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Chen P, Zhu J, Yu J, Liu R, Lao M, Yu L, Gao F, Jiang Y, Liu C, Tong W, Liu H, Tong G, Zhou Y. Porcine epidemic diarrhea virus strain FJzz1 infection induces type I/III IFNs production through RLRs and TLRs-mediated signaling. Front Immunol 2022; 13:984448. [PMID: 35958569 PMCID: PMC9357978 DOI: 10.3389/fimmu.2022.984448] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Accepted: 07/06/2022] [Indexed: 11/13/2022] Open
Abstract
Interferons (IFNs) including type I/III IFNs are the major components of the host innate immune response against porcine epidemic diarrhea virus (PEDV) infection, and several viral proteins have been identified to antagonize type I/III IFNs productions through diverse strategies. However, the modulation of PEDV infection upon the activation of the host’s innate immune response has not been fully characterized. In this study, we observed that various IFN-stimulated genes (ISGs) were upregulated significantly in a time- and dose-dependent manner in LLC-PK1 cells infected with the PEDV G2 strain FJzz1. The transcriptions of IRF9 and STAT1 were increased markedly in the late stage of FJzz1 infection and the promotion of the phosphorylation and nuclear translocation of STAT1, implicating the activation of the JAK-STAT signaling pathway during FJzz1 infection. In addition, abundant type I/III IFNs were produced after FJzz1 infection. However, type I/III IFNs and ISGs decreased greatly in FJzz1-infected LLC-PK1 cells following the silencing of the RIG-I-like receptors (RLRs), including RIG-I and MDA5, and the Toll-like receptors (TLRs) adaptors, MyD88 and TRIF. Altogether, FJzz1 infection induces the production of type-I/III IFNs in LLC-PK1 cells, in which RLRs and TLRs signaling pathways are involved, followed by the activation of the JAK-STAT signaling cascade, triggering the production of numerous ISGs to exert antiviral effects of innate immunity.
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Affiliation(s)
- Pengfei Chen
- Department of Swine Infectious Diseases, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, China
- Institute of Animal Husbandry and Veterinary, Shanghai Academy of Agricultural Science, Shanghai, China
| | - Junrui Zhu
- Department of Swine Infectious Diseases, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, China
| | - Jiarong Yu
- Department of Swine Infectious Diseases, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, China
| | - Ruilin Liu
- Department of Swine Infectious Diseases, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, China
| | - Mengqin Lao
- Department of Swine Infectious Diseases, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, China
| | - Lingxue Yu
- Department of Swine Infectious Diseases, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, China
| | - Fei Gao
- Department of Swine Infectious Diseases, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, China
| | - Yifeng Jiang
- Department of Swine Infectious Diseases, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, China
| | - Changlong Liu
- Department of Swine Infectious Diseases, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, China
| | - Wu Tong
- Department of Swine Infectious Diseases, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, China
| | - Huili Liu
- Institute of Animal Husbandry and Veterinary, Shanghai Academy of Agricultural Science, Shanghai, China
| | - Guangzhi Tong
- Department of Swine Infectious Diseases, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, China
- *Correspondence: Guangzhi Tong, ; Yanjun Zhou,
| | - Yanjun Zhou
- Department of Swine Infectious Diseases, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, China
- *Correspondence: Guangzhi Tong, ; Yanjun Zhou,
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Miri HH, Fazeli P, Ali-Hassanzadeh M, Bemani P, Kabelitz D, Kalantar K. Correlation between IL-28 polymorphism and spontaneous clearance in HCV patients: systematic review and meta-analysis. Arch Virol 2021; 166:2469-2478. [PMID: 34216268 DOI: 10.1007/s00705-021-05141-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Accepted: 04/29/2021] [Indexed: 10/20/2022]
Abstract
Hepatitis C virus (HCV) is a serious global health issue. Nearly 20% of HCV patients spontaneously clear the virus. While some studies have shown an association of spontaneous clearance (SC) of the virus with interleukin (IL) 28B single-nucleotide polymorphisms (SNPs), others did not show such a relationship. Thus, the purpose of the present study was to investigate the association of IL28B polymorphisms (12979860 SNP) with SC of HCV infection. Upon initial screening of the databases, a total of 545 articles were retrieved, of which 22 studies that met predefined eligibility criteria were entered into the meta-analysis. Odds ratios (ORs) with confidence intervals (95% CI), heterogeneity, publication bias, and sensitivity analysis were assessed. According to the meta-analysis results, a significant association was observed between the rs12979860 SNP and SC of HCV infection. The results indicated that the ORs of SC from hepatitis C virus infection were 2.75 times higher in those with cytokine gene polymorphisms (95% CI, 2.23 to 3.38). Moreover, it was found that the prevalence of rs12979860 CC was 0.33 with 95 CI 0.28-0.38 in genotype 1 and was 0.40 with 95 CI 0.34-0.47 in other genotypes. Our meta-analysis results suggest that IL28B rs12979860 CC is a strong predictor for SC of hepatitis C infection in PEG IFN-a/RBV-treated patients.
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Affiliation(s)
- Hamid Heidarian Miri
- Social Determinants of Health Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Pooria Fazeli
- Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, 7134845794, Shiraz, Iran
| | - Mohammad Ali-Hassanzadeh
- Department of Immunology, School of Medicine, Jiroft University of Medical Sciences, Jiroft, Iran
| | - Peyman Bemani
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | | | - Kurosh Kalantar
- Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, 7134845794, Shiraz, Iran.
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Chihab H, Badre W, Tahiri M, Jadid FZ, Zaidane I, Elfihry R, Marchio A, Pineau P, Ezzikouri S, Benjelloun S. IFNL4 rs12979860 polymorphism influences HBV DNA viral loads but not the outcome of HBV infection in Moroccan patients. Microbes Infect 2021; 23:104802. [PMID: 33607264 DOI: 10.1016/j.micinf.2021.104802] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Revised: 01/20/2021] [Accepted: 02/08/2021] [Indexed: 12/18/2022]
Abstract
OBJECTIVES The interferon (IFN) is known to bridge innate and adaptive immune responses, and to play a critical role particularly against hepatitis B virus (HBV) infection. Defects in IFN signals may result, therefore, in attenuated responses against HBV. Accordingly, polymorphisms in genes coding for immune response effectors may affect the clinical outcome of HBV infection. We analyzed the putative association between IFNL4 rs12979860 polymorphism and the outcome of HBV infection in Moroccan patients. METHODS In this study, 237 chronic HBV (CHB) patients and 129 spontaneously resolved HBV (SRB) individuals were enrolled and genotyped using a predesigned Taqman allelic discrimination assay. RESULTS Our data show a significant increase of HBV DNA loads in patients with IFNL4 rs12979860 CC genotype compared to patients with CT and TT genotypes (p = 0.0008). However, there was no consistent association between IFNL4 rs12979860 polymorphism and the outcome of HBV infection. CONCLUSIONS Although IFNL4 rs12979860 polymorphism seems to modulate circulating HBV DNA levels, it is disconnected from chronic disease progression. This observation suggests that the role of rs12979860 in liver disease is restricted to viral control and inactive in the deleterious immune pathology that affects liver tissue. Taken together, our data suggest that rs12979860 CC genotypes could be useful as a predictor of success or failure of IFN-based therapy in chronic HBV-infected patients.
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Affiliation(s)
- Hajar Chihab
- Virology Unit, Viral Hepatitis Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco
| | - Wafaa Badre
- Faculté de Médecine de Casablanca, CHU Ibn Rochd, Casablanca, Morocco
| | - Mohamed Tahiri
- Faculté de Médecine de Casablanca, CHU Ibn Rochd, Casablanca, Morocco
| | - Fatima-Zahra Jadid
- Virology Unit, Viral Hepatitis Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco
| | - Imane Zaidane
- Virology Unit, Viral Hepatitis Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco
| | - Raouia Elfihry
- Virology Unit, Viral Hepatitis Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco
| | - Agnès Marchio
- Unité "Organisation Nucléaire et Oncogenèse", INSERM U993, Institut Pasteur, Paris, France
| | - Pascal Pineau
- Unité "Organisation Nucléaire et Oncogenèse", INSERM U993, Institut Pasteur, Paris, France
| | - Sayeh Ezzikouri
- Virology Unit, Viral Hepatitis Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco
| | - Soumaya Benjelloun
- Virology Unit, Viral Hepatitis Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco.
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Zhang MQ, Zhao Q, Zhang JP. A new transcription factor ATG10S activates IFNL2 transcription by binding at an IRF1 site in HepG2 cells. Autophagy 2020; 16:2167-2179. [PMID: 31996071 PMCID: PMC7751675 DOI: 10.1080/15548627.2020.1719681] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2019] [Revised: 01/14/2020] [Accepted: 01/17/2020] [Indexed: 10/25/2022] Open
Abstract
IFNL2 is a potent antiviral interferon, but the regulation of its gene expression is not fully clear. Here, we report the regulation of ATG10S for IFNL2 transcription. Through sequential deletion of the IFNL2 promoter sequence, we found LP1-1, a fragment of the promoter responding to ATG10S activity. Subcellular localization and DNA immunoprecipitation assays showed ATG10S translocating into the nucleus and binding to LP1-1. Online prediction for transcription factor binding sites showed an IRF1 targeting locus in LP1-1. Luciferase assays, RT-PCR, and western blot analysis revealed a core motif (CAAGAC) existing in LP1-1, which determined ATG10S and IRF1 activity; individual nucleotide substitution showed that the functional nucleotides of ATG10S targeting were C1, A3, and C6, and the ones associated with IRF1 were A3 and G4 within the core motif. Co-immunoprecipitation assays revealed ATG10S combination with KPNA1/importin α, KPNB1/importin β, and IRF1. The knockdown of endogenous IRF1 increased ATG10S activity on IFNL2 transcription. These results indicate that ATG10S as a transcription factor competes with IRF1 for the same binding site to promote IFNL2 gene transcription. Abbreviations: ATG10: autophagy related 10; ATG10S: the shorter isoform of autophagy related 10; BD: binding domain; CM: core motif; co-IP: co-immunoprecipitation; GFP: green fluorescent protein; HCV: hepatitis C virus; IF: immunofluorescence; IFN: interferon; IRF: interferon regulatory factor; LP: lambda promoter; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; RLU: relative light unit; SQSTM1: sequestosome 1.
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Affiliation(s)
- Miao-Qing Zhang
- Key Laboratory of Biotechnology of Antibiotics, the National Health Commission (NHC), Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Postdoctoral Scientific Research Workstation, China Resources Sanjiu Medical & Pharmaceutical Co., Ltd., Shenzhen, China
- Postdoctoral Mobile Research Station, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, China
| | - Qiong Zhao
- Key Laboratory of Biotechnology of Antibiotics, the National Health Commission (NHC), Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jing-Pu Zhang
- Key Laboratory of Biotechnology of Antibiotics, the National Health Commission (NHC), Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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Nafari AH, Ayadi A, Noormohamadi Z, Sakhaee F, Vaziri F, Siadat SD, Fateh A. Occult hepatitis C virus infection in hemophilia patients and its correlation with interferon lambda 3 and 4 polymorphisms. INFECTION, GENETICS AND EVOLUTION : JOURNAL OF MOLECULAR EPIDEMIOLOGY AND EVOLUTIONARY GENETICS IN INFECTIOUS DISEASES 2020; 79:104144. [PMID: 31838260 DOI: 10.1016/j.meegid.2019.104144] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/02/2019] [Revised: 12/05/2019] [Accepted: 12/12/2019] [Indexed: 12/11/2022]
Abstract
Occult HCV infection (OCI) is described as the presence of HCV RNA in the liver and peripheral blood mononuclear cells (PBMCs), with no HCV RNA in the serum. Single-nucleotide polymorphisms (SNPs) near interferon lambda 3/4 (IFNL3/4) gene are associated with spontaneous clearance and treatment response in patients with hepatitis C virus (HCV) infection. In this study, we evaluated the frequency of OCI in hemophilia patients and determined the association of three IFNL3 SNPs (rs12979860, rs12980275, and rs8099917) and IFNL4 ss469415590 with OCI positivity. A total of 450 hemophilia patients with HCV negative markers were included in this study. Positive- and negative-stranded HCV-RNA was determined in peripheral blood mononuclear cells (PBMCs) samples by reverse-transcription polymerase chain reaction (RT-PCR) method. IFNL3 SNPs and IFNL4 ss469415590 were genotyped by PCR-RFLP and TaqMan® Real-Time PCR methods, respectively. The frequency of OCI was estimated at 10.2%. Among 46 OCI patients, 56.5%, 23.9%, and 19.6% were infected with HCV-1b, HCV-1a, and HCV-3a, respectively. Compared to patients without OCI, unfavorable IFNL3 rs12979860 TT, IFNL3 rs8099917 GG, IFNL3 rs12980275 GG, and IFNL4 ss469415590 ∆G/∆G genotypes were more frequently reported in OCI patients. The multivariate logistic regression analysis showed that alanine aminotransferase (ALT), cholesterol, triglyceride, IFNL3 rs12979860 (TT), IFNL3 rs8099917 (GG), IFNL3 rs12980275 (GG), and IFNL4 ss469415590 (∆G/∆G) were associated with OCI positivity. In conclusion, we studied the incidence of OCI in Iranian patients with hemophilia for the first time. Our results demonstrated that unfavorable genotypes of IFNL3 SNPs and IFNL4 ss469415590 have a strong relationship with OCI positivity. It seems that the host immune response plays a vital role in OCI positivity.
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Affiliation(s)
- Amir Hossein Nafari
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Ahmad Ayadi
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Zahra Noormohamadi
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Fatemeh Sakhaee
- Department of Mycobacteriology and Pulmonary Research, Pasteur Institute of Iran, Tehran, Iran
| | - Farzam Vaziri
- Department of Mycobacteriology and Pulmonary Research, Pasteur Institute of Iran, Tehran, Iran; Microbiology Research Center (MRC), Pasteur Institute of Iran, Tehran, Iran
| | - Seyed Davar Siadat
- Department of Mycobacteriology and Pulmonary Research, Pasteur Institute of Iran, Tehran, Iran; Microbiology Research Center (MRC), Pasteur Institute of Iran, Tehran, Iran
| | - Abolfazl Fateh
- Department of Mycobacteriology and Pulmonary Research, Pasteur Institute of Iran, Tehran, Iran; Microbiology Research Center (MRC), Pasteur Institute of Iran, Tehran, Iran.
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Choobin H, Bamdad T, Shekarabi M. The pattern of antiviral protein expression induced by interferon λ1 in peripheral blood mononuclear cells of patients with chronic hepatitis C virus infection. Arch Virol 2020; 165:583-592. [PMID: 31927635 DOI: 10.1007/s00705-019-04438-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2018] [Accepted: 09/12/2019] [Indexed: 12/28/2022]
Abstract
Interferon lambda was discovered in recent years to be an antiviral agent, and research on different aspects of this antiviral factor in viral infection and investigations of its effectiveness are also progressing. The immunological effects of interferon lambda on different cell populations is not precisely known, which may be due to its use of a heterodimeric receptor consisting of IL-10R2 and IFN-λR1, which are not broadly expressed in all types of cells. In the present study, signaling by interferon lambda and its effect on the expression of hepatitis C virus (HCV) proteins were measured, and the expression pattern of some antiviral proteins and IL-10 levels were investigated in peripheral blood mononuclear cells (PBMCs). PBMCs were isolated from 50 patients with chronic genotype 1a HCV infection and 10 healthy individuals as controls. The PBMCs were treated with various doses of interferon lambda at different times of cultivation. Real-time PCR was used for relative quantification of Mxa, PKR, OAS, ISG15 and HCV core mRNAs. Expression of the NS5A protein was measured by flow cytometry, and IL-10 production was assessed by ELISA. A significant increase in the expression of mRNA encoding antiviral proteins and a decrease in the expression of mRNAs encoding the HCV core protein were observed when cells were treated with interferon lambda in an intermittent manner. The expression of HCV NS5A protein and interleukin 10 levels were also lower than in the control group. It was shown that the maximum antiviral effect of interferon lambda in PBMCs is dependent on the dose and treatment time.
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Affiliation(s)
- Hamzeh Choobin
- Department of Virology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Taravat Bamdad
- Department of Virology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Mehdi Shekarabi
- Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran.
- Department of Immunology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran.
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Guo X, Chen D, Cai Q, Huang Z, Xu W, Peng L, Chen P. Minicircle DNA vector expressing interferon-lambda-3 inhibits hepatitis B virus replication and expression in hepatocyte-derived cell line. BMC Mol Cell Biol 2020; 21:6. [PMID: 32070272 PMCID: PMC7027252 DOI: 10.1186/s12860-020-00250-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2019] [Accepted: 02/06/2020] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Interferon-alpha (IFNα) is a first-line treatment option for chronic hepatitis B virus (HBV) infection, but the severe systemic side-effects limited its clinical application. Interferon-lambda (IFNλ) with comparable antiviral activity and less toxic side-effects is thought to be a good alternative interferon to IFNα. Additionally, the gene vector mediated sustainably expression of therapeutic product in the target cells/tissue may overcome the shortcomings resulted from the short half-life of IFNs. RESULTS We constructed a liver-specific IFNλ3-expressing minicircle (MC) vector under the control of a hepatocyte-specific ApoE promoter (MC.IFNλ3) and investigated its anti-HBV activity in a HBV-expressing hepatocyte-derived cell model (HepG2.2.15). As expected, the MC.IFNλ3 vector capable of expressing IFNλ3 in the recipient hepatocytes has demonstrated robust anti-HBV activity, in terms of suppressing viral antigen expression and viral DNA replication, via activation the interferon-stimulated gene (ISG) expression in HepG2.2.15 cells. CONCLUSIONS Given the MC vector can be easily delivered into liver, the liver-targeted IFN gene-transfer (MC.IFNλ3), instead of systemic administrating IFN repeatedly, provides a promising concept for the treatment of chronic HBV infection.
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Affiliation(s)
- Xiaoyan Guo
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Dianke Chen
- Department of Medical Oncology, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Qingxian Cai
- Department of Hepatology, The Third People's Hospital of Shenzhen, Shenzhen, China
| | - Zhanlian Huang
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Wenxiong Xu
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Liang Peng
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
| | - Ping Chen
- Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China.
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Zakaria ZA, Knapp S, Hashem M, Zaghla H, Thursz M, Waked I, Abdelwahab S. Interleukin 28A.rs12980602 and interleukin 28B.rs8103142 genotypes could be protective against HCV infection among Egyptians. Immunol Res 2019; 67:123-133. [PMID: 30402710 DOI: 10.1007/s12026-018-9035-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Previous studies showed that interleukin (IL)-28B gene polymorphisms were associated with hepatitis C Virus (HCV) infection and treatment outcomes. We tested whether single-nucleotide polymorphisms (SNPs) in IL-28A and IL-28B are associated with HCV infection among Egyptians with HCV genotype 4 infections. We enrolled 144 chronic HCV patients, 72 spontaneously resolved HCV subjects, and 69 healthy controls. Four SNPs in IL-28A and IL-28B genes (IL-28A.rs12980602, IL-28B.rs12979860, IL-28B.rs8099917, and IL-28B.rs8103142) were genotyped. The most frequent IL-28B haplotype "TCT" was significantly more frequent in HCV-infected subjects than in HCV negative subjects (62.2% vs. 48.6%, respectively; p = 0.005). The frequency of IL-28A.rs12980602 "T" allele was significantly higher than the "C" allele in healthy controls compared to HCV-infected subjects (p < 0.001) with the "TT" genotype significantly higher in healthy controls compared to HCV-infected subjects (p < 0.001) with no association with viral load (p = 0.11) among chronically infected subjects. The results, also, confirmed the previous role of IL-28B SNPs in predicting HCV infection outcome. Importantly, IL-28B.rs8099917 "TT" genotype was significantly associated with low viral load in HCV-infected subjects, while the remaining three SNPs did not. The three IL-28B SNPs were in linkage disequilibrium (D' > 0.68; r2 > 0.43) for all comparisons in HCV patients, while there was no linkage disequilibrium of IL-28A polymorphisms and the three IL-28B SNPs. In conclusion, IL-28A.rs12980602 and IL-28B.rs8103142 TT genotype could be protective against HCV infection. Also, IL-28B.rs12979860, IL-28B.rs8099917, and IL-28B.rs8103142 SNPs predicted the outcome of HCV infection among genotype-4-infected Egyptians. Moreover, IL-28B.rs8099917 SNP affected the viral load in chronic HCV patients.
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Affiliation(s)
- Zainab A Zakaria
- The Holding Company for Biological Products and Vaccines (VACSERA), 51 Wizaret El-Zeraa St., Agouza, Giza, 22311, Egypt
- Biomedical Research Laboratory, Faculty of Pharmacy, Heliopolis University for Sustainable Development, Cairo, Egypt
| | - Susanne Knapp
- Department of Hepatology and Gastroenterology, Imperial College, St. Mary's Hospital, London, W21NY, UK
| | - Mohamed Hashem
- The Holding Company for Biological Products and Vaccines (VACSERA), 51 Wizaret El-Zeraa St., Agouza, Giza, 22311, Egypt
- Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD21201, USA
| | - Hassan Zaghla
- Department of Hepatology and Gastroenterology, National Liver Institute, Menoufia University, Menoufia, 32511, Egypt
| | - Mark Thursz
- Department of Hepatology and Gastroenterology, Imperial College, St. Mary's Hospital, London, W21NY, UK
| | - Imam Waked
- Department of Hepatology and Gastroenterology, National Liver Institute, Menoufia University, Menoufia, 32511, Egypt
| | - Sayed Abdelwahab
- The Holding Company for Biological Products and Vaccines (VACSERA), 51 Wizaret El-Zeraa St., Agouza, Giza, 22311, Egypt.
- Department of Microbiology and Immunology, Faculty of Medicine, Minia University, Minia, 61511, Egypt.
- Department of Microbiology, College of Pharmacy, Taif University, Al-Haweiah, Taif, 21974, Saudi Arabia.
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Cakmak Genc G, Dursun A, Karakas Celik S, Calik M, Kokturk F, Piskin IE. IL28B, IL29 and micro-RNA 548 in subacute sclerosing panencephalitis as a rare disease. Gene 2018; 678:73-78. [PMID: 30077763 DOI: 10.1016/j.gene.2018.07.062] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2018] [Revised: 07/18/2018] [Accepted: 07/24/2018] [Indexed: 12/18/2022]
Abstract
Subacute sclerosing panencephalitis (SSPE) is a progressive neurodegenerative disease which affects children and young adults, caused by a persistent infection of defective measles virus. IFN-λs (IL-28A, IL-28B and IL-29) are a group of cytokines mediating antiviral responses. It has been shown that IL-29 levels are significantly higher in infected cells with defective measles virus. IL-29 expression is thought to be regulated at post-transcriptional level and miRNA-548 family targets the 3'UTR of the IFNL1 gene. Impaired immune system has an important role as well as viral factors in SSPE. The aim of our study investigates whether IL-28B, IL-29 levels and gene polymorphisms contribute to the damaged immune response leading to the development of SSPE. Also possible association of miR-548 family with IL-29 and SSPE is explored. Frequencies of rs12979860, rs8099917, rs30461, serum levels of IL-28B, IL-29 and expression levels of miR-548b, miR-548c, miR-548i are determined at 64 SSPE patients and 68 healthy controls. Serum IL-29 levels are statistically significant higher in SSPE patients. Allele frequencies of rs8099917 are statistically significant higher in SSPE patients and resulted G allele is found to increase 2.183-fold risk of SSPE. The expression levels of miR-548b-5p, miR-548c-5p and miR-548i are found to be statistically significant higher in SSPE patients. Dramatically increased level of IL-29 seen in patient group indicates that the elevated miR-548 expression is compensatory result of the over-activated immune system response. Further studies referred to IL28, IL29 and related miRNA's will be enlightened the pathogenesis of SSPE.
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Affiliation(s)
- Gunes Cakmak Genc
- Faculty of Medicine, Department of Medical Genetics, Bulent Ecevit University, Zonguldak, Turkey.
| | - Ahmet Dursun
- Faculty of Medicine, Department of Medical Genetics, Bulent Ecevit University, Zonguldak, Turkey
| | - Sevim Karakas Celik
- Faculty of Sciences and Arts, Department of Molecular Biology and Genetics, Bulent Ecevit University, Zonguldak, Turkey
| | - Mustafa Calik
- Faculty of Medicine, Department of Pediatric Neurology, Harran University, Sanlıurfa, Turkey
| | - Furuzan Kokturk
- Faculty of Medicine, Department of Biostatistics, Bulent Ecevit University, Zonguldak, Turkey
| | - Ibrahim Etem Piskin
- Faculty of Medicine, Department of Pediatrics, Bulent Ecevit University, Zonguldak, Turkey
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Singh P, Dass JFP. Nearly neutral evolution in IFNL3 gene retains the immune function to detect and clear the viral infection in HCV. PROGRESS IN BIOPHYSICS AND MOLECULAR BIOLOGY 2018; 140:107-116. [PMID: 29746888 DOI: 10.1016/j.pbiomolbio.2018.05.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/13/2017] [Revised: 04/24/2018] [Accepted: 05/05/2018] [Indexed: 02/07/2023]
Abstract
IFNL3 gene plays a crucial role in immune defense against viruses. It induces the interferon stimulated genes (ISGs) with antiviral properties by activating the JAK-STAT pathway. In this study, we investigated the evolutionary force involved in shaping the IFNL3 gene to perform its downstream function as a regulatory gene in HCV clearance. We have selected 25 IFNL3 coding sequences with human gene as a reference sequence and constructed a phylogeny. Furthermore, rate of variation, substitution saturation test, phylogenetic informativeness and differential selection were also analysed. The codon evolution result suggests that nearly neutral mutation is the key pattern in shaping the IFNL3 evolution. The results were validated by subjecting the human IFNL3 protein variants to that of the native through a molecular dynamics simulation study. The molecular dynamics simulation clearly depicts the negative impact on the reported variants in human IFNL3 protein. However, these detrimental mutations (R157Q and R157W) were shown to be negatively selected in the evolutionary study of the mammals. Hence, the variation revealed a mild impact on the IFNL3 function and may be removed from the population through negative selection due to its high functional constraints. In a nutshell, our study may contribute the overall evidence in phylotyping and structural transformation that takes place in the non-synonymous substitutions of IFNL3 protein. Substantially, our obtained theoretical knowledge will lay the path to extend the experimental validation in HCV clearance.
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Affiliation(s)
- Pratichi Singh
- Department of Integrative Biology, School of Biosciences and Technology, VIT University, Vellore, Tamil Nadu 632014, India
| | - J Febin Prabhu Dass
- Department of Integrative Biology, School of Biosciences and Technology, VIT University, Vellore, Tamil Nadu 632014, India.
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11
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Wang H, Xin X, Wang M, Han L, Li J, Hao Y, Zheng C, Shen C. Myxovirus resistance protein A inhibits hepatitis C virus replication through JAK-STAT pathway activation. Arch Virol 2018; 163:1429-1438. [PMID: 29417241 DOI: 10.1007/s00705-018-3748-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2017] [Accepted: 01/11/2018] [Indexed: 12/30/2022]
Abstract
The interferon-inducible dynamin-like GTPase myxovirus resistance protein A (MxA) exhibits activity against multiple viruses. However, its role in the life cycle of hepatitis C virus (HCV) is unclear, and the mechanisms underlying the anti-HCV activity of MxA require further investigation. In this study, we demonstrated that exogenous MxA expression in the Huh7 and Huh7.5.1 hepatoma cell lines significantly decreased the levels of HCV RNA and core proteins, whereas MxA knockdown exerted the opposite effect. MxA-mediated inhibition of HCV replication was found to involve the JAK-STAT pathway: STAT1 phosphorylation and the expression of IFN-stimulated genes (ISGs) such as guanylate-binding protein 1 and 2'-5'-oligoadenylate synthetase 1 were augmented by MxA overexpression and reduced by endogenous MxA silencing. Treatment with the JAK inhibitor ruxolitinib abrogated the MxA-mediated suppression of HCV replication and activation of the JAK-STAT pathway. Additionally, transfection with an MxA mutant with disrupted GTP-binding consensus motifs abrogated activation of the JAK-STAT pathway and resistance to HCV replication. This study shows that MxA inhibits HCV replication by activating the JAK-STAT signaling pathway through a mechanism involving its GTPase function.
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Affiliation(s)
- Hailong Wang
- State Key Laboratory of Virology, School of Life Sciences, Wuhan University, Wuhan, 430072, Hubei, People's Republic of China
| | - Xiu Xin
- State Key Laboratory of Virology, School of Life Sciences, Wuhan University, Wuhan, 430072, Hubei, People's Republic of China
| | - Mingzhen Wang
- State Key Laboratory of Virology, School of Life Sciences, Wuhan University, Wuhan, 430072, Hubei, People's Republic of China
| | - Lingling Han
- State Key Laboratory of Virology, School of Life Sciences, Wuhan University, Wuhan, 430072, Hubei, People's Republic of China
| | - Jiadai Li
- State Key Laboratory of Virology, School of Life Sciences, Wuhan University, Wuhan, 430072, Hubei, People's Republic of China
| | - Yao Hao
- State Key Laboratory of Virology, School of Life Sciences, Wuhan University, Wuhan, 430072, Hubei, People's Republic of China
| | - Congyi Zheng
- State Key Laboratory of Virology, School of Life Sciences, Wuhan University, Wuhan, 430072, Hubei, People's Republic of China.,China Center for Type Culture Collection, Wuhan University, Wuhan, China
| | - Chao Shen
- State Key Laboratory of Virology, School of Life Sciences, Wuhan University, Wuhan, 430072, Hubei, People's Republic of China. .,China Center for Type Culture Collection, Wuhan University, Wuhan, China.
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12
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A Biomolecular Network Driven Proteinic Interaction in HCV Clearance. Cell Biochem Biophys 2018; 76:161-172. [PMID: 29313175 DOI: 10.1007/s12013-017-0837-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2016] [Accepted: 12/26/2017] [Indexed: 12/20/2022]
Abstract
Hepatitis C virus infection causes chronic liver disease that leads to cancer-related mortality. Presently around 30% of the HCV (infected) affected population get rid of the infection through spontaneous disease clearance. This phenomenon is conducted by a set of reported immune candidate genes. Hence, this study focuses only on these immune-response related genes with aid of network approach, where the idea is to disseminate the network for better understanding of key functional genes and their transcription control activity. Based on the network analysis the IFNG, TNF, IFNB1, STAT1, NFKB1, STAT3, SOCS1, and MYD88 genes are prioritized as hub genes along with their common transcription factors (TFs), IRF9, NFKB1, and STAT1. The dinucleotide frequency of TF binding elements indicated GG-rich motifs in these regulatory elements. On the other hand, gene enrichment report suggests the regulation of response to interferon gamma signaling pathway, which plays central role in the spontaneous HCV clearance. Therefore, our study tends to prioritize the genes, TFs, and their regulatory pathway towards HCV clearance. Even so, the resultant hub genes and their TFs and TF binding elements could be crucial in underscoring the clearance activity in specific populations.
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13
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Finotti G, Tamassia N, Cassatella MA. Interferon-λs and Plasmacytoid Dendritic Cells: A Close Relationship. Front Immunol 2017; 8:1015. [PMID: 28878776 PMCID: PMC5572322 DOI: 10.3389/fimmu.2017.01015] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2017] [Accepted: 08/08/2017] [Indexed: 12/21/2022] Open
Abstract
Interferon lambdas (IFNλs) are recently discovered cytokines acting not only at the first line of defense against viral infections but also at the mucosal barriers. In fact, a peculiar feature of the IFNλ system is the restricted expression of the functional IFNλR, which is known to be limited to epithelial cells and discrete leukocyte subsets, including the plasmacytoid dendritic cells (pDCs). In the latter case, current data, discussed in this minireview, indicate that IFNλs positively regulate various pDC functions, including pDC expression of interferon-dependent gene (ISG) mRNAs, production of cytokines, survival, and phenotype. Although the knowledge of the effects on pDCs by IFNλs is still incomplete, we speculate that the peculiar pDC responsiveness to IFNλs provide unique advantages for these innate immune cells, not only for viral infections but also during autoimmune disorders and/or tumors, in which pDC involvement and activation variably contribute to their pathogenesis.
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Affiliation(s)
- Giulia Finotti
- Department of Medicine, Section of General Pathology, University of Verona, Verona, Italy
| | - Nicola Tamassia
- Department of Medicine, Section of General Pathology, University of Verona, Verona, Italy
| | - Marco A Cassatella
- Department of Medicine, Section of General Pathology, University of Verona, Verona, Italy
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14
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Świątek-Kościelna B, Kałużna E, Strauss E, Nowak J, Bereszyńska I, Gowin E, Wysocki J, Rembowska J, Barcińska D, Mozer-Lisewska I, Januszkiewicz-Lewandowska D. Prevalence of IFNL3 rs4803217 single nucleotide polymorphism and clinical course of chronic hepatitis C. World J Gastroenterol 2017; 23:3815-3824. [PMID: 28638221 PMCID: PMC5467067 DOI: 10.3748/wjg.v23.i21.3815] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2017] [Revised: 03/17/2017] [Accepted: 05/04/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate the association of IFNL3 (IL28B) SNP rs4803217 with severity of disease and treatment outcome in chronic hepatitis C (CHC). METHODS The study enrolled 196 CHC Polish patients (82 women and 114 men in age 20-64) infected with hepatitis C virus (HCV) genotype 1. They were treatment naïve and qualified to pegylated interferon alpha (PEG-IFN-α) and ribavirin (RBV) therapy. The analyzed baseline parameters included: degree of inflammation, stage of fibrosis, viral load as well as alanine aminotransferase (ALT), asparagine aminotransferase (AST) and total bilirubin (TBIL). The analysis of response to therapy included: sustained virological response (SVR), defined as undetectable serum HCV RNA level six month after completion of 48-wk therapy, and relapse, defined as achieving undetectable viral load at the end of treatment but not SVR. HCV genotyping and HCV RNA quantification were performed using commercially available tests. DNA was isolated from peripheral blood mononuclear cells or from buccal cell swabs. In addition to rs4803217, also single nucleotide polymorphisms (SNPs) (rs12979860, rs8099917 and rs12980275) of known significance in predicting of HCV clearance were analyzed. SNPs were determined by high resolution melt analysis and confirmed by sequencing of amplicons. RESULTS Frequency of rs4803217 genotypes in studied group was as follows: 27.55%; 54.59% and 17.86% for CC, CA and AA, respectively. The rs4803217 SNP, similar to other analyzed SNPs, was not associated with severity of CHC (grade of inflammation, stage of fibrosis, baseline viral load as well as biochemical parameters: ALT, AST, TBIL). It was demonstrated that the rs4803217C allele is associated with SVR (C vs A: P < 0.0001; dose of C allele: P = 0.0002) and non-relapse (C vs A: P = 0.001; dose of C allele: P = 0.002). Moreover, it was found that patients with CC genotype have significantly higher response rates as compared with CA/AA patients (P < 0.0001), whereas patients carrying A allele are significantly predisposed to relapse after treatment (P = 0.0007). Moreover, the association of rs4803217 with SVR was comparable to that of rs12979860 and stronger as observed for rs12980275 and rs8099917. Association of rs4803217 with relapse, was the strongest as compared with the other SNPs. The analysis of combined rs4803217 and rs8099917 genotypes demonstrated that additional genotyping of rs8099917 had no significant impact on the prediction of SVR. Multivariate analysis revealed that among analyzed SNPs only rs4803217 is an independent predictor of SVR (P = 0.016) and relapse (P = 0.024). CONCLUSION The rs4803217 SNP is a strong, independent and superior predictor of SVR and relapse in HCV genotype 1 infected CHC patients treated with PEG-IFN-α and RBV.
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15
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Kao JH, Ahn SH, Chien RN, Cho M, Chuang WL, Jeong SH, Liu CH, Paik SW. Urgency to treat patients with chronic hepatitis C in Asia. J Gastroenterol Hepatol 2017; 32:966-974. [PMID: 28005275 DOI: 10.1111/jgh.13709] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2016] [Revised: 12/05/2016] [Accepted: 12/12/2016] [Indexed: 02/06/2023]
Abstract
Chronic hepatitis C (CHC) infection poses a global healthcare burden, being associated with serious complications if untreated. The prevalence of hepatitis C virus (HCV) infection is highest in areas of Central, South, and East Asia; over 50% of HCV patients worldwide live in the region, where HCV genotypes 1b, 2, 3, and 6 are the most prevalent. Treatment outcomes for chronic hepatitis C vary by ethnicity, and Asian patients achieve higher sustained virologic response rates following interferon (IFN)-based therapy than non-Asians. However, low efficacy, poor safety profile, and subcutaneous administration limit the use of IFN-based therapies. Superior virologic outcomes have been observed with different classes of direct-acting antivirals (DAAs) alone or in combination, and several all-oral DAA regimens are available in Asia. These regimens have shown excellent efficacy and favorable tolerability in clinical trials, yet there is a need for further studies of DAAs in a real world context, particularly in Asia. Furthermore, IFN-free treatment may not be accessible for many patients in the region, and IFN-based regimens remain an option in some countries. There is a need to improve current clinical practices for HCV management in Asia, including effective screening, disease awareness, and prevention programs, and to further understand the cost-effectiveness of IFN-free regimens. The evolution of potent treatments makes HCV eradication a possibility that should be available to all patients. However, access to these therapies in Asian countries has been slow, primarily because of economic barriers that continue to present a hurdle to optimal treatment.
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Affiliation(s)
- Jia-Horng Kao
- National Taiwan University College of Medicine, Taipei, Taiwan
| | | | - Rong-Nan Chien
- Chang-Gung Memorial Hospital, Kee-Lung Branch, Keelung, Taiwan
| | - Mong Cho
- Pusan National University Yangsan Hospital, Busan, Korea
| | - Wan-Long Chuang
- Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Sook-Hyang Jeong
- Seoul National University, College of Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Chen-Hua Liu
- National Taiwan University Hospital, Taipei, Taiwan
| | - Seung-Woon Paik
- Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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16
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Pervolaraki K, Stanifer ML, Münchau S, Renn LA, Albrecht D, Kurzhals S, Senís E, Grimm D, Schröder-Braunstein J, Rabin RL, Boulant S. Type I and Type III Interferons Display Different Dependency on Mitogen-Activated Protein Kinases to Mount an Antiviral State in the Human Gut. Front Immunol 2017; 8:459. [PMID: 28484457 PMCID: PMC5399069 DOI: 10.3389/fimmu.2017.00459] [Citation(s) in RCA: 75] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2017] [Accepted: 04/04/2017] [Indexed: 12/17/2022] Open
Abstract
Intestinal epithelial cells (IECs) are constantly exposed to commensal flora and pathogen challenges. How IECs regulate their innate immune response to maintain gut homeostasis remains unclear. Interferons (IFNs) are cytokines produced during infections. While type I IFN receptors are ubiquitously expressed, type III IFN receptors are expressed only on epithelial cells. This epithelium specificity strongly suggests exclusive functions at epithelial surfaces, but the relative roles of type I and III IFNs in the establishment of an antiviral innate immune response in human IECs are not clearly defined. Here, we used mini-gut organoids to define the functions of types I and III IFNs to protect the human gut against viral infection. We show that primary non-transformed human IECs, upon viral challenge, upregulate the expression of both type I and type III IFNs at the transcriptional level but only secrete type III IFN in the supernatant. However, human IECs respond to both type I and type III IFNs by producing IFN-stimulated genes that in turn induce an antiviral state. Using genetic ablation of either type I or type III IFN receptors, we show that either IFN can independently restrict virus infection in human IECs. Importantly, we report, for the first time, differences in the mechanisms by which each IFN establishes the antiviral state. Contrary to type I IFN, the antiviral activity induced by type III IFN is strongly dependent on the mitogen-activated protein kinases signaling pathway, suggesting a pathway used by type III IFNs that non-redundantly contributes to the antiviral state. In conclusion, we demonstrate that human intestinal epithelial cells specifically regulate their innate immune response favoring type III IFN-mediated signaling, which allows for efficient protection against pathogens without producing excessive inflammation. Our results strongly suggest that type III IFN constitutes the frontline of antiviral response in the human gut. We propose that mucosal surfaces, particularly the gastrointestinal tract, have evolved to favor type III IFN-mediated response to pathogen infections as it allows for spatial segregation of signaling and moderate production of inflammatory signals which we propose are key to maintain gut homeostasis.
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Affiliation(s)
- Kalliopi Pervolaraki
- Schaller Research Group at CellNetworks, Department of Infectious Diseases, Virology, Heidelberg University Hospital, Heidelberg, Germany.,Research Group "Cellular Polarity and Viral Infection" (F140), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Megan L Stanifer
- Schaller Research Group at CellNetworks, Department of Infectious Diseases, Virology, Heidelberg University Hospital, Heidelberg, Germany
| | - Stephanie Münchau
- Schaller Research Group at CellNetworks, Department of Infectious Diseases, Virology, Heidelberg University Hospital, Heidelberg, Germany
| | - Lynnsey A Renn
- Center for Biologics Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA
| | - Dorothee Albrecht
- Schaller Research Group at CellNetworks, Department of Infectious Diseases, Virology, Heidelberg University Hospital, Heidelberg, Germany
| | - Stefan Kurzhals
- Institute of Immunology, Heidelberg University Hospital, Heidelberg, Germany
| | - Elena Senís
- Department of Infectious Diseases, Virology, BioQuant, Heidelberg University Hospital, Heidelberg, Germany
| | - Dirk Grimm
- Department of Infectious Diseases, Virology, BioQuant, Heidelberg University Hospital, Heidelberg, Germany
| | | | - Ronald L Rabin
- Center for Biologics Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA
| | - Steeve Boulant
- Schaller Research Group at CellNetworks, Department of Infectious Diseases, Virology, Heidelberg University Hospital, Heidelberg, Germany.,Research Group "Cellular Polarity and Viral Infection" (F140), German Cancer Research Center (DKFZ), Heidelberg, Germany
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17
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Chang QJ, Lv C, Zhao F, Xu TS, Li P. Elevated Serum Levels of Interleukin-29 Are Associated with Disease Activity in Rheumatoid Arthritis Patients with Anti-Cyclic Citrullinated Peptide Antibodies. TOHOKU J EXP MED 2017; 241:89-95. [PMID: 28154345 DOI: 10.1620/tjem.241.89] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Rheumatoid arthritis (RA) is an inflammatory autoimmune disease that may lead to progressive joint destruction. The anti-cyclic citrullinated peptide (anti-CCP) antibody is an essential marker for the diagnosis of RA and has a crucial role in the bone destruction in RA. Recent studies have shown that interleukin (IL)-29, a vital member of type III interferon (IFN) family, could enhance proinflammatory cytokine production and might be involved in the joint destruction in RA. Therefore, in this study, we aimed to examine the role of IL-29 in RA patients with anti-CCP antibodies. The result showed that the serum IL-29 levels were higher in RA patients (n = 68) compared with healthy controls (HC, n = 68, P = 0.019). Correlation analysis demonstrated a significant positive correlation among serum IL-29 level, rheumatoid factor (RF, P < 0.001) and anti-CCP antibodies (P = 0.042). However, when RA patients were divided into two groups according to anti-CCP antibodies, the serum IL-29 levels were significantly higher in anti-CCP-antibodies positive RA patients (n = 54) than those in HC (n = 68) and anti-CCP-antibodies negative RA patients (n = 14). Furthermore, the serum IL-29 levels were positively correlated with the disease activity (P < 0.05) and significantly declined after 6 months of treatment (P < 0.01) in the anti-CCP-antibodies positive RA patients, whereas no significant change was found in the anti-CCP-antibodies negative RA patients (P > 0.05). The findings indicate that IL-29 is a potential biomarker for disease activity in anti-CCP-antibodies positive RA patients.
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Affiliation(s)
- Qiong-Jie Chang
- Department of Rheumatology and Immunology, China-Japan Union Hospital of Jilin University
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18
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Sedighimehr P, Irani S, Sakhaee F, Vaziri F, Aghasadeghi M, Sadat SM, Jamnani FR, Fateh A, Siadat SD. IL28B rs12980275 and HLA rs4273729 genotypes as a powerful predictor factor for rapid, early, and sustained virologic response in patients with chronic hepatitis C. Arch Virol 2017; 162:181-189. [PMID: 27714501 DOI: 10.1007/s00705-016-3095-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2016] [Accepted: 09/29/2016] [Indexed: 12/14/2022]
Abstract
Single-nucleotide polymorphisms (SNPs) in the Interleukin-28B (IL28B) gene and rs4273729 in the human leukocyte antigen (HLA) gene in chronic hepatitis C (CHC) virus infection are important for predicting treatment outcome. In this study, the distribution of IL28B SNPs (rs12979860 and rs12980275) and HLA rs4273729 in rapid virologic response (RVR), complete early virologic response (cEVR) and sustained virologic response (SVR) in HCV Iranian patients with CHC virus infection was assessed. IL28B genotyping and rs4273729 were performed using the amplification refractory mutation system (ARMS)-PCR and direct sequencing in 190 CHC virus infections, respectively. RVR, cEVR, and SVR were 53.2 %, 78.9 %, and 65.8 %, respectively. Multivariate regression analysis demonstrated that the responses significantly predicted SVR in patients with age <40 years (p = 0.008), HCV genotypes (p = 0.032), IL28B rs12979860 CC genotype (p < 0.001), rs12980275 AA genotype (p < 0.001), rs4273729 GG genotype (p < 0.001), RVR (p < 0.001) and cEVR (p = 0.024). Three critical predictor factors based on RVR response were rs12979860 CC genotype (p = 0.033), rs12980275 AA genotype (p < 0.001) and rs4273729 GG genotype (p < 0.001), while rs12980275 AA (p = 0.003) and rs4273729 GG genotypes (p < 0.001) predicted cEVR. For the first time in Iran, these results revealed that the rs12980275 and HLA rs4273729 are important for the treatment of CHC infection. These findings may help predict responses to CHC infection treatment and reduce the cost and side effects of therapy.
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Affiliation(s)
- Parvaneh Sedighimehr
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Shiva Irani
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Fatemeh Sakhaee
- Departments of Mycobacteriology and Pulmonary Research, Pasteur Institute of Iran, Tehran, Iran
| | - Farzam Vaziri
- Departments of Mycobacteriology and Pulmonary Research, Pasteur Institute of Iran, Tehran, Iran
- Microbiology Research Center (MRC), Pasteur Institute of Iran, Tehran, Iran
| | | | - Seyed Mehdi Sadat
- Department of Hepatitis and AIDS, Pasteur Institute of Iran, Tehran, Iran
| | - Fatemeh Rahimi Jamnani
- Departments of Mycobacteriology and Pulmonary Research, Pasteur Institute of Iran, Tehran, Iran
- Microbiology Research Center (MRC), Pasteur Institute of Iran, Tehran, Iran
| | - Abolfazl Fateh
- Departments of Mycobacteriology and Pulmonary Research, Pasteur Institute of Iran, Tehran, Iran.
- Microbiology Research Center (MRC), Pasteur Institute of Iran, Tehran, Iran.
| | - Seyed Davar Siadat
- Departments of Mycobacteriology and Pulmonary Research, Pasteur Institute of Iran, Tehran, Iran
- Microbiology Research Center (MRC), Pasteur Institute of Iran, Tehran, Iran
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19
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Morán-Auth Y, Penna-Martinez M, Perner D, Susser S, Wicker S, Zeuzem S, Sarrazin C, Badenhoop K. IL28B gene variants and glucose metabolism in Type 2 Diabetes. Hum Immunol 2016; 77:1280-1283. [PMID: 27664841 DOI: 10.1016/j.humimm.2016.09.007] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2015] [Revised: 08/14/2016] [Accepted: 09/19/2016] [Indexed: 11/28/2022]
Abstract
Type 2 Diabetes (T2D) develops, when β-cell insulin response fails to compensate for insulin resistance. Recent studies reported associations between the IL28B polymorphisms (rs12979860 and rs8099917) and T2D development in Hepatitis C virus (HCV) patients. To identify possible association with T2D independent from virus infection, we investigated both IL28B polymorphisms in T2D patients and healthy controls (HC). No association was found comparing the genotype and allele frequencies of both IL28B polymorphisms between T2D patients and HC. However, higher glucose levels were found in T2D patients carrying the IL28B CT/TT rs12979860 and GT/GG rs8099917 HCV risk genotypes compared to those with the protective CC and TT genotype (p=0.06 and p=0.02, respectively). Moreover, T2D patients with CT/TT rs12979860 HCV risk genotypes possessed significantly higher HbA1c levels than CC carriers (p=0.04). In conclusion, the IL28B HCV risk genotypes may influence glucose homeostasis in T2D patients without HCV.
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Affiliation(s)
- Y Morán-Auth
- Department of Internal Medicine I, Division of Endocrinology, Diabetes and Metabolism, University Frankfurt, Frankfurt am Main, Germany.
| | - M Penna-Martinez
- Department of Internal Medicine I, Division of Endocrinology, Diabetes and Metabolism, University Frankfurt, Frankfurt am Main, Germany
| | - D Perner
- Department of Internal Medicine I, Division of Endocrinology, Diabetes and Metabolism, University Frankfurt, Frankfurt am Main, Germany
| | - S Susser
- Department of Internal Medicine I, Division of Endocrinology, Diabetes and Metabolism, University Frankfurt, Frankfurt am Main, Germany
| | - S Wicker
- Occupational Health Service, University Frankfurt, Frankfurt am Main, Germany
| | - S Zeuzem
- Department of Internal Medicine I, Division of Endocrinology, Diabetes and Metabolism, University Frankfurt, Frankfurt am Main, Germany
| | - C Sarrazin
- Department of Internal Medicine I, Division of Endocrinology, Diabetes and Metabolism, University Frankfurt, Frankfurt am Main, Germany
| | - K Badenhoop
- Department of Internal Medicine I, Division of Endocrinology, Diabetes and Metabolism, University Frankfurt, Frankfurt am Main, Germany
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20
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Hayes CN, Chayama K. Interferon stimulated genes and innate immune activation following infection with hepatitis B and C viruses. J Med Virol 2016; 89:388-396. [DOI: 10.1002/jmv.24659] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/08/2016] [Indexed: 12/28/2022]
Affiliation(s)
- C. Nelson Hayes
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences; Hiroshima University; Hiroshima Japan
- Liver Research Project Center; Hiroshima University; Hiroshima Japan
| | - Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences; Hiroshima University; Hiroshima Japan
- Liver Research Project Center; Hiroshima University; Hiroshima Japan
- Laboratory for Digestive Diseases; Center for Genomic Medicine, RIKEN; Hiroshima Japan
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21
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IQGAP2 is a novel interferon-alpha antiviral effector gene acting non-conventionally through the NF-κB pathway. J Hepatol 2016; 65:972-979. [PMID: 27401546 PMCID: PMC5656012 DOI: 10.1016/j.jhep.2016.06.028] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2016] [Revised: 06/05/2016] [Accepted: 06/27/2016] [Indexed: 02/04/2023]
Abstract
BACKGROUND & AIMS Type I interferons (IFN) provide the first line of defense against invading pathogens but its mechanism of action is still not well understood. Using unbiased genome-wide siRNA screens, we recently identified IQ-motif containing GTPase activating protein 2 (IQGAP2), a tumor suppressor predominantly expressed in the liver, as a novel gene putatively required for IFN antiviral response against hepatitis C virus (HCV) infection. Here we sought to characterize IQGAP2 role in IFN response. METHODS We used transient small interfering RNA knockdown strategy in hepatic cell lines highly permissive to JFH1 strain of HCV infection. RESULTS We found that IQGAP2 acts downstream of IFN binding to its receptor, and independently of the JAK-STAT pathway, by physically interacting with RelA (also known as p65), a subunit of the NF-κB transcription factor. Interestingly, our data reveal a mechanism distinct from the well-characterized role of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in IFN production. Indeed, IFN alone was sufficient to stimulate NF-κB-dependent transcription in the absence of viral infection. Finally, both IQGAP2 and RelA were required for the induction by IFN of a subset of IFN-stimulated genes (ISG) with known antiviral properties. CONCLUSIONS Our data identify a novel function for IQGAP2 in IFN antiviral response in hepatoma cells. We demonstrate the involvement of IQGAP2 in regulating ISG induction by IFN in an NF-κB-dependent manner. The IQGAP2 pathway may provide new targets for antiviral strategies in the liver, and may have a wider therapeutic implication in other disease pathogeneses driven by NF-κB activation. LAY SUMMARY In this study, we identify a novel mechanism of action of interferon involving the IQGAP2 protein and the NF-κB pathway that is ultimately protective against hepatitis C virus infection. This newly identified pathway functions independently of the well-known STAT pathway and may therefore provide new targets for antiviral strategies in the liver.
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Romagnoli R, Martini S, Tandoi F, Dell Olio D, Magistroni P, Bertinetto FE, Dametto E, Rizzetto M, Salizzoni M, Amoroso A. Early reduced liver graft survival in hepatitis C recipients identified by two combined genetic markers. Transpl Int 2016; 29:1070-84. [PMID: 27172242 DOI: 10.1111/tri.12795] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2015] [Revised: 02/23/2016] [Accepted: 05/09/2016] [Indexed: 01/08/2023]
Abstract
HLA and IL-28B genes were independently associated with severity of HCV-related liver disease. We investigated the effects of these combined genetic factors on post-transplant survival in HCV-infected recipients, aiming to provide new data to define the optimal timing of novel antiviral therapies in the transplant setting. HLA-A/B/DRB1 alleles and IL-28B rs12979860 (C > T) polymorphism frequencies were determined in 449 HCV viremic recipients and in their donors. Median follow-up was 10 years; study outcome was graft survival. HLA-DRB1*11 phenotype and IL-28B C/C genotype were significantly less frequent in recipients than donors (27.8% vs. 45.9% and 27.4% vs. 44.9%, respectively, P < 0.00001). Ten-year graft survival was better in patients with HLA-DRB1*11 (P = 0.0183) or IL-28B C/C (P = 0.0436). Conversely, concomitant absence of HLA-DRB1*11 and IL-28B C/C in 228 (50.8%) predicted worse survival (P = 0.0006), which was already evident at the first post-transplant year (P = 0.0370). In multivariable Cox analysis, absence of both markers ranked second as risk factor for survival (HR = 1.74), following donor age ≥ 70 years (HR = 1.77). In the current era of direct-acting antiviral agents, the negative effects of this common immunogenetic profile in HCV-infected recipients could be most effectively neutralized by peri-transplant treatment. This should be particularly relevant in countries where elderly donors represent an unavoidable resource.
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Affiliation(s)
- Renato Romagnoli
- Liver Transplantation Center, General Surgery Unit 2U, AOU Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy
| | - Silvia Martini
- Liver Transplantation Center, Gastrohepatology Unit, AOU Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy
| | - Francesco Tandoi
- Liver Transplantation Center, General Surgery Unit 2U, AOU Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy
| | - Dominic Dell Olio
- Regional Transplantation Center - Piedmont, AOU Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy
| | - Paola Magistroni
- Regional Transplantation Center - Piedmont, AOU Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy
- Immunogenetics Laboratory, AOU Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy
| | - Francesca E Bertinetto
- Regional Transplantation Center - Piedmont, AOU Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy
- Immunogenetics Laboratory, AOU Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy
| | - Ennia Dametto
- Regional Transplantation Center - Piedmont, AOU Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy
- Immunogenetics Laboratory, AOU Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy
| | - Mario Rizzetto
- Liver Transplantation Center, Gastrohepatology Unit, AOU Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy
| | - Mauro Salizzoni
- Liver Transplantation Center, General Surgery Unit 2U, AOU Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy
| | - Antonio Amoroso
- Regional Transplantation Center - Piedmont, AOU Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy.
- Immunogenetics Laboratory, AOU Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy.
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Kelly A, Robinson MW, Roche G, Biron CA, O'Farrelly C, Ryan EJ. Immune Cell Profiling of IFN-λ Response Shows pDCs Express Highest Level of IFN-λR1 and Are Directly Responsive via the JAK-STAT Pathway. J Interferon Cytokine Res 2016; 36:671-680. [PMID: 27617757 DOI: 10.1089/jir.2015.0169] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
The interferon lambda (IFN-λ) cytokines have well-known antiviral properties, yet their contribution to immune regulation is not well understood. Epithelial cells represent the major target cell of IFN-λ; peripheral blood mononuclear cells are generally considered nonresponsive, with the exception of plasmacytoid dendritic cells (pDCs). In this study we aimed to define the potential for discrete subpopulations of cells to directly respond to IFN-λ. Analysis of peripheral blood leukocytes reveals that, while pDCs uniformly express the highest levels of IFN-λ receptor, a small proportion of B cells and monocytes also express the receptor. Nevertheless, B cells and monocytes respond poorly to IFN-λ stimulation in vitro, with minimal STAT phosphorylation and interferon-stimulated gene (ISG) induction observed. We confirm that pDCs respond to IFN-λ in vitro, upregulating their expression of pSTAT1, pSTAT3, and pSTAT5. However, we found that pDCs do not upregulate pSTAT6 in response to IFN-λ treatment. Our results highlight unique aspects of the response to IFN-λ and confirm that while the IFN-λ receptor is expressed by a small proportion of several different circulating immune cell lineages, under normal conditions only pDCs respond to IFN-λ stimulation with robust STAT phosphorylation and ISG induction. The difference in STAT6 responsiveness of pDCs to type I and type III interferons may help explain the divergence in their biological activities.
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Affiliation(s)
- Aoife Kelly
- 1 School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin , Dublin, Ireland
| | - Mark W Robinson
- 1 School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin , Dublin, Ireland
| | - Gerard Roche
- 1 School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin , Dublin, Ireland
| | - Christine A Biron
- 2 Department of Molecular Microbiology and Immunology, Brown University , Providence, Rhode Island
| | - Cliona O'Farrelly
- 1 School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin , Dublin, Ireland .,3 School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin , Dublin, Ireland
| | - Elizabeth J Ryan
- 4 Centre for Colorectal Disease, Education and Research Centre, St. Vincent's University Hospital , Dublin, Ireland .,5 School of Medicine and Medical Sciences, University College Dublin , Dublin, Ireland
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Daneshvar M, Nikbin M, Talebi S, Javadi F, Aghasadeghi MR, Mahmazi S, Sadat SM. Role of IL28-B Polymorphism (rs12979860) on Sustained Virological Response to Pegylated Interferon/Ribavirin in Iranian Patients With Chronic Hepatitis C. IRANIAN RED CRESCENT MEDICAL JOURNAL 2016; 18:e28566. [PMID: 28144454 PMCID: PMC5253204 DOI: 10.5812/ircmj.28566] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/19/2015] [Revised: 07/12/2015] [Accepted: 08/09/2015] [Indexed: 12/13/2022]
Abstract
Background The current medical treatment for hepatitis C virus (HCV) infection is pegylated interferon plus ribavirin, but just 50% of genotype 1 HCV patients and about 80% of HCV genotype 3 patients are treated completely. Recently, the rs12979860 C/T polymorphism, which is located 3 kb upstream of the IL28b gene that codes IFNλ3, shows a powerful association in response to the treatment in HCV patients. Objectives The aim of this study was to evaluate the relationship between IL28b single nucleotide polymorphism (SNP) and treatment outcomes among chronic HCV patients in Iran. Patients and Methods In this cross-sectional study, 108 blood samples were collected from chronic patients in Iran; 50 unrelated healthy subject samples were also collected. Genomic DNA was extracted, and rs12979860 SNP was done by PCR-RFLP. Finally, products were detected on 12% polyacrylamide gel electrophoresis. Results The analysis of data for C/T SNP showed that the CC genotype is more common in the control group than in the group of patients. In contrast, the frequency of TT as a mutant genotype is more frequent in patients than in uninfected people. In addition, results showed a statistically significant relationship between CC, CT, and TT genotypes in sensitive and resistant groups (P value: < 0.001, Or: 0.003, CI: 0-0.047). This relationship was also examined in terms of allele frequency, to determine whether the possibility of resistance to treatment in patients with T allele is more than in patients who carry C allele (P value: < 0.001). Conclusions These results showed a significant effect between rs12979860 SNP and sustained virological response (SVR) rate in Iranian patients with chronic HCV. To decrease the cost of long treatments and to prevent severe side effects, determining this polymorphism at the beginning of treatment can be very helpful for patients and physicians.
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Affiliation(s)
- Mahtab Daneshvar
- Department of Hepatitis and AIDS, Pasteur Institute of Iran, Tehran, IR Iran
- Genetics Department, Zanjan Branch, Islamic Azad University, Zanjan, IR Iran
| | | | - Solmaz Talebi
- Department of Biostatistics and Epidemiology, Tehran University of Medical Sciences, Tehran, IR Iran
| | - Foozieh Javadi
- Department of Hepatitis and AIDS, Pasteur Institute of Iran, Tehran, IR Iran
| | | | - Sanaz Mahmazi
- Genetics Department, Zanjan Branch, Islamic Azad University, Zanjan, IR Iran
| | - Seyed Mehdi Sadat
- Department of Hepatitis and AIDS, Pasteur Institute of Iran, Tehran, IR Iran
- Corresponding Author: Seyed Mehdi Sadat, No:69, Pasteur Ave, Department of Hepatitis and AIDS, Pasteur Institute of Iran, P. O. Box: 1316943551, Tehran, IR Iran. Tel/Fax: +98-2166969291, E-mail:
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Fan W, Xie S, Zhao X, Li N, Chang C, Li L, Yu G, Chi X, Pan Y, Niu J, Zhong J, Sun B. IFN-λ4 desensitizes the response to IFN-α treatment in chronic hepatitis C through long-term induction of USP18. J Gen Virol 2016; 97:2210-2220. [PMID: 27302182 DOI: 10.1099/jgv.0.000522] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
The recently discovered interferon lambda 4 (IFN-λ4) is a new member of the human type III interferons which could induce a strong antiviral effect through the JAK-STAT cascade. However, hepatitis C virus (HCV) patients who are capable of expressing IFN-λ4 usually have poor response to IFN-α treatment, and the mechanism behind this paradox remains unknown. Here, we reported that IFN-λ4 desensitized IFN-α-stimulated JAK-STAT signalling. Microarray analysis revealed that IFN-λ4 could induce ubiquitin specific peptidase 18 (USP18), a known inhibitor of the type I IFN signalling pathway, in a more sustained pattern compared with type I interferon induction. Moreover, only HCV genotype 1b but not 2a replicon cells pretreated with IFN-λ4 had an attenuated response to type I IFN treatment, which might be due to the different level of USP18 expression. Consistently, knockdown of USP18 in HCV genotype 1b-containing replicon cells reversed the resistance induced by IFN-λ4 and promoted viral clearance. Finally, IFN-λ4 is also strongly associated with the poor response to IFN-α in a Chinese HCV genotype 1b cohort. In conclusion, these data indicate that IFN-λ4 attenuates the response of HCV genotype 1b to IFN-α therapy and inhibits the JAK-STAT signalling pathway by inducing USP18 expression.
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Affiliation(s)
- Weiguo Fan
- Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, PR China
| | - Shiqi Xie
- Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, PR China
| | - Xinhao Zhao
- Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, PR China
| | - Nan Li
- Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, PR China.,School of Life Sciences and Technology, Shanghai Tech University, Shanghai 200031, PR China
| | - Chong Chang
- Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, PR China
| | - Li Li
- Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, PR China
| | - Ge Yu
- Hepatology Section, First Hospital, University of Jilin, Changchun 130021, Jilin, PR China
| | - Xiumei Chi
- Hepatology Section, First Hospital, University of Jilin, Changchun 130021, Jilin, PR China
| | - Yu Pan
- Hepatology Section, First Hospital, University of Jilin, Changchun 130021, Jilin, PR China
| | - Junqi Niu
- Hepatology Section, First Hospital, University of Jilin, Changchun 130021, Jilin, PR China
| | - Jin Zhong
- Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, PR China
| | - Bing Sun
- Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai, PR China.,Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, PR China
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Zhang Y, Zhu SL, Chen J, Li LQ. Meta-analysis of associations of interleukin-28B polymorphisms rs8099917 and rs12979860 with development of hepatitis virus-related hepatocellular carcinoma. Onco Targets Ther 2016; 9:3249-57. [PMID: 27313470 PMCID: PMC4892830 DOI: 10.2147/ott.s104904] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
Background This meta-analysis aimed to assess available evidence on possible associations of interleukin-28B polymorphisms rs8099917 and rs12979860 with development of hepatitis virus-related hepatocellular carcinoma (HCC). Methods PubMed, EMBASE, Google Scholar, and the Chinese National Knowledge Infrastructure databases were systematically searched to identify relevant studies. Meta-analyses were performed to examine the association of interleukin-28B rs8099917 G/T and rs12979860 T/C polymorphisms with development of hepatitis virus-related HCC. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Results A total of ten studies involving 2,529 cases and 2,412 controls were included. The G-allele and GT genotype of rs8099917 were significantly associated with increased risk of hepatitis B virus (HBV)-related HCC (allelic model, OR 1.49, 95% CI 1.13–1.96, P=0.005; heterozygous model, OR 1.39, 95% CI 1.04–1.88, P=0.03). Conversely, the TT genotype was found to be significantly associated with lower risk of HBV-related HCC (dominant model, OR 0.68, 95% CI 0.51–0.91, P=0.01). Similar results were observed in the subgroup of Chinese patients and controls. In the pooled data set, the T-allele and TT genotype of rs12979860 showed a significant association with increased HCC risk (allelic model, OR 1.36, 95% CI 1.05–1.78, P=0.02; recessive model, OR 1.75, 95% CI 1.28–2.39, P=0.005; homozygous model, OR 1.99, 95% CI 1.41–2.80, P<0.001). Subgroup analysis based on ethnicity and etiology showed rs12979860 polymorphism to be significantly associated with HCC risk in Caucasians, especially hepatitis C virus-related HCC, according to all five genetic models. In contrast, only the TT genotype of rs12979860 was found to be significantly associated with increased risk of HBV-related HCC, especially in Asians. Conclusion The G-allele of rs8099917 may confer elevated risk of HBV-related HCC, while the wild-type TT genotype may protect against the disease. The T-allele of rs12979860 may increase the risk of HCC, in Caucasians, especially hepatitis C virus-related HCC. The TT genotype of rs12979860 may confer increased risk of HBV-related HCC, especially in Asians. These conclusions should be verified in large, well-designed studies.
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Affiliation(s)
- Yu Zhang
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, People's Republic of China
| | - Shao-Liang Zhu
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, People's Republic of China
| | - Jie Chen
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, People's Republic of China
| | - Le-Qun Li
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, People's Republic of China
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Hepatitis C Virus Infection Induces Autophagy as a Prosurvival Mechanism to Alleviate Hepatic ER-Stress Response. Viruses 2016; 8:v8050150. [PMID: 27223299 PMCID: PMC4885105 DOI: 10.3390/v8050150] [Citation(s) in RCA: 58] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2016] [Revised: 05/04/2016] [Accepted: 05/18/2016] [Indexed: 12/17/2022] Open
Abstract
Hepatitis C virus (HCV) infection frequently leads to chronic liver disease, liver cirrhosis and hepatocellular carcinoma (HCC). The molecular mechanisms by which HCV infection leads to chronic liver disease and HCC are not well understood. The infection cycle of HCV is initiated by the attachment and entry of virus particles into a hepatocyte. Replication of the HCV genome inside hepatocytes leads to accumulation of large amounts of viral proteins and RNA replication intermediates in the endoplasmic reticulum (ER), resulting in production of thousands of new virus particles. HCV-infected hepatocytes mount a substantial stress response. How the infected hepatocyte integrates the viral-induced stress response with chronic infection is unknown. The unfolded protein response (UPR), an ER-associated cellular transcriptional response, is activated in HCV infected hepatocytes. Over the past several years, research performed by a number of laboratories, including ours, has shown that HCV induced UPR robustly activates autophagy to sustain viral replication in the infected hepatocyte. Induction of the cellular autophagy response is required to improve survival of infected cells by inhibition of cellular apoptosis. The autophagy response also inhibits the cellular innate antiviral program that usually inhibits HCV replication. In this review, we discuss the physiological implications of the HCV-induced chronic ER-stress response in the liver disease progression.
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Reid E, Juleff N, Windsor M, Gubbins S, Roberts L, Morgan S, Meyers G, Perez-Martin E, Tchilian E, Charleston B, Seago J. Type I and III IFNs Produced by Plasmacytoid Dendritic Cells in Response to a Member of the Flaviviridae Suppress Cellular Immune Responses. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2016; 196:4214-26. [PMID: 27053760 DOI: 10.4049/jimmunol.1600049] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/08/2016] [Accepted: 03/09/2016] [Indexed: 12/16/2023]
Abstract
The pestivirus noncytopathic bovine viral diarrhea virus (BVDV) can suppress IFN production in the majority of cell types in vitro. However, IFN is detectable in serum during acute infection in vivo for ∼5-7 d, which correlates with a period of leucopoenia and immunosuppression. In this study, we demonstrate that a highly enriched population of bovine plasmacytoid dendritic cells (DCs) produced IFN in response to BVDV in vitro. We further show that the majority of the IFN produced in response to infection both in vitro and in vivo is type III IFN and acid labile. Further, we show IL-28B (IFN-λ3) mRNA is induced in this cell population in vitro. Supernatant from plasmacytoid DCs harvested postinfection with BVDV or recombinant bovine IFN-α or human IL-28B significantly reduced CD4(+) T cell proliferation induced by tubercle bacillus Ag 85-stimulated monocyte-derived DCs. Furthermore, these IFNs induced IFN-stimulated gene expression predominantly in monocyte-derived DCs. IFN-treated immature DCs derived from murine bone marrow also had a reduced capacity to stimulate T cell proliferative responses to tubercle bacillus Ag 85. Immature DCs derived from either source had a reduced capacity for Ag uptake following IFN treatment that is dose dependent. Immunosuppression is a feature of a number of pestivirus infections; our studies suggest type III IFN production plays a key role in the pathogenesis of this family of viruses. Overall, in a natural host, we have demonstrated a link between the induction of type I and III IFN after acute viral infection and transient immunosuppression.
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Affiliation(s)
- Elizabeth Reid
- Viral Immunology, The Pirbright Institute, Surrey GU24 0NF, United Kingdom;
| | - Nicholas Juleff
- Viral Immunology, The Pirbright Institute, Surrey GU24 0NF, United Kingdom
| | - Miriam Windsor
- Viral Immunology, The Pirbright Institute, Surrey GU24 0NF, United Kingdom
| | - Simon Gubbins
- Viral Immunology, The Pirbright Institute, Surrey GU24 0NF, United Kingdom
| | - Lisa Roberts
- Faculty of Health and Medical Sciences, University of Surrey, Surrey GU2 7XH, United Kingdom; and
| | - Sophie Morgan
- Viral Immunology, The Pirbright Institute, Surrey GU24 0NF, United Kingdom
| | - Gregor Meyers
- Institut für Immunologie, Friedrich-Loeffler-Institut, Riems D-17493, Germany
| | - Eva Perez-Martin
- Viral Immunology, The Pirbright Institute, Surrey GU24 0NF, United Kingdom
| | - Elma Tchilian
- Viral Immunology, The Pirbright Institute, Surrey GU24 0NF, United Kingdom
| | - Bryan Charleston
- Viral Immunology, The Pirbright Institute, Surrey GU24 0NF, United Kingdom
| | - Julian Seago
- Viral Immunology, The Pirbright Institute, Surrey GU24 0NF, United Kingdom
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Bartolomé J, Castillo I, Quiroga JA, Carreño V. Interleukin-28B polymorphisms and interferon gamma inducible protein-10 serum levels in seronegative occult hepatitis C virus infection. J Med Virol 2016; 88:268-74. [PMID: 26147900 DOI: 10.1002/jmv.24322] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/26/2015] [Indexed: 12/31/2022]
Abstract
Polymorphisms upstream interleukin (IL)-28B gene and serum levels of interferon gamma inducible protein-10 (IP-10) are associated with spontaneous and treatment-induced hepatitis C virus (HCV) clearance. Patients with seronegative occult HCV infection are anti-HCV and serum HCV-RNA negative but have viral RNA in liver and abnormal values of liver enzymes. We examined if the rs12979860 polymorphism of IL-28B and serum IP-10 levels differ between chronic and seronegative occult CV infection. IL-28B polymorphism was determined with allele specific TaqMan probes in total DNA isolated from peripheral blood mononuclear cells and IP-10 by an enzyme-linked immunosorbent assay in serum from 99 patients with seronegative occult HCV infection and 130 untreated patients with chronic hepatitis C. IL-28B genotypes were also determined in 54 healthy volunteers. Prevalence of the IL-28B CC genotype was significantly higher in seronegative occult HCV infection (52/99; 52.5%) than in chronic hepatitis C (32/130; 24.6%, P < 0.0001) or healthy controls (19/54: 32.5%, P = 0.039). Among patients with seronegative occult HCV infection, HCV-RNA load in liver was significantly lower in those with the IL-28B CC genotype than in those with CT + TT genotypes (2.8 × 10(5) ± 5.8 × 10(4) vs. 4.1 × 10(5) ± 5.9 × 10(4) copies/μg of total RNA respectively; P = 0.023). Mean serum IP-10 levels were significantly lower in patients with seronegative occult HCV infection than in patients with chronic hepatitis C (160.8 ± 17.9 vs. 288.7 ± 13.3 pg/ml respectively; P < 0.0001). These findings suggest that the host immune response plays an important role in seronegative occult HCV infection in comparison with chronic hepatitis C.
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Affiliation(s)
- Javier Bartolomé
- Fundación para el Estudio de las Hepatitis Virales, Madrid, Spain
| | | | | | - Vicente Carreño
- Fundación para el Estudio de las Hepatitis Virales, Madrid, Spain
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Wu LS, Jimmerson LC, MacBrayne CE, Kiser JJ, D'Argenio DZ. Modeling Ribavirin-Induced Anemia in Patients with Chronic Hepatitis C Virus. CPT Pharmacometrics Syst Pharmacol 2016; 5:65-73. [PMID: 26933517 PMCID: PMC4761234 DOI: 10.1002/psp4.12058] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2015] [Accepted: 12/30/2015] [Indexed: 12/17/2022] Open
Abstract
Ribavirin remains an important component of hepatitis C treatment in certain clinical scenarios, but it causes hemolytic anemia. A quantitative understanding of the ribavirin exposure-anemia relationship is important in dose individualization/optimization. We developed a model relating ribavirin triphosphate (RTP) exposure in red blood cells (RBCs), RBC lifespan, feedback regulation of RBC production when anemia occurs, and the resulting hemoglobin decline. Inosine triphosphatase (ITPA) and interleukin 28B (IL28B) genetics were found to be significant covariates. Clinical trial simulations predicted that anemia is least severe in IL28B non-CC (rs12979860, CT or TT), ITPA variant subjects, followed by IL28B non-CC, ITPA wild-type, IL28B CC, ITPA variant, and IL28B CC, ITPA wild-type subjects (most severe). Reducing the ribavirin dose from 1,200/1,000 mg to 800/600 mg could reduce the proportions of grade 2 anemia by about half. The resulting model framework will aid the development of dosing strategies that minimize the incidence of anemia in treatment regimens that include ribavirin.
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Affiliation(s)
- LS Wu
- University of Southern California, Biomedical EngineeringLos AngelesCaliforniaUSA
| | - LC Jimmerson
- University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Department of Pharmaceutical SciencesAuroraColoradoUSA
| | - CE MacBrayne
- University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Department of Pharmaceutical SciencesAuroraColoradoUSA
| | - JJ Kiser
- University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Department of Pharmaceutical SciencesAuroraColoradoUSA
| | - DZ D'Argenio
- University of Southern California, Biomedical EngineeringLos AngelesCaliforniaUSA
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Aboulnasr F, Hazari S, Nayak S, Chandra PK, Panigrahi R, Ferraris P, Chava S, Kurt R, Song K, Dash A, Balart LA, Garry RF, Wu T, Dash S. IFN-λ Inhibits MiR-122 Transcription through a Stat3-HNF4α Inflammatory Feedback Loop in an IFN-α Resistant HCV Cell Culture System. PLoS One 2015; 10:e0141655. [PMID: 26657215 PMCID: PMC4686105 DOI: 10.1371/journal.pone.0141655] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2015] [Accepted: 10/12/2015] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND HCV replication in persistently infected cell culture remains resistant to IFN-α/RBV combination treatment, whereas IFN-λ1 induces viral clearance. The antiviral mechanisms by which IFN-λ1 induces sustained HCV clearance have not been determined. AIM To investigate the mechanisms by which IFN-λ clears HCV replication in an HCV cell culture model. METHODS IFN-α sensitive (S3-GFP) and resistant (R4-GFP) cells were treated with equivalent concentrations of either IFN-α or IFN-λ. The relative antiviral effects of IFN-α and IFN-λ1 were compared by measuring the HCV replication, quantification of HCV-GFP expression by flow cytometry, and viral RNA levels by real time RT-PCR. Activation of Jak-Stat signaling, interferon stimulated gene (ISG) expression, and miRNA-122 transcription in S3-GFP and R4-GFP cells were examined. RESULTS We have shown that IFN-λ1 induces HCV clearance in IFN-α resistant and sensitive replicon cell lines in a dose dependent manner through Jak-Stat signaling, and induces STAT 1 and STAT 2 activation, ISRE-luciferase promoter activation and ISG expression. Stat 3 activation is also involved in IFN-λ1 induced antiviral activity in HCV cell culture. IFN-λ1 induced Stat 3 phosphorylation reduces the expression of hepatocyte nuclear factor 4 alpha (HNF4α) through miR-24 in R4-GFP cells. Reduced expression of HNF4α is associated with decreased expression of miR-122 resulting in an anti-HCV effect. Northern blot analysis confirms that IFN-λ1 reduces miR-122 levels in R4-GFP cells. Our results indicate that IFN-λ1 activates the Stat 3-HNF4α feedback inflammatory loop to inhibit miR-122 transcription in HCV cell culture. CONCLUSIONS In addition to the classical Jak-Stat antiviral signaling pathway, IFN-λ1 inhibits HCV replication through the suppression of miRNA-122 transcription via an inflammatory Stat 3-HNF4α feedback loop. Inflammatory feedback circuits activated by IFNs during chronic inflammation expose non-responders to the risk of hepatocellular carcinoma.
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Affiliation(s)
- Fatma Aboulnasr
- Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA-70112, United States of America
| | - Sidhartha Hazari
- Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA-70112, United States of America
| | - Satyam Nayak
- Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA-70112, United States of America
| | - Partha K. Chandra
- Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA-70112, United States of America
| | - Rajesh Panigrahi
- Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA-70112, United States of America
| | - Pauline Ferraris
- Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA-70112, United States of America
| | - Srinivas Chava
- Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA-70112, United States of America
| | - Ramazan Kurt
- Department of Medicine, Division of Gastroenterology and Hepatology
| | - Kyongsub Song
- Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA-70112, United States of America
| | - Asha Dash
- Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA-70112, United States of America
| | - Luis A. Balart
- Department of Medicine, Division of Gastroenterology and Hepatology
| | - Robert F. Garry
- Microbiology and Immunology Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA-70112, United States of America
| | - Tong Wu
- Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA-70112, United States of America
| | - Srikanta Dash
- Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA-70112, United States of America
- Department of Medicine, Division of Gastroenterology and Hepatology
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Akkız H, Akgöllü E, Bekar A, Yıldırım S, Sandıkçı M, Ülger Y, Yalınbaş Kaya B, Kuran S, Üsküdar O. Relationship between IL28B gene rs8099917 polymorphism and SVR in Turkish patients with hepatitis C virus genotype 1. Clin Res Hepatol Gastroenterol 2015; 39:711-7. [PMID: 25857516 DOI: 10.1016/j.clinre.2015.02.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2015] [Accepted: 02/25/2015] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND OBJECTIVE The hepatitis C virus (HCV) which infects 3% of the world's population is a global challenge. Recently, genome-wide association studies (GWAS) have identified that the IL28B gene rs8099917 polymorphism was associated with the response to the pegylated-interferon alpha/ribavirin (PegIFNα/RBV) combination therapy in patients infected with HCV genotype 1. IL28B gene rs8099917 polymorphism should be determined before beginning treatment of HCV-infected patients to predict an individual's response. The aims of this study were to analyze the correlation between IL28B gene rs8099917 (T/G) polymorphism and PegIFNα/RBV therapy outcome in the Turkish population. METHODS Genotypes of the IL28B gene rs8099917 (T/G) single nucleotide polymorphism (SNP) were determined in 308 patients with HCV infection by using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. One group consisted of 148 patients with a sustained virological response (SVR), whereas the second group consisted of 160 nonresponders (non-SVR). RESULTS Allele and genotype associations of IL28B gene rs8099917 polymorphism with a sustained virological response were observed in comparisons between the SVR and non-SVR groups (P<0.001). In addition, the characteristics of the subjects did not differ between these two groups except for age and fibrosis stage (P<0.05). Additionally, neither SVR nor rs80999917 genotypes were associated by HCV RNA levels. CONCLUSIONS In conclusion, the rs8099917 polymorphism was thus found strongly associated with a sustained virological response to therapy in Turkish patients infected with HCV genotype 1. Consequently, we suggest determining IL28B gene rs8099917 polymorphism of patients with HCV genotype 1 before onset of treatment.
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Affiliation(s)
- Hikmet Akkız
- Çukurova University, Faculty of Medicine, Department of Gastroenterology, 01330 Adana, Turkey.
| | - Ersin Akgöllü
- Çukurova University, Faculty of Medicine, Department of Gastroenterology, 01330 Adana, Turkey.
| | - Aynur Bekar
- Çukurova University, Faculty of Medicine, Department of Gastroenterology, 01330 Adana, Turkey.
| | - Selçuk Yıldırım
- Çukurova University, Faculty of Medicine, Department of Gastroenterology, 01330 Adana, Turkey.
| | - Macit Sandıkçı
- Çukurova University, Faculty of Medicine, Department of Gastroenterology, 01330 Adana, Turkey.
| | - Yakup Ülger
- Çukurova University, Faculty of Medicine, Department of Gastroenterology, 01330 Adana, Turkey.
| | - Berrin Yalınbaş Kaya
- Çukurova University, Faculty of Medicine, Department of Gastroenterology, 01330 Adana, Turkey.
| | - Sedef Kuran
- Çukurova University, Faculty of Medicine, Department of Gastroenterology, 01330 Adana, Turkey.
| | - Oğuz Üsküdar
- Çukurova University, Faculty of Medicine, Department of Gastroenterology, 01330 Adana, Turkey.
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Ren Y, Wang W, Zhang X, Xu Y, Di Bisceglie AM, Fan X. Evidence for deleterious hepatitis C virus quasispecies mutation loads that differentiate the response patterns in IFN-based antiviral therapy. J Gen Virol 2015; 97:334-343. [PMID: 26581744 DOI: 10.1099/jgv.0.000346] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Viral quasispecies (QS) have long been considered to affect the efficiency of hepatitis C virus (HCV) antiviral therapy, but a correlation between QS diversity and treatment outcomes has not been established conclusively. We previously measured HCV QS diversity by genome-wide quantification of high-resolution mutation load in HCV genotype 1a patients achieving a sustained virological response (1a/SVR) or a null response (1a/null). The current study extended this work into HCV 1a patients experiencing relapse (1a/relapse, n = 19) and genotype 2b patients with SVR (2b/SVR, n = 10). The mean mutation load per patient in 2b/SVR and 1a/relapse was similar, respectively, to 1a/SVR (517.6 ± 174.3 vs 524 ± 278.8 mutations, P = 0.95) and 1a/null (829.2 ± 282.8 vs 805.6 ± 270.7 mutations, P = 0.78). Notably, a deleterious mutation load, as indicated by the percentage of non-synonymous mutations, was highest in 2b/SVR (33.2 ± 8.5%) as compared with 1a/SVR (23.6 ± 7.8%, P = 0.002), 1a/null (18.2 ± 5.1%, P = 1.9 × 10(-7)) or 1a/relapse (17.8 ± 5.3%, P = 1.8) × 10(-6). In the 1a/relapse group, continuous virus evolution was observed with excessive accumulation of a deleterious load (17.8 ± 5.3% vs 35.4 ± 12.9%, P = 3.5 × 10(-6)), supporting the functionality of Muller's ratchet in a treatment-induced population bottleneck. Taken together, the magnitude of HCV mutation load, particularly the deleterious mutation load, provides an evolutionary explanation for the emergence of multiple response patterns as well as an overall high SVR rate in HCV genotype 2 patients. Augmentation of Muller's ratchet represents a potential strategy to reduce or even eliminate viral relapse in HCV antiviral therapy.
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Affiliation(s)
- Yi Ren
- Division of Gastroenterology & Hepatology, Department of Internal Medicine, Saint Louis University School of Medicine, St Louis, MO 63104, USA.,Wuhan Center for Tuberculosis Control, Wuhan 430030, Hubei, PR China
| | - Weihua Wang
- Division of Gastroenterology & Hepatology, Department of Internal Medicine, Saint Louis University School of Medicine, St Louis, MO 63104, USA
| | - Xiaoan Zhang
- Division of Gastroenterology & Hepatology, Department of Internal Medicine, Saint Louis University School of Medicine, St Louis, MO 63104, USA
| | - Yanjuan Xu
- Division of Gastroenterology & Hepatology, Department of Internal Medicine, Saint Louis University School of Medicine, St Louis, MO 63104, USA
| | - Adrian M Di Bisceglie
- Division of Gastroenterology & Hepatology, Department of Internal Medicine, Saint Louis University School of Medicine, St Louis, MO 63104, USA.,Saint Louis University Liver Center, Saint Louis University School of Medicine, St Louis, MO 63104, USA
| | - Xiaofeng Fan
- Division of Gastroenterology & Hepatology, Department of Internal Medicine, Saint Louis University School of Medicine, St Louis, MO 63104, USA.,Saint Louis University Liver Center, Saint Louis University School of Medicine, St Louis, MO 63104, USA
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Sung PS, Shin EC, Yoon SK. Interferon Response in Hepatitis C Virus (HCV) Infection: Lessons from Cell Culture Systems of HCV Infection. Int J Mol Sci 2015; 16:23683-94. [PMID: 26457705 PMCID: PMC4632721 DOI: 10.3390/ijms161023683] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2015] [Revised: 09/18/2015] [Accepted: 09/24/2015] [Indexed: 12/22/2022] Open
Abstract
Hepatitis C virus (HCV) is a positive-stranded RNA virus that infects approximately 130–170 million people worldwide. In 2005, the first HCV infection system in cell culture was established using clone JFH-1, which was isolated from a Japanese patient with fulminant HCV infection. JFH-1 replicates efficiently in hepatoma cells and infectious virion particles are released into the culture supernatant. The development of cell culture-derived HCV (HCVcc) systems has allowed us to understand how hosts respond to HCV infection and how HCV evades host responses. Although the mechanisms underlying the different outcomes of HCV infection are not fully understood, innate immune responses seem to have a critical impact on the outcome of HCV infection, as demonstrated by the prognostic value of IFN-λ gene polymorphisms among patients with chronic HCV infection. Herein, we review recent research on interferon response in HCV infection, particularly studies using HCVcc infection systems.
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Affiliation(s)
- Pil Soo Sung
- Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, KAIST, Daejeon 34141, Korea.
| | - Eui-Cheol Shin
- Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, KAIST, Daejeon 34141, Korea.
| | - Seung Kew Yoon
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea.
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Finotti G, Tamassia N, Calzetti F, Fattovich G, Cassatella MA. Endogenously produced TNF-α contributes to the expression of CXCL10/IP-10 in IFN-λ3-activated plasmacytoid dendritic cells. J Leukoc Biol 2015; 99:107-19. [PMID: 26382296 DOI: 10.1189/jlb.3vma0415-144r] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2015] [Accepted: 08/28/2015] [Indexed: 12/31/2022] Open
Abstract
The interplay between IFN-λs and dendritic cells is becoming increasingly relevant, particularly in light of their key role in inducing the antiviral state, including in hepatitis C virus infection. In this work, we have analyzed extensively how human plasmacytoid dendritic cells respond to IFN-λ3. We report that plasmacytoid dendritic cells incubated with IFN-λ3 prolong their survival; alter their expression pattern of surface HLA-DRα, CD123, CD86, and CD303; and time dependently produce IFN-α, CXCL10/IFN-γ-induced protein 10, and even modest quantities of TNF-α. Nevertheless, endogenously produced TNF-α, but not IFN-α, was found to be essential for driving the expression of CXCL10/IFN-γ-induced protein 10 in IFN-λ3-treated plasmacytoid dendritic cells, as revealed by neutralizing experiments by use of adalimumab, etanercept, and infliximab. We also observed that based on the kinetics and levels of IFN-α and CXCL10/IFN-γ-induced protein 10 produced by their IFN-λ3-treated plasmacytoid dendritic cells, healthy donors could be categorized into 2 and 3 groups, respectively. In particular, we identified a group of donors whose plasmacytoid dendritic cells produced modest quantities of CXCL10/IFN-γ-induced protein 10; another one whose plasmacytoid dendritic cells produced elevated CXCL10/IFN-γ-induced protein 10 levels, already after 18 h, declining thereafter; and a 3rd group characterized by plasmacytoid dendritic cells releasing very high CXCL10/IFN-γ-induced protein 10 levels after 42 h only. Finally, we report that in plasmacytoid dendritic cells, equivalent concentrations of IFN-λ3 and IFN-λ1 promote survival, antigen modulation, and cytokine production in a comparable manner and without acting additively/synergistically. Altogether, data not only extend the knowledge on the biologic effects that IFN-λs exert on plasmacytoid dendritic cells but also add novel light to the networking between IFN-λs and plasmacytoid dendritic cells in fighting viral diseases.
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Affiliation(s)
- Giulia Finotti
- Department of Medicine, Sections of *General Pathology and Gastroenterology, University of Verona, Verona, Italy
| | - Nicola Tamassia
- Department of Medicine, Sections of *General Pathology and Gastroenterology, University of Verona, Verona, Italy
| | - Federica Calzetti
- Department of Medicine, Sections of *General Pathology and Gastroenterology, University of Verona, Verona, Italy
| | - Giovanna Fattovich
- Department of Medicine, Sections of *General Pathology and Gastroenterology, University of Verona, Verona, Italy
| | - Marco A Cassatella
- Department of Medicine, Sections of *General Pathology and Gastroenterology, University of Verona, Verona, Italy
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37
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Shuldiner SR, Gong L, Muir AJ, Altman RB, Klein TE. PharmGKB summary: peginterferon-α pathway. Pharmacogenet Genomics 2015; 25:465-74. [PMID: 26111151 PMCID: PMC4757589 DOI: 10.1097/fpc.0000000000000158] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Affiliation(s)
| | - Li Gong
- Department of Genetics, Stanford University, Stanford, California
| | - Andrew J. Muir
- Duke Clinical Research Institute, Duke University, Durham, North Carolina, USA
| | - Russ B. Altman
- Department of Genetics, Stanford University, Stanford, California
- Department of Bioengineering, Stanford University, Stanford, California
| | - Teri E. Klein
- Department of Genetics, Stanford University, Stanford, California
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Zhu C, Xiao F, Hong J, Wang K, Liu X, Cai D, Fusco DN, Zhao L, Jeong SW, Brisac C, Chusri P, Schaefer EA, Zhao H, Peng LF, Lin W, Chung RT. EFTUD2 Is a Novel Innate Immune Regulator Restricting Hepatitis C Virus Infection through the RIG-I/MDA5 Pathway. J Virol 2015; 89:6608-6618. [PMID: 25878102 PMCID: PMC4468487 DOI: 10.1128/jvi.00364-15] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2015] [Accepted: 04/03/2015] [Indexed: 12/13/2022] Open
Abstract
UNLABELLED The elongation factor Tu GTP binding domain-containing protein 2 (EFTUD2) was identified as an anti-hepatitis C virus (HCV) host factor in our recent genome-wide small interfering RNA (siRNA) screen. In this study, we sought to further determine EFTUD2's role in HCV infection and investigate the interaction between EFTUD2 and other regulators involved in HCV innate immune (RIG-I, MDA5, TBK1, and IRF3) and JAK-STAT1 pathways. We found that HCV infection decreased the expression of EFTUD2 and the viral RNA sensors RIG-I and MDA5 in HCV-infected Huh7 and Huh7.5.1 cells and in liver tissue from in HCV-infected patients, suggesting that HCV infection downregulated EFTUD2 expression to circumvent the innate immune response. EFTUD2 inhibited HCV infection by inducing expression of the interferon (IFN)-stimulated genes (ISGs) in Huh7 cells. However, its impact on HCV infection was absent in both RIG-I knockdown Huh7 cells and RIG-I-defective Huh7.5.1 cells, indicating that the antiviral effect of EFTUD2 is dependent on RIG-I. Furthermore, EFTUD2 upregulated the expression of the RIG-I-like receptors (RLRs) RIG-I and MDA5 to enhance the innate immune response by gene splicing. Functional experiments revealed that EFTUD2-induced expression of ISGs was mediated through interaction of the EFTUD2 downstream regulators RIG-I, MDA5, TBK1, and IRF3. Interestingly, the EFTUD2-induced antiviral effect was independent of the classical IFN-induced JAK-STAT pathway. Our data demonstrate that EFTUD2 restricts HCV infection mainly through an RIG-I/MDA5-mediated, JAK-STAT-independent pathway, thereby revealing the participation of EFTUD2 as a novel innate immune regulator and suggesting a potentially targetable antiviral pathway. IMPORTANCE Innate immunity is the first line defense against HCV and determines the outcome of HCV infection. Based on a recent high-throughput whole-genome siRNA library screen revealing a network of host factors mediating antiviral effects against HCV, we identified EFTUD2 as a novel innate immune regulator against HCV in the infectious HCV cell culture model and confirmed that its expression in HCV-infected liver tissue is inversely related to HCV infection. Furthermore, we determined that EFTUD2 exerts its antiviral activity mainly through governing its downstream regulators RIG-I and MDA5 by gene splicing to activate IRF3 and induce classical ISG expression independent of the JAT-STAT signaling pathway. This study broadens our understanding of the HCV innate immune response and provides a possible new antiviral strategy targeting this novel regulator of the innate response.
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Affiliation(s)
- Chuanlong Zhu
- Department of Infectious Disease, Anhui Provincial Hospital, Anhui Medical University, Hefei, Anhui, China Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA Department of Infectious Diseases, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Fei Xiao
- Department of Infectious Disease, Anhui Provincial Hospital, Anhui Medical University, Hefei, Anhui, China Department of Infectious Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Jian Hong
- Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Kun Wang
- Department of Infectious Disease, Anhui Provincial Hospital, Anhui Medical University, Hefei, Anhui, China
| | - Xiao Liu
- Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Dachuan Cai
- Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Dahlene N Fusco
- Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Lei Zhao
- Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Soung Won Jeong
- Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Cynthia Brisac
- Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Pattranuch Chusri
- Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Esperance A Schaefer
- Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Hong Zhao
- Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA Department of Infectious Diseases, Peking University First Hospital, Beijing, China
| | - Lee F Peng
- Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Wenyu Lin
- Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Raymond T Chung
- Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
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Meng X, Yang D, Yu R, Zhu H. EPSTI1 Is Involved in IL-28A-Mediated Inhibition of HCV Infection. Mediators Inflamm 2015; 2015:716315. [PMID: 26146465 PMCID: PMC4469844 DOI: 10.1155/2015/716315] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2015] [Accepted: 05/17/2015] [Indexed: 12/12/2022] Open
Abstract
It has been reported that IFN-λs inhibit HCV replication in vitro. But the mechanisms of how IL-28A conducts antiviral activity and the functions of IL-28A-induced ISGs (IFN-stimulated genes) are not fully understood. In this study, we found that IL-28A has the antiviral effect on HCV life cycle including viral replication, assembly, and release. IL-28A and IFN-α synergistically inhibit virus replication. EPSTI1 (epithelial-stromal interaction 1), one of IL-28A-induced ISGs, plays a vital role in IL-28A-mediated antiviral activity. Furthermore, forced expression of EPSTI1 effectively inhibits HCV replication in the absence of interferon treatment, and knockdown of EPSTI1 contributes to viral enhancement. EPSTI1 can activate PKR promoter and induce several PKR-dependent genes, including IFN-β, IFIT1, OAS1, and RNase L, which is responsible for EPSTI1-mediated antiviral activity.
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Affiliation(s)
- Xianghe Meng
- Department of Molecular Medicine of College of Biology, State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan University, Changsha 410082, China
| | - Darong Yang
- Department of Molecular Medicine of College of Biology, State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan University, Changsha 410082, China
| | - Rong Yu
- Department of Molecular Medicine of College of Biology, State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan University, Changsha 410082, China
| | - Haizhen Zhu
- Department of Molecular Medicine of College of Biology, State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan University, Changsha 410082, China
- Research Center of Cancer Prevention & Treatment, Translational Medicine Research Center of Liver Cancer, Hunan Provincial Tumor Hospital, Affiliated Tumor Hospital of Xiangya Medical School of Central South University, Changsha 410013, China
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40
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Kurt R, Chandra PK, Aboulnasr F, Panigrahi R, Ferraris P, Aydin Y, Reiss K, Wu T, Balart LA, Dash S. Chaperone-Mediated Autophagy Targets IFNAR1 for Lysosomal Degradation in Free Fatty Acid Treated HCV Cell Culture. PLoS One 2015; 10:e0125962. [PMID: 25961570 PMCID: PMC4427131 DOI: 10.1371/journal.pone.0125962] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2015] [Accepted: 03/27/2015] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Hepatic steatosis is a risk factor for both liver disease progression and an impaired response to interferon alpha (IFN-α)-based combination therapy in chronic hepatitis C virus (HCV) infection. Previously, we reported that free fatty acid (FFA)-treated HCV cell culture induces hepatocellular steatosis and impairs the expression of interferon alpha receptor-1 (IFNAR1), which is why the antiviral activity of IFN-α against HCV is impaired. AIM To investigate the molecular mechanism by which IFNAR1 expression is impaired in HCV cell culture with or without free fatty acid-treatment. METHOD HCV-infected Huh 7.5 cells were cultured with or without a mixture of saturated (palmitate) and unsaturated (oleate) long-chain free fatty acids (FFA). Intracytoplasmic fat accumulation in HCV-infected culture was visualized by oil red staining. Clearance of HCV in FFA cell culture treated with type I IFN (IFN-α) and Type III IFN (IFN-λ) was determined by Renilla luciferase activity, and the expression of HCV core was determined by immunostaining. Activation of Jak-Stat signaling in the FFA-treated HCV culture by IFN-α alone and IFN-λ alone was examined by Western blot analysis and confocal microscopy. Lysosomal degradation of IFNAR1 by chaperone-mediated autophagy (CMA) in the FFA-treated HCV cell culture model was investigated. RESULTS FFA treatment induced dose-dependent hepatocellular steatosis and lipid droplet accumulation in HCV-infected Huh-7.5 cells. FFA treatment of infected culture increased HCV replication in a concentration-dependent manner. Intracellular lipid accumulation led to reduced Stat phosphorylation and nuclear translocation, causing an impaired IFN-α antiviral response and HCV clearance. Type III IFN (IFN-λ), which binds to a separate receptor, induces Stat phosphorylation, and nuclear translocation as well as antiviral clearance in FFA-treated HCV cell culture. We show here that the HCV-induced autophagy response is increased in FFA-treated cell culture. Pharmacological inhibitors of lysosomal degradation, such as ammonium chloride and bafilomycin, prevented IFNAR1 degradation in FFA-treated HCV cell culture. Activators of chaperone-mediated autophagy, including 6-aminonicotinamide and nutrient starvation, decreased IFNAR1 levels in Huh-7.5 cells. Co-immunoprecipitation, colocalization and siRNA knockdown experiments revealed that IFNAR1 but not IFNLR1 interacts with HSC70 and LAMP2A, which are core components of chaperone-mediated autophagy (CMA). CONCLUSION Our study presents evidence indicating that chaperone-mediated autophagy targets IFNAR1 degradation in the lysosome in FFA-treated HCV cell culture. These results provide a mechanism for why HCV induced autophagy response selectively degrades type I but not the type III IFNAR1.
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Affiliation(s)
- Ramazan Kurt
- Department of Medicine, Division of Gastroenterology and Hepatology, Tulane University School of Medicine, New Orleans, Louisiana, United States of America
| | - Partha K. Chandra
- Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana, United States of America
| | - Fatma Aboulnasr
- Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana, United States of America
| | - Rajesh Panigrahi
- Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana, United States of America
| | - Pauline Ferraris
- Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana, United States of America
| | - Yucel Aydin
- Department of Medicine, Division of Gastroenterology and Hepatology, Tulane University School of Medicine, New Orleans, Louisiana, United States of America
| | - Krzysztof Reiss
- Neurological Cancer Research, Stanley S Scott Cancer Center, LSU Health Science Center, New Orleans, Louisiana, United States of America
| | - Tong Wu
- Department of Medicine, Division of Gastroenterology and Hepatology, Tulane University School of Medicine, New Orleans, Louisiana, United States of America
| | - Luis A. Balart
- Department of Medicine, Division of Gastroenterology and Hepatology, Tulane University School of Medicine, New Orleans, Louisiana, United States of America
| | - Srikanta Dash
- Department of Medicine, Division of Gastroenterology and Hepatology, Tulane University School of Medicine, New Orleans, Louisiana, United States of America
- Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana, United States of America
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Abstract
Background High-throughput technologies became common tools to decipher genome-wide changes of gene expression (GE) patterns. Functional analysis of GE patterns is a daunting task as it requires often recourse to the public repositories of biological knowledge. On the other hand, in many cases researcher's inquiry can be served by a comprehensive glimpse. The KEGG PATHWAY database is a compilation of manually verified maps of biological interactions represented by the complete set of pathways related to signal transduction and other cellular processes. Rapid mapping of the differentially expressed genes to the KEGG pathways may provide an idea about the functional relevance of the gene lists corresponding to the high-throughput expression data. Results Here we present a web based graphic tool KEGG Pathway Painter (KPP). KPP paints pathways from the KEGG database using large sets of the candidate genes accompanied by "overexpressed" or "underexpressed" marks, for example, those generated by microarrays or miRNA profilings. Conclusion KPP provides fast and comprehensive visualization of the global GE changes by consolidating a list of the color-coded candidate genes into the KEGG pathways. KPP is freely available and can be accessed at http://web.cos.gmu.edu/~gmanyam/kegg/
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42
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Ling Q, Chen J, Zhou H, Zhong J, Chen Y, Ye Q, Zhuo Y, Min N, Shang B. Baseline factors associated with treatment response in patients infected with hepatitis C virus 1b by stratification of IL28B polymorphisms. Arch Virol 2015; 160:1105-12. [PMID: 25687192 DOI: 10.1007/s00705-015-2364-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2014] [Accepted: 02/06/2015] [Indexed: 01/14/2023]
Abstract
Although the single-nucleotide polymorphism (SNP) rs12979860 in the IL28B gene is a better predictor of sustained virological response to treatment of chronic hepatitis C (CHC) than other baseline factors, some CHC patients with the favorable C allele cannot achieve a sustained virological response when treated with peginterferon plus ribavirin. The aim of this study was to examine baseline factors as predictors of rapid virological response (RVR) and complete early virological response (cEVR) to peginterferon alfa-2a plus ribavirin treatment in Chinese CHC patients with hepatitis C virus (HCV) genotype 1b, with emphasis on the difference between the rs129860 CC and CT/TT genotypes. A total of 337 treatment-naïve patients participated in this study. All patients were treated with peginterferon alfa-2a plus ribavirin at standard dosage. Serum samples from all patients were collected at baseline, week 4, and week 12 for testing of laboratory parameters, and IL28B genotypes were determined. Multivariate analysis showed that among rs12979860 CC genotype patients, glucose level and aspartate amino transferase (AST) activity were inversely associated with RVR, while abnormal platelet count and allergy inversely associated with cEVR. Among rs12979860 CT genotype patients, age below 40 years and short infection duration were associated with RVR, while age below 40 years, short infection duration, high body mass index (BMI), and no history of allergies were associated with cEVR. The baseline factors associated with the response to CHC treatment may depend on the IL28B genotype. Refinement of the baseline predictors based on IL28B genotypes may be useful for management of HCV infection.
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Affiliation(s)
- Qihua Ling
- Department of Hepatology, Shanghai Shuguang Hospital, Shanghai University of T.C.M., 185 Anpu Road, Shanghai, 200021, China
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43
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Wang Y, Li J, Wang X, Zhou Y, Zhang T, Ho W. Comparison of antiviral activity of lambda-interferons against HIV replication in macrophages. J Interferon Cytokine Res 2015; 35:213-21. [PMID: 25268605 PMCID: PMC4350265 DOI: 10.1089/jir.2014.0064] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2014] [Accepted: 08/27/2014] [Indexed: 12/17/2022] Open
Abstract
Lambda-interferons (IFN-λs) have been demonstrated as having the ability to inhibit HIV replication in macrophages. However, specific differences in signaling transduction and anti-HIV activity in macrophages between different IFN-λs are unclear. Here, we showed that although all 3 members of (IFN-λ1, λ2, and λ3) IFN-λ family induced the expression of a number of genes of janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling pathway in monocyte-derived macrophages, IFN-λ1 or IFN-λ3 induced higher levels of antiviral IFN-stimulated genes (ISGs) expression than did IFN-λ2. In addition, IFN-λ1 or IFN-λ3 induced higher levels of several pattern recognition receptors (PPRs) than did IFN-λ2. Incubation of IFN-λs with HIV-infected macrophages showed that IFN-λ1 or IFN-λ3 is more potent in anti-HIV activity than IFN-λ2. We also showed that IFN-λ treatment before HIV infection was more potent in HIV inhibition than that after HIV infection. Further investigations showed that the inductions of ISGs and PPRs expression by IFN-λs were largely compromised by HIV infection. These findings provide further experimental evidence that IFN-λs have therapeutic potential in treatment of HIV infection.
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Affiliation(s)
- Yizhong Wang
- Department of Infectious Diseases, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Jieliang Li
- Department of Pathology and Laboratory Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania
| | - Xu Wang
- Department of Pathology and Laboratory Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania
| | - Yu Zhou
- Department of Pathology and Laboratory Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania
| | - Ting Zhang
- Department of Infectious Diseases, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Wenzhe Ho
- Department of Pathology and Laboratory Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania
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44
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Hepatitis C virus-mediated enhancement of microRNA miR-373 impairs the JAK/STAT signaling pathway. J Virol 2015; 89:3356-65. [PMID: 25589644 DOI: 10.1128/jvi.03085-14] [Citation(s) in RCA: 74] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
UNLABELLED Hepatitis C virus (HCV) is a serious global health problem and establishes chronic infection in a significant number of infected humans worldwide. Interferon (IFN) and IFN-stimulated genes (ISGs) are amplified during HCV infection but fail to eliminate virus from the liver in a large number of infected patients, and the mechanism is not fully understood. MicroRNAs (miRNAs) have been implicated in the control of many biological processes, including IFN signaling. To gain more insights into the role of cellular miRNAs in possible countermeasures of HCV for suppression of the host antiviral response, a miRNA array was performed by using primary human hepatocytes infected with in vitro cell culture-grown HCV. A group of miRNAs were modulated in HCV-infected primary human hepatocytes. We focused on miR-373, as this miRNA was significantly upregulated in HCV-infected primary human hepatocytes. Here, we analyzed the function of miR-373 in the context of HCV infection. HCV infection upregulates miR-373 expression in hepatocytes and HCV-infected liver biopsy specimens. Furthermore, we discovered that miR-373 directly targets Janus kinase 1 (JAK1) and IFN-regulating factor 9 (IRF9), important factors in the IFN signaling pathway. The upregulation of miR-373 by HCV also inhibited STAT1 phosphorylation, which is involved in ISG factor 3 (ISGF3) complex formation and ISG expression. The knockdown of miR-373 in hepatocytes enhanced JAK1 and IRF9 expression and reduced HCV RNA replication. Taken together, our results demonstrated that miR-373 is upregulated during HCV infection and negatively regulated the type I IFN signaling pathway by suppressing JAK1 and IRF9. Our results offer a potential therapeutic approach for antiviral intervention. IMPORTANCE Chronic HCV infection is one of the major causes of end-stage liver disease worldwide. Although the recent introduction of direct-acting antiviral (DAA) therapy is extremely encouraging, some infected individuals do not respond to this therapy. Furthermore, these drugs target HCV nonstructural proteins, and with selective pressure, the virus may develop a resistant strain. Therefore, understanding the impairment of IFN signals will help in designing additional therapeutic modalities. In this study, we provide evidence of HCV-mediated upregulation of miR-373 and show that miR-373 impairs IFN signaling by targeting JAK1/IRF9 molecules. The knockdown of miR-373 inhibited HCV replication by upregulating interferon-stimulating gene expression. Together, these results provided new mechanistic insights into the role of miR-373 in HCV infection and suggest a new potential target against HCV infection.
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45
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O’Connor KS, George J, Booth D, Ahlenstiel G. Dendritic cells in hepatitis C virus infection: key players in the IFNL3-genotype response. World J Gastroenterol 2014; 20:17830-8. [PMID: 25548481 PMCID: PMC4273133 DOI: 10.3748/wjg.v20.i47.17830] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2014] [Revised: 07/14/2014] [Accepted: 07/24/2014] [Indexed: 02/06/2023] Open
Abstract
Recently, single nucleotide polymorphisms, in the vicinity of the interferon lambda 3 (IFNL3) gene have been identified as the strongest predictor of spontaneous and treatment induced clearance of hepatitis C virus (HCV) infection. Since then, increasing evidence has implicated the innate immune response in mediating the IFNL3 genotype effect. Dendritic cells (DCs) are key to the host immune response in HCV infection and their vital role in the IFNL3 genotype effect is emerging. Reports have identified subclasses of DCs, particularly myeloid DC2s and potentially plasmacytoid DCs as the major producers of IFNL3 in the setting of HCV infection. Given the complexities of dendritic cell biology and the conflicting current available data, this review aims to summarize what is currently known regarding the role of dendritic cells in HCV infection and to place it into context of what is know about lambda interferons and dendritic cells in general.
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46
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Hepatitis C virus resistance to interferon therapy: an alarming situation. Open Life Sci 2014. [DOI: 10.2478/s11535-014-0352-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
AbstractHepatitis C virus is presently a major public health problem across the globe. The main objective in treating hepatitis C virus (HCV) infection is to achieve a sustained virological response (SVR). Interferon-α (IFN-α) and pegylated interferon (PegIFN) in combination with Ribavirin (RBV) are the choice of treatment nowadays against chronic hepatitis C. There are several mechanisms evolved by the hepatitis C virus that facilitate the persistence of virus and further lead the patient’s status as non responder. Various factors involved in patient’s lack ofresponse to the therapy include: (1) viral factors, (2) host factors, (3) molecular mechanisms related to the lack of response and (4) social factors. Herein we have made an attempt to summarize all the related predictors of drug resistance in one article so that the future polices can be planned to overcome this obstacle and potential therapies can be designed by considering these factors.
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47
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Trinks J, Hulaniuk ML, Redal MA, Flichman D. Clinical utility of pharmacogenomics in the management of hepatitis C. PHARMACOGENOMICS & PERSONALIZED MEDICINE 2014; 7:339-47. [PMID: 25382982 PMCID: PMC4222698 DOI: 10.2147/pgpm.s52624] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Hepatitis C virus (HCV) was identified for the first time more than 20 years ago. Since then, several studies have highlighted the complicated aspects of this viral infection in relation to its worldwide prevalence, its clinical presentation, and its therapeutic response. Recently, two landmark scientific breakthroughs have moved us closer to the successful eradication of chronic HCV infection. First, response rates in treatment-naïve patients and in prior non-responders to pegylated-interferon-α and ribavirin therapy are increasing as a direct consequence of the development of direct-acting antiviral drugs. Secondly, the discovery of single-nucleotide polymorphisms near the interleukin 28B gene significantly related to spontaneous and treatment-induced HCV clearance represents a milestone in the HCV therapeutic landscape. The implementation of this pharmacogenomics finding as a routine test for HCV-infected patients has enhanced our understanding of viral pathogenesis, has encouraged the design of ground-breaking antiviral treatment regimens, and has become useful for pretreatment decision making. Nowadays, interleukin 28B genotyping is considered to be a key diagnostic tool for the management of HCV-infected patients and will maintain its significance for new combination treatment schemes using direct-acting antiviral agents and even in interferon-free regimens. Such pharmacogenomics insights represent a challenge to clinicians, researchers, and health administrators to transform this information into knowledge with the aim of elaborating safer and more effective therapeutic strategies specifically designed for each patient. In conclusion, the individualization of treatment regimens for patients with hepatitis C, that may lead to a universal cure in future years, is becoming a reality due to recent developments in biomarker and genomic medicine. In light of these advances, we review the scientific evidence and clinical implications of recent findings related to host genetic factors in the management of HCV infection.
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Affiliation(s)
- Julieta Trinks
- Instituto de Ciencias Básicas y Medicina Experimental, Hospital Italiano de Buenos Aires, Universidad de Buenos Aires, Buenos Aires, Argentina ; National Scientific and Technical Research Council, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - María Laura Hulaniuk
- Instituto de Ciencias Básicas y Medicina Experimental, Hospital Italiano de Buenos Aires, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - María Ana Redal
- Instituto de Ciencias Básicas y Medicina Experimental, Hospital Italiano de Buenos Aires, Universidad de Buenos Aires, Buenos Aires, Argentina ; Instituto Universitario del Hospital Italiano de Buenos Aires, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Diego Flichman
- National Scientific and Technical Research Council, Universidad de Buenos Aires, Buenos Aires, Argentina ; Cátedra de Virología, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina
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Knapp S, Meghjee N, Cassidy S, Jamil K, Thursz M. Detection of allele specific differences in IFNL3 (IL28B) mRNA expression. BMC MEDICAL GENETICS 2014; 15:104. [PMID: 25287681 PMCID: PMC4411934 DOI: 10.1186/s12881-014-0104-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/23/2013] [Accepted: 09/05/2014] [Indexed: 12/14/2022]
Abstract
BACKGROUND Variants of the interferon-lambda3 (IFNL3) gene have been associated with both spontaneous and treatment induced clearance of HCV infection. Attempts to link polymorphisms of the IFNL3 gene with variation in the level of IFNL3 expression have been inconclusive. This is partially due to the difficulty to design assays distinguishing IFNL3 from IFNL2. METHODS In this study an allele specific real-time PCR (RT-PCR) assay was developed which allows the relative quantification of the two IFNL3 transcripts in cells heterozygous for SNP IFNL3.rs4803217 in the 3'UTR of the IFNL3 gene. This SNP is in strong linkage disequilibrium (LD) with the predictive marker rs12979860. RESULTS Raji cells showed two-fold increased levels of IFNL3.rs4803217 C-allele expression. In peripheral blood mononuclear cells (PBMCs) of eight uninfected donors, two donors showed increased IFNL3.rs4803217 C-allele expression. CONCLUSION This indicates that allele specific differences in IFNL3 expression vary between individuals and might contribute to the variety of outcomes in HCV infected patients.
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Affiliation(s)
- Susanne Knapp
- Imperial College, St Mary's Hospital, 10th floor QEQM Wing, Liver Unit, South Wharf Road, London, W2 1NY, UK.
| | - Naeem Meghjee
- Imperial College, St Mary's Hospital, 10th floor QEQM Wing, Liver Unit, South Wharf Road, London, W2 1NY, UK.
| | - Sorcha Cassidy
- Imperial College, St Mary's Hospital, 10th floor QEQM Wing, Liver Unit, South Wharf Road, London, W2 1NY, UK.
| | - Khaleel Jamil
- Imperial College, St Mary's Hospital, 10th floor QEQM Wing, Liver Unit, South Wharf Road, London, W2 1NY, UK.
| | - Mark Thursz
- Imperial College, St Mary's Hospital, 10th floor QEQM Wing, Liver Unit, South Wharf Road, London, W2 1NY, UK.
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Ansaldi F, Orsi A, Sticchi L, Bruzzone B, Icardi G. Hepatitis C virus in the new era: Perspectives in epidemiology, prevention, diagnostics and predictors of response to therapy. World J Gastroenterol 2014; 20:9633-9652. [PMID: 25110404 PMCID: PMC4123355 DOI: 10.3748/wjg.v20.i29.9633] [Citation(s) in RCA: 110] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2013] [Revised: 04/18/2014] [Accepted: 05/19/2014] [Indexed: 02/06/2023] Open
Abstract
Despite the great successes achieved in the fields of virology and diagnostics, several difficulties affect improvements in hepatitis C virus (HCV) infection control and eradication in the new era. New HCV infections still occur, especially in some of the poorest regions of the world, where HCV is endemic and long-term sequelae have a growing economic and health burden. An HCV vaccine is still no available, despite years of researches and discoveries about the natural history of infection and host-virus interactions: several HCV vaccine candidates have been developed in the last years, targeting different HCV antigens or using alternative delivery systems, but viral variability and adaption ability constitute major challenges for vaccine development. Many new antiviral drugs for HCV therapy are in preclinical or early clinical development, but different limitations affect treatment validity. Treatment predictors are important tools, as they provide some guidance for the management of therapy in patients with chronic HCV infection: in particular, the role of host genomics in HCV infection outcomes in the new era of direct-acting antivirals may evolve for new therapeutic targets, representing a chance for modulated and personalized treatment management, when also very potent therapies will be available. In the present review we discuss the most recent data about HCV epidemiology, the new perspectives for the prevention of HCV infection and the most recent evidence regarding HCV diagnosis, therapy and predictors of response to it.
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50
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Recent advances in the anti-HCV mechanisms of interferon. Acta Pharm Sin B 2014; 4:241-7. [PMID: 26579391 PMCID: PMC4629091 DOI: 10.1016/j.apsb.2014.06.010] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2014] [Revised: 06/03/2014] [Accepted: 06/18/2014] [Indexed: 12/14/2022] Open
Abstract
Interferon (IFN) in combination with ribavirin has been the standard of care (SOC) for chronic hepatitis C for the past few decades. Although the current SOC lacks the desired efficacy, and 4 new direct-acting antiviral agents have been recently approved, interferons are still likely to remain the cornerstone of therapy for some time. Moreover, as an important cytokine system of innate immunity, host interferon signaling provides a powerful antiviral response. Nevertheless, the mechanisms by which HCV infection controls interferon production, and how interferons, in turn, trigger anti-HCV activities as well as control the outcome of HCV infection remain to be clarified. In this report, we review current progress in understanding the mechanisms of IFN against HCV, and also summarize the knowledge of induction of interferon signaling by HCV infection.
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Key Words
- Antiviral agent
- CHC, chronic hepatitis C
- DCs, dendritic cells
- DNAM1, DNAX accessory molecule-1
- E2, envelop 2
- GAS, IFN-γ-activated site
- GWAS, genome-wide association studies
- Hepatitis C virus
- IFN, interferon
- IFN-α, interferon-α
- IFNAR1, interferon-alpha receptor 1
- IFNAR2, interferon-alpha receptor 2
- IFNGR1, interferon gamma receptor 1
- IFNGR2, interferon gamma receptor 2
- IFNL4, IFN-lambda 4
- IL-10R2, interleukin-10 receptor 2
- IL-29, interleukin-29
- IRF-3, interferon regulatory factor 3
- IRGs, IFN regulatory genes
- ISG15, interferon-stimulated gene 15
- ISGF3, IFN-stimulated gene factor 3
- ISGs, IFN-stimulated genes
- ISREs, IFN-stimulated response elements
- Interferon
- JAKs, Janus activated kinases
- MAVS, mitochondrial antiviral signaling protein
- MDA-5, melanoma differentiation-associated gene-5
- MHC, major histocompatibility complex
- Molecular mechanism
- NKCs, natural killer cells
- NKTCs, natural killer T cells
- OAS, 2′-5′-oligoadenylate synthetase
- PAMPs, pathogen-associated molecular patterns
- PBMCs, peripheral blood mononuclear cells
- PKR, protein kinase R
- PRRs, pattern recognition receptors
- RIG-I, retinoic acid-inducible gene-I
- RLRs, RIG-I-like receptors
- RdRp, RNA dependent RNA polymerase
- SNPs, single-nucleotide polymorphisms
- SOC, standard of care
- STAT1, signal transducer and activator of transcription 1
- STAT2, signal transducer and activator of transcription 2
- SVR, sustained virological response
- TH1, T-helper-1
- TH2, T-helper-2
- TLRs, Toll-like receptors
- TYK2, tyrosine kinase 2
- USP18, ubiquitin specific peptidase 18
- dsRNA, double-stranded RNA
- pDC, plasmacytoid dendritic cell
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