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IFN-Λ4 Attenuates Antiviral Responses by Enhancing Negative Regulation of IFN Signaling

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IFN-Λ4 Attenuates Antiviral Responses by Enhancing Negative Regulation of IFN Signaling IFN-λ4 Attenuates Antiviral Responses by Enhancing Negative Regulation of IFN Signaling This information is current as Adeola A. Obajemu, Nina Rao, Kari A. Dilley, Joselin M. of September 29, 2021. Vargas, Faruk Sheikh, Raymond P. Donnelly, Reed S. Shabman, Eric G. Meissner, Ludmila Prokunina-Olsson and Olusegun O. Onabajo J Immunol published online 25 October 2017 http://www.jimmunol.org/content/early/2017/10/25/jimmun Downloaded from ol.1700807 Supplementary http://www.jimmunol.org/content/suppl/2017/10/25/jimmunol.170080 Material 7.DCSupplemental http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 29, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2017 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published October 25, 2017, doi:10.4049/jimmunol.1700807 The Journal of Immunology IFN-l4 Attenuates Antiviral Responses by Enhancing Negative Regulation of IFN Signaling Adeola A. Obajemu,* Nina Rao,* Kari A. Dilley,† Joselin M. Vargas,* Faruk Sheikh,‡ Raymond P. Donnelly,‡ Reed S. Shabman,† Eric G. Meissner,x Ludmila Prokunina-Olsson,*,1 and Olusegun O. Onabajo*,1 Type III IFNs are important mediators of antiviral immunity. IFN-l4 is a unique type III IFN because it is produced only in individuals who carry a dG allele of a genetic variant rs368234815-dG/TT. Counterintuitively, those individuals who can produce IFN-l4, an antiviral cytokine, are also less likely to clear hepatitis C virus infection. In this study, we searched for unique functional properties of IFN-l4 that might explain its negative effect on hepatitis C virus clearance. We used fresh primary human hepatocytes (PHHs) treated with recombinant type III IFNs or infected with Sendai virus to model acute viral infection and subsequently validated our findings in HepG2 cell line models. Endogenous IFN-l4 protein was detectable only in Sendai Downloaded from virus–infected PHHs from individuals with the dG allele, where it was poorly secreted but highly functional, even at concentra- tions < 50 pg/ml. IFN-l4 acted faster than other type III IFNs in inducing antiviral genes, as well as negative regulators of the IFN response, such as USP18 and SOCS1. Transient treatment of PHHs with IFN-l4, but not IFN-l3, caused a strong and sustained induction of SOCS1 and refractoriness to further stimulation with IFN-l3. Our results suggest unique functional properties of IFN-l4 that can be important in viral clearance and other clinical conditions. The Journal of Immunology, 2017, 199: 000–000. http://www.jimmunol.org/ nterferon-l4 is a novel type III IFN that was discovered as a the TT allele introduces a frame-shift and eliminates this IFN (1). factor interfering with clearance of hepatitis C virus (HCV) The dG allele is very common in individuals of African ancestry I infection (1). A decreased ability to clear HCV is associated (up to 78% allele frequency) but is less common in Europeans with the dG allele of a genetic variant (rs368234815-dG/TT); this (∼30%) and Asians (0–10%) (1). This strong variation between allele creates an open reading frame for IFN-l4 protein, whereas individuals in the ability to produce IFN-l4 might be important for health disparity in the immune response to viral infections and other relevant conditions. *Laboratory of Translational Genomics, Division of Cancer Epidemiology and Ge- Before the discovery of rs368234815 (1), its association was by guest on September 29, 2021 netics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; captured by either of the two single nucleotide polymorphisms †Virology Group, J. Craig Venter Institute, Rockville, MD 20850; ‡Office of Bio- technology Products, Center for Drug Evaluation and Research, U.S. Food and Drug (SNPs) used in genome-wide association studies: rs12979860 (2, Administration, Silver Spring, MD 20993; and xDivision of Infectious Diseases, 3) and rs8099917 (4, 5). SNP rs12979860 is located within the Department of Microbiology and Immunology, Medical University of South Caro- lina, Charleston, SC 29425 first intron of IFNL4, with the dG and TT alleles of rs368234815 corresponding to the T and C alleles, respectively, of rs12979860 1L.P.-O. and O.O.O. contributed equally to this work. (1). SNP rs8099917 is located upstream of IFNL4 and captures the ORCIDs: 0000-0002-0695-5276 (R.P.D.); 0000-0002-5240-7115 (E.G.M.); 0000- 0002-9622-2091 (L.P.-O.); 0000-0001-6342-2380 (O.O.O.). difference additionally contributed by a missense IFNL4 variant, Received for publication June 5, 2017. Accepted for publication September 27, 2017. rs117648444-A/G (Pro70Ser), which affects the activity of IFN-l4(1, This work was supported by the Intramural Research Programs of the Division of 6). Thus, rs8099917-G allele tags IFNL4 haplotype (rs368234815-dG/ Cancer Epidemiology and Genetics, National Cancer Institute (to A.A.O., N.R., J.M.V., rs117648444-G) that produces a more active protein (IFN-l4–70Pro), L.P.-O., and O.O.O.) and the National Institute of Allergy and Infectious Diseases (to whereas rs8099917-T allele captures two other IFNL4 haplotypes E.G.M.), the Critical Care Medicine Department and the Clinical Research Center of the National Institutes of Health (to E.G.M.), intramural research funds from the U.S. Food corresponding to lack of IFN-l4 (rs368234815-TT/rs117648444-G) or and Drug Administration (to F.S. and R.P.D.), and internal funding from the J. Craig alessactiveIFN-l4–70Ser protein (rs368234815-dG/rs117648444-A) Venter Institute (project code 9260 to K.A.D. and R.S.S.). (1, 4–6). A.A.O., N.R., O.O.O., K.A.D., J.M.V., F.S., R.P.D., and R.S.S. performed experi- The ability to produce IFN-l4, with or without further modi- ments; E.G.M. contributed data; L.P.-O. and O.O.O. designed the experiments and supervised the research; A.A.O., O.O.O., and L.P.-O. wrote the manuscript; and all fication by P70S, was linked with differential pretreatment blood authors critically reviewed and revised the manuscript. HCV load and hepatic IFN-stimulated gene (ISG) expression (1, Address correspondence and reprint requests to Dr. Olusegun O. Onabajo, Laboratory 6–10), variable clearance of HCV infection spontaneously or after of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 8717 Grovemont Circle, Bethesda, treatment with IFN-a–based therapies (1, 2, 9, 11), and slower MD 20892-4605. E-mail address: [email protected] kinetics of HCV clearance in patients treated with IFN-free direct- The online version of this article contains supplemental material. acting antivirals (DAAs) (10). Growing literature demonstrates Abbreviations used in this article: Ct, PCR cycle at detection threshold; DAA, direct- genetic associations between rs368234815 or its linked variants acting antiviral; HCV, hepatitis C virus; HepG2–IFN-l3–GFP cell, stable HepG2 cell with other clinical phenotypes, such as relapse on DAA treatment line expressing doxycycline-inducible GFP-tagged IFN-l3 protein; HepG2–ISRE– Luc cell, stable HepG2 cell line carrying the ISRE-Luc reporter; ISG, IFN-stimulated of HCV (12), liver fibrosis (13, 14), hepatic metallothionein ex- gene; PHH, primary human hepatocyte; PNGaseF, peptide–N-glycosidase F; qRT- pression (15), postpartum immune activation (16, 17), and risk for PCR, quantitative RT-PCR; SeV, Sendai virus; siRNA, small interfering RNA; SNP, mucinous ovarian cancer (18), among others. Although other single nucleotide polymorphism. invariantly expressed type III IFNs might also be important for Copyright Ó 2017 by The American Association of Immunologists, Inc. 0022-1767/17/$35.00 these phenotypes, only IFN-l4 is directly and most dramatically www.jimmunol.org/cgi/doi/10.4049/jimmunol.1700807 2 IFN-l4 ENHANCES NEGATIVE REGULATION OF IFN SIGNALING affected by the associated variant, rs368234815, which either Expression of IFN-l3–GFP and IFN-l4–GFP was induced by 0.5 mg/ml creates or eliminates IFN-l4. Thus, IFN-l4 might be the primary doxycycline for the indicated times and monitored by flow cytometry cause of further functional effects, including on other type III analysis on a FACSAria III (BD Biosciences). Intracellular IFN-l3–GFP was detectable only after blocking protein secretion with 6 mM GolgiStop IFNs, that have been attributed to these genetic associations. (BD Biosciences) for 4 h, whereas IFN-l4–GFP was detectable even Although genetic association studies provide strong support for without GolgiStop. All cell lines were regularly tested for mycoplasma the role of IFN-l4 in diverse clinical phenotypes, functional using the MycoAlert Mycoplasma Detection Kit (Lonza). studies on IFN-l4 are still limited. Mouse models have been rIFNs successfully used to study other type III IFNs (19–21), but IFN-l4 is missing in the mouse genome, making it difficult to perform Commercially available IFN-l1, IFN-l2, and IFN-l4 (all from R&D Systems) were generated in mouse myeloma cells, human HEK293 cells, comprehensive comparisons between type III IFNs in the same and Escherichia coli, respectively. Custom IFN-l3 was generated in a experimental models. baculoviral system (1), and custom IFN-l4 was generated in E.
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