<scp>IL</scp>28B genotype and the expression of <scp>ISG</scp>s in normal liver

Raglow, Zoe; Thoma-Perry, Carly; Gilroy, Richard; Wan, Yu‐Jui Yvonne

doi:10.1111/liv.12148

Cited by 17 publications

(14 citation statements)

References 39 publications

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“…Clearance under therapy was not associated here (data not shown). Association of IRAK2 rs3844283 with spontaneous clearance but not clearance under IFN‐based therapy is in line with the notion that IRAK2 acts upstream of IFN signaling and IFN‐stimulated gene regulation, whereas some IL28B genotypes, which are associated with both, also appear to influence the latter . On average, about 10%‐20% of infected individuals are able to clear HCV infection spontaneously .…”

Section: Discussionsupporting

confidence: 81%

“…Association of IRAK2 rs3844283 with spontaneous clearance but not clearance under IFN-based therapy is in line with the notion that IRAK2 acts upstream of IFN signaling and IFN-stimulated gene regulation, 1,3 whereas some IL28B genotypes, which are associated with both, also appear to influence the latter. [44][45][46][47][48] On average, about 10%-20% of infected individuals are able to clear HCV infection spontaneously. 49 The remainder follows a chronic course of infection, thus facing long-term morbidities such as hepatocellular carcinoma or liver cirrhosis.…”

Section: Discussionmentioning

confidence: 99%

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A frequent hypofunctional IRAK2 variant is associated with reduced spontaneous hepatitis C virus clearance

et al. 2015

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Patients carrying very rare loss‐of‐function mutations in interleukin‐1 receptor–associated kinase 4 (IRAK4), a critical signaling mediator in Toll‐like receptor signaling, are severely immunodeficient, highlighting the paramount role of IRAK kinases in innate immunity. We discovered a comparatively frequent coding variant of the enigmatic human IRAK2, L392V (rs3844283), which is found homozygously in ∼15% of Caucasians, to be associated with a reduced ability to induce interferon‐alpha in primary human plasmacytoid dendritic cells in response to hepatitis C virus (HCV). Cytokine production in response to purified Toll‐like receptor agonists was also impaired. Additionally, rs3844283 was epidemiologically associated with a chronic course of HCV infection in two independent HCV cohorts and emerged as an independent predictor of chronic HCV disease. Mechanistically, IRAK2 L392V showed intact binding to, but impaired ubiquitination of, tumor necrosis factor receptor–associated factor 6, a vital step in signal transduction. Conclusion: Our study highlights IRAK2 and its genetic variants as critical factors and potentially novel biomarkers for human antiviral innate immunity. (Hepatology 2015;62:1375–1387)

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Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

A frequent hypofunctional IRAK2 variant is associated with reduced spontaneous hepatitis C virus clearance

et al. 2015

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“…We observed a significant enrichment in cell death related genes in cells from donors with IFNL major alleles. Recent clinical studies report a higher basal ISG expression in non-infected livers of patients with IFNL3 major alleles (Raglow et al, 2013) and chronically infected major allele patients exhibit increased liver necroinflammation and poorer clinical outcomes as compared to patients with minor alleles (Noureddin et al, 2013). Taken together, these data collectively suggest that innate genotype dependent differences could make hepatocytes more poised to respond to infection through activation of cell death and/or antiviral programs.…”

Section: Discussionmentioning

confidence: 99%

Interferon Lambda Alleles Predict Innate Antiviral Immune Responses and Hepatitis C Virus Permissiveness

Sheahan

Imanaka

Marukian

et al. 2014

Cell Host & Microbe

102

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Summary Hepatitis C virus (HCV) infection can result in viral chronicity or clearance. Although host genetics and particularly genetic variation in the interferon lambda (IFNL) locus are associated with spontaneous HCV clearance and treatment success, the mechanisms guiding these clinical outcomes remain unknown. Using a laser capture microdissection-driven unbiased systems virology approach, we isolated and transcriptionally profiled HCV-infected and adjacent primary human hepatocytes (PHH) approaching single cell resolution. An innate antiviral immune signature dominated the transcriptional response, but differed in magnitude and diversity between HCV-infected and adjacent cells. Molecular signatures associated with more effective antiviral control were determined by comparing donors with high and low infection frequencies. Cells from donors with clinically unfavorable IFNL genotypes were infected at a greater frequency and exhibited dampened antiviral and cell death responses. These data suggest that early virus-host interactions, particularly host genetics and induction of innate immunity, critically determine the outcome of HCV infection.

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“…4). As the SNPs in IFNL3 do appear to impact IFNL3 expression [6][7]70,[77][78]82 , it is unlikely that these SNPs are simply in linkage disequilibrium with some other gene involved in HCV pathogenesis. Defining how IFNL3 polymorphisms enhance HCV therapy response rates will be important for the development of new therapeutic strategies to suppress HCV through treatment with recombinant IFN-λ and to better understand the role of IFNL3 in the host response to HCV infection.…”

Section: Host Genetic Components That Determine the Outcome Of Hcv Inmentioning

confidence: 99%

Regulation of hepatic innate immunity by hepatitis C virus

Horner

Gale

2013

Nat Med

253

288

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Hepatitis C virus (HCV) is a global public health problem involving chronic infection of the liver in over 170 million people. Chronic HCV causes liver disease and is linked with liver cancer. Viral innate immune evasion strategies and human genetic determinants underlie the transition of acute HCV infection to viral persistence and the support of chronic infection. Host genetic factors, such as sequence polymorphisms in IFNL3, a gene in the host interferon system, can influence both the outcome of infection and response to antiviral therapy. Recent insights into how HCV regulates innate immune signaling within the liver reveal a complex interaction of patient genetic background with viral and host factors of innate immune triggering and control that impart the outcome of HCV infection and immunity.

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IL28B genotype and the expression of ISGs in normal liver

Abstract: A subset of ISGs was found to be differentially expressed in normal liver by IL28B genotype. This suggests a relationship between IL28B genotype and gene expression before HCV infection.

Cited by 17 publications

References 39 publications

A frequent hypofunctional IRAK2 variant is associated with reduced spontaneous hepatitis C virus clearance

A frequent hypofunctional IRAK2 variant is associated with reduced spontaneous hepatitis C virus clearance

Interferon Lambda Alleles Predict Innate Antiviral Immune Responses and Hepatitis C Virus Permissiveness

Regulation of hepatic innate immunity by hepatitis C virus

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