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Interferon lambda 4 signals via the IFN? receptor to regulate antiviral activity against HCV and coronaviruses.

ABSTRACT: The IFNL4 gene is a recently discovered type III interferon, which in a significant fraction of the human population harbours a frameshift mutation abolishing the IFN?4 ORF. The expression of IFN?4 is correlated with both poor spontaneous clearance of hepatitis C virus (HCV) and poor response to treatment with type I interferon. Here, we show that the IFNL4 gene encodes an active type III interferon, named IFN?4, which signals through the IFN?R1 and IL-10R2 receptor chains. Recombinant IFN?4 is antiviral against both HCV and coronaviruses at levels comparable to IFN?3. However, the secretion of IFN?4 is impaired compared to that of IFN?3, and this impairment is not due to a weak signal peptide, which was previously believed. We found that IFN?4 gets N-linked glycosylated and that this glycosylation is required for secretion. Nevertheless, this glycosylation is not required for activity. Together, these findings result in the paradox that IFN?4 is strongly antiviral but a disadvantage during HCV infection.

SUBMITTER: Hamming OJ

PROVIDER: S-EPMC3844954 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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Interferon lambda 4 signals via the IFNλ receptor to regulate antiviral activity against HCV and coronaviruses.

Hamming Ole J OJ Terczyńska-Dyla Ewa E Vieyres Gabrielle G Dijkman Ronald R Jørgensen Sanne E SE Akhtar Hashaam H Siupka Piotr P Pietschmann Thomas T Thiel Volker V Hartmann Rune R

The EMBO journal 20131029 23

The IFNL4 gene is a recently discovered type III interferon, which in a significant fraction of the human population harbours a frameshift mutation abolishing the IFNλ4 ORF. The expression of IFNλ4 is correlated with both poor spontaneous clearance of hepatitis C virus (HCV) and poor response to treatment with type I interferon. Here, we show that the IFNL4 gene encodes an active type III interferon, named IFNλ4, which signals through the IFNλR1 and IL-10R2 receptor chains. Recombinant IFNλ4 is ...[more]

PMID: 24169568

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Project description:Sustained virologic response (SVR) in chronic hepatitis C (CHC) treatment denotes that the host genetics controls the immune response and unequivocally contribute to viral clearance or disease severity. In this context, single nucleotide polymorphisms (SNPs) in the locus of interferon lambda 3 and 4 genes (IFNL3/4) have been important genetic markers of responsiveness to CHC as prognostic markers for the pegylated-Interferon-alpha/ribavirin (Peg-IFN-α/RBV). Here, we analyzed 12 SNPs at the IFNL3/4 region in 740 treatment-naïve patients with CHC infected with hepatitis C virus (HCV) genotypes 1, 2, or 3 treated with Peg-IFN-α/RBV. Individually, rs12979860-CC, rs8109886-CC, or rs8099917-TT were predictive markers of SVR, while rs12979860-CC demonstrated the stronger effect. Besides, the genotypic combination of these three predictors' genotypes, CC/CC/TT, increased the rate of SVR. Serum levels of cytokines and gene expression analysis on the genes IFNL3, IFNL4, IFNA1, and some of the IFN-stimulated genes (ISGs) were measured in a subgroup of 24 treated patients and 24 healthy volunteers. An antagonist effect was highlighted between the expression of IFNL3/4 and IFNA1 mRNA among patients. Besides, a prominent production of the pro-inflammatory chemokines CCL4 and CXCL10 was observed at a 12-week treatment follow-up. Lower serum levels of these chemokines were detected in patients with an rs12979860-CC genotype associated with the better treatment outcome. Also, lower expression levels of the IFI6, IFI16, IRF9 genes were observed among rs12979860-CC individuals. In conclusion, a combination of the genotypes at the IFNL3/4 locus can act as a better marker for the prognosis for virological responses in an admixed Brazilian population presenting the modulating effect over innate immunity and inflammation that are controlling the outcome of the viral infection, but also other infectious diseases. This study is registered on the ClinicalTrials.gov platform (accession number NCT01889849 and NCT01623336).

Dataset Information

Interferon lambda 4 signals via the IFN? receptor to regulate antiviral activity against HCV and coronaviruses.

Publications

Interferon lambda 4 signals via the IFNλ receptor to regulate antiviral activity against HCV and coronaviruses.

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