cells (MDSCs) and microRNAs (miRNAs) contribute to attenuating immune responses during chronic viral infection; however, the precise mechanisms underlying their suppressive activities remain incompletely understood. We have recently shown marked expansion of MDSCs that promote regulatory T (Treg) cell development in patients with chronic hepatitis C virus (HCV) infection. Here we further investigated whether the HCV-induced expansion of MDSCs and Treg cells is regulated by an miRNA-mediated mechanism. The RNA array analysis revealed that six miRNAs were up-regulated and six miRNAs were down-regulated significantly in myeloid cells during HCV infection. Real-time RT-PCR confirmed the down-regulation of miR-124 in MDSCs from HCV patients. Bioinformatic analysis suggested that miR-124 may be involved in the regulation of signal transducer and activator of transcription 3 (STAT-3), which was overexpressed in MDSCs from HCV patients. Notably, silencing of STAT-3 significantly increased the miR-124 expression, whereas reconstituting miR-124 decreased the levels of STAT-3, as well as interleukin-10 and transforming growth factor-β, which were overexpressed in MDCSs, and reduced the frequencies of Foxp3 Treg cells that were developed during chronic HCV infection. These results suggest that reciprocal regulation of miR-124 and STAT-3 in MDSCs promotes Treg cell development, thus uncovering a novel mechanism for the expansion of MDSC and Treg cells during HCV infection.

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Section: Introductionmentioning

confidence: 99%

Decline of miR‐124 in myeloid cells promotes regulatory T‐cell development in hepatitis C virus infection

et al. 2016

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“…For example, changes in circulating miR-122 abundance have been reported in persons with chronic HCV infection and also in drug-induced liver injury (40) and nonalcoholic steatohepatitis (47). In addition, serum miR-122 levels in persons with chronic HCV infection who were treated with interferon and attained a sustained virologic response were higher than those in persons who had a null response (49,50), and these results were explained largely by the genetic susceptibility marker near the IFNL3 gene. In contrast, we did not find an association between the change in miR-122 levels upon acute infection and the outcome of infection or IFNL3 genotype (see Fig.…”

Section: Discussionmentioning

confidence: 85%

Acute Hepatitis C Virus Infection Induces Consistent Changes in Circulating MicroRNAs That Are Associated with Nonlytic Hepatocyte Release

El-Diwany

Wasilewski

Witwer

et al. 2015

J Virol

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Plasma microRNAs (miRNAs) change in abundance in response to disease and have been associated with liver fibrosis severity in chronic hepatitis C virus (HCV) infection. However, the early dynamics of miRNA release during acute HCV infection are poorly understood. In addition, circulating miRNA signatures have been difficult to reproduce among separate populations. We studied plasma miRNA abundance during acute HCV infection to identify an miRNA signature of early infection. We measured 754 plasma miRNAs by quantitative PCR array in a discovery cohort of 22 individuals before and during acute HCV infection and after spontaneous resolution (n ‫؍‬ 11) or persistence (n ‫؍‬ 11) to identify a plasma miRNA signature. The discovery cohort derived from the Baltimore Before and After Acute Study of Hepatitis. During acute HCV infection, increases in miR-122 (P < 0.01) and miR-885-5p (P corrected < 0.05) and a decrease in miR-494 (P corrected < 0.05) were observed at the earliest time points after virus detection. Changes in miR-122 and miR-885-5p were sustained in persistent (P < 0.001) but not resolved HCV infection. The circulating miRNA signature of acute HCV infection was confirmed in a separate validation cohort that was derived from the San Francisco-based You Find Out (UFO) Study (n ‫؍‬ 28). As further confirmation, cellular changes of signature miRNAs were examined in a tissue culture model of HCV in hepatoma cells: HCV infection induced extracellular release of miR-122 and miR-885-5p despite unperturbed intracellular levels. In contrast, miR-494 accumulated intracellularly (P < 0.05). Collectively, these data are inconsistent with necrolytic release of hepatocyte miRNAs into the plasma during acute HCV infection of humans. IMPORTANCEMicroRNAs are small noncoding RNA molecules that emerging research shows can transmit regulatory signals between cells in health and disease. HCV infects 2% of humans worldwide, and chronic HCV infection is a major cause of severe liver disease. We profiled plasma miRNAs in injection drug users before, during, and (in the people with resolution) after HCV infection. We discovered miRNA signatures of acute and persistent viremia and confirmed these findings two ways: (i) in a separate cohort of people with newly acquired HCV infection and (ii) in an HCV cell culture system. Our results demonstrate that acute HCV infection induces early changes in the abundance of specific plasma miRNAs that may affect the host response to HCV infection. H epatitis C virus (HCV) is a single-stranded positive-sense hepatotropic RNA virus that infects over 170 million people worldwide. Acute HCV infection progresses to chronic infection in ϳ75% of cases (1-3). Little is understood about early hostpathogen interactions due to a lack of representative animal models and the difficulty in studying acute HCV, which is largely asymptomatic.MicroRNAs (miRNAs) are 18-to 25-nucleotide noncoding RNA molecules with widespread gene network regulatory capacity. miRNAs are readily detectable in cell-free compo...

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“…MicroRNAs (miRNAs or miR) are noncoding 12‐ to 23‐nucleotide RNA molecules that regulate gene expression through posttranscriptional repression or target messenger RNA (mRNA) degradation . Compelling evidence has suggested that some miRNAs are able to regulate HCV replication and its related liver diseases by directly interacting with the HCV genome or indirectly controlling virus‐associated host pathways . How HCV modulates the expression of miRNAs and host cellular proteins in infected individuals, particularly in T cells for the benefit of its survival and persistence in vivo , is less understood.…”

mentioning

confidence: 99%

Hepatitis C virus–induced reduction in miR‐181a impairs CD4+ T‐cell responses through overexpression of DUSP6

Zhou

Ying

et al. 2015

Hepatology

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T cells play a crucial role for viral clearance or persistence; however, the precise mechanisms that control their responses during viral infection remain incompletely understood. microRNAs (miR) have been implicated as key regulators controlling diverse biological processes through posttranscriptional repression. Here, we demonstrate that hepatitis C virus (HCV)-mediated decline of miR-181a expression impairs CD4+ T cell responses via over-expression of dual specific phosphatase 6 (DUSP6). Specifically, a significant decline of miR-181a expression along with over-expression of DUSP6 were observed in CD4+ T cells from chronically HCV-infected individuals compared to healthy subjects, and the levels of miR-181a loss were found to be negatively associated with the levels of DUSP6 over-expression in these cells. Importantly, reconstitution of miR-181a or blockade of DUSP6 expression in CD4+ T cells led to improved T cell responses including enhanced CD25 and CD69 expressions, increased IL-2 expression, and improved proliferation of CD4+ T cells derived from chronically HCV-infected individuals. Since a decline of miR-181a concomitant with DUSP6 over-expression are the signature markers for age-associated T cell senescence, these findings provide novel mechanistic insights into HCV-mediated premature T cell aging via miR-181a-regulated DUSP6 signaling, and reveal new targets for therapeutic rejuvenation of impaired T cell responses during chronic viral infection.

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Reduction of MicroRNA 122 Expression in IFNL3 CT/TT Carriers and during Progression of Fibrosis in Patients with Chronic Hepatitis C

Cited by 30 publications

References 45 publications

Decline of miR‐124 in myeloid cells promotes regulatory T‐cell development in hepatitis C virus infection

Decline of miR‐124 in myeloid cells promotes regulatory T‐cell development in hepatitis C virus infection

Acute Hepatitis C Virus Infection Induces Consistent Changes in Circulating MicroRNAs That Are Associated with Nonlytic Hepatocyte Release

Hepatitis C virus–induced reduction in miR‐181a impairs CD4+ T‐cell responses through overexpression of DUSP6

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