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Novotny LA, Kappler CS, Meissner EG. Function of Interferon Lambda Receptor 1 Variants in Stem Cell-Derived Hepatocytes with Abrogated Endogenous IFNLR1. J Interferon Cytokine Res 2025; 45:174-183. [PMID: 39929255 DOI: 10.1089/jir.2024.0262] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/02/2025] Open
Abstract
Distinct transcriptional isoforms of the interferon lambda receptor 1 (IFNLR1) are expressed in hepatocytes, but whether corresponding full-length and truncated IFNLR1 protein variants have discrete function is unclear. We quantitated IFNLR1 isoforms in liver and blood from individuals with chronic hepatitis C virus (HCV) infection before and after antiviral treatment, hypothesizing their relative expression may differentially change during resolution of virus-induced inflammation. We also expressed FLAG-tagged IFNLR1 variants in stem cell-derived hepatocytes (iHeps) with abrogated endogenous IFNLR1 to evaluate their function. IFNLR1 isoforms decreased in liver and blood during treatment of HCV, but no distinct pattern of decline was observed for any individual isoform. Expression of full-length IFNLR1 enabled lambda interferon (IFNL)-induced expression of antiviral and proinflammatory genes and augmented inhibition of hepatitis B virus (HBV) replication relative to wild-type (WT) iHeps. A noncanonical IFNLR1 variant missing part of the JAK1 binding domain enabled IFNLs to induce antiviral genes but could not support induction of proinflammatory genes or augmented HBV inhibition beyond that observed in WT iHeps with intact endogenous IFNLR1. A secreted IFNLR1 variant had no identified function in iHeps lacking endogenous IFNLR1. Although relative expression of individual IFNLR1 isoforms did not distinctly change during HCV treatment, functional studies in iHeps suggest IFNLR1 variants could function to titrate antiviral versus proinflammatory responses in hepatocytes in the context of viral hepatitis.
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Affiliation(s)
- Laura A Novotny
- Division of Infectious Diseases, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Christiana S Kappler
- Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Eric G Meissner
- Division of Infectious Diseases, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA
- Department of Pharmacology and Immunology, Medical University of South Carolina, Charleston, South Carolina, USA
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Novotny LA, Meissner EG. Expression and function of interferon lambda receptor 1 variants. FEBS Lett 2025; 599:466-475. [PMID: 39435588 PMCID: PMC11850208 DOI: 10.1002/1873-3468.15041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Revised: 09/05/2024] [Accepted: 09/26/2024] [Indexed: 10/23/2024]
Abstract
Lambda interferons (IFNLs) provide critical host defense against pathogens encountered at mucosal surfaces. In humans, IFNL signaling is regulated in part by low and cell-type restricted expression of the lambda interferon receptor 1 protein with expression restricted primarily to epithelial cells located at mucosal surfaces. This review will examine the evidence suggesting a role for IFNLR1 transcriptional variants in mediating cell responsiveness to IFNL ligand exposure and regulation of pathway activity.
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Affiliation(s)
- Laura A. Novotny
- Division of Infectious Diseases, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Eric G. Meissner
- Division of Infectious Diseases, Medical University of South Carolina, Charleston, SC 29425, USA
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425, USA
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Tilden SG, Ricco MH, Hemann EA, Anchordoquy TJ. Exploiting a type III interferon response to improve chemotherapeutic safety and efficacy. Eur J Pharm Sci 2025; 204:106974. [PMID: 39608735 PMCID: PMC11753202 DOI: 10.1016/j.ejps.2024.106974] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Revised: 11/22/2024] [Accepted: 11/25/2024] [Indexed: 11/30/2024]
Abstract
Immune reactions to nanomedicines can be detrimental to the patient and compromise efficacy. However, our recent study characterizing the effects of a type III interferon (IFN-λ) response to lipid nanoparticles complexed with nucleic acids (lipoplexes) suggests that an IFN-λ pretreatment can increase tumor accumulation while decreasing off-target distribution of chemotherapeutic nanomedicines. This project provides a direct follow-up to our previously published works by clarifying 1) which cell type(s) can produce IFN-λ in response to lipoplexes and how the effects of IFN-λ may be propagated in humans. Additionally, we demonstrate 2) that an IFN-λ pretreatment is also capable of altering the accumulation profile of chemotherapeutic small molecules like doxorubicin. Finally, we determined 3) that the subcutaneous administration route for an IFN-λ pretreatment is the most efficacious, and 4) that an IFN-λ pretreatment can significantly increase the survival time of mice receiving Doxil® in a murine CT26 tumor model. With several chemotherapeutic nanomedicines available in the clinic and an IFN-λ product recently completing late phase clinical trials, this study provides the model for a novel anti-cancer treatment regime that can be rapidly translated to the clinic and improve the efficacy of contemporary treatment protocols.
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Affiliation(s)
- Scott G Tilden
- University of Colorado, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO.
| | - Madison H Ricco
- University of Colorado, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO
| | - Emily A Hemann
- Ohio State University, Ohio State University College of Medicine, Columbus, OH
| | - Thomas J Anchordoquy
- University of Colorado, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO
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Dedloff MR, Lazear HM. Antiviral and Immunomodulatory Effects of Interferon Lambda at the Maternal-Fetal Interface. Annu Rev Virol 2024; 11:363-379. [PMID: 38848605 DOI: 10.1146/annurev-virology-111821-101531] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/09/2024]
Abstract
Interferon lambda (IFN-λ, type III IFN, IL-28/29) is a family of antiviral cytokines that are especially important at barrier sites, including the maternal-fetal interface. Recent discoveries have identified important roles for IFN-λ during pregnancy, particularly in the context of congenital infections. Here, we provide a comprehensive review of the activity of IFN-λ at the maternal-fetal interface, highlighting cell types that produce and respond to IFN-λ in the placenta, decidua, and endometrium. Further, we discuss the role of IFN-λ during infections with congenital pathogens including Zika virus, human cytomegalovirus, rubella virus, and Listeria monocytogenes. We discuss advances in experimental models that can be used to fill important knowledge gaps about IFN-λ-mediated immunity.
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Affiliation(s)
- Margaret R Dedloff
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA;
| | - Helen M Lazear
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA;
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Sularea VM, Sharma R, Hay DC, O’Farrelly C. Early interferon lambda production is induced by double-stranded RNA in iPS-derived hepatocyte-like cells. OXFORD OPEN IMMUNOLOGY 2024; 5:iqae004. [PMID: 39193476 PMCID: PMC11219478 DOI: 10.1093/oxfimm/iqae004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Revised: 04/22/2024] [Accepted: 04/23/2024] [Indexed: 08/29/2024] Open
Abstract
Hepatotropic viruses are amongst the most ubiquitous pathogens worldwide, causing significant morbidity and mortality. As hepatocytes are among the primary targets of these viruses, their ability to mount early effective innate defence responses is of major research interest. Interferon lambda (IFNL) is produced early in response to viral stimulation in other cell types, but hepatocyte production of this interferon is little investigated. Due to the difficulty and significant costs in obtaining and culturing human primary hepatocytes, surrogate systems are widely sought. Here we used induced pluripotent stem (iPS)-derived hepatocyte-like cells (HLCs) to investigate hepatic IFNL expression in response to viral-like ligands. We demonstrate that hepatocytes rely on cytoplasmic pattern recognition receptors (PRRs) such as Protein Kinase RNA-dependent (PKR) and retinoic acid-inducible gene-I (RIG-I)-like receptors (RLR) for the detection of double stranded RNA. Stimulation of HLCs by viral-like RNA ligands activating cytosolic RNA sensors resulted in thousand fold increase of type III interferon gene expression. These results are in contrast with type I IFN expression, which was induced to a lower extent. Concomitant induction of interferon stimulated genes, such as interferon-stimulated gene 15 (ISG15) and CXCL10, indicated the ability of HLCs to activate interferon-dependent activity. These results demonstrate that HLCs mount an innate antiviral response upon stimulation with viral-like RNA characterized by the induction of type III IFN.
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Affiliation(s)
- Vasile Mihai Sularea
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152 - 160 Pearse St, Dublin, D02R590, Ireland
| | - Ruchi Sharma
- Stemnovate LTD, Cambridge, Maia Building 270, Babraham Research Campus, Cambridge, CB223AT, United Kingdom
| | - David C Hay
- Institute for Regeneration and Repair, Centre for Regenerative Medicine, University of Edinburgh, 5 Little France Drive, Edinburgh, EH16 4UU, United Kingdom
| | - Cliona O’Farrelly
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152 - 160 Pearse St, Dublin, D02R590, Ireland
- School of Medicine, Trinity College Dublin, 152 - 160 Pearse St, Dublin, D02R590, Ireland
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6
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Novotny LA, Evans JG, Guo H, Kappler CS, Meissner EG. Interferon lambda receptor-1 isoforms differentially influence gene expression and HBV replication in stem cell-derived hepatocytes. Antiviral Res 2024; 221:105779. [PMID: 38070830 PMCID: PMC10872352 DOI: 10.1016/j.antiviral.2023.105779] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Revised: 11/02/2023] [Accepted: 12/04/2023] [Indexed: 12/28/2023]
Abstract
BACKGROUND In the tolerogenic liver, inadequate or ineffective interferon signaling fails to clear chronic HBV infection. Lambda IFNs (IFNL) bind the interferon lambda receptor-1 (IFNLR1) which dimerizes with IL10RB to induce transcription of antiviral interferon-stimulated genes (ISG). IFNLR1 is expressed on hepatocytes, but low expression may limit the strength and antiviral efficacy of IFNL signaling. Three IFNLR1 transcriptional variants are detected in hepatocytes whose role in regulation of IFNL signaling is unclear: a full-length and signaling-capable form (isoform 1), a form that lacks a portion of the intracellular JAK1 binding domain (isoform 2), and a secreted form (isoform 3), the latter two predicted to be signaling defective. We hypothesized that altering expression of IFNLR1 isoforms would differentially impact the hepatocellular response to IFNLs and HBV replication. METHODS Induced pluripotent stem-cell derived hepatocytes (iHeps) engineered to contain FLAG-tagged, doxycycline-inducible IFNLR1 isoform constructs were HBV-infected then treated with IFNL3 followed by assessment of gene expression, HBV replication, and cellular viability. RESULTS Minimal overexpression of IFNLR1 isoform 1 markedly augmented ISG expression, induced de novo proinflammatory gene expression, and enhanced inhibition of HBV replication after IFNL treatment without adversely affecting cell viability. In contrast, overexpression of IFNLR1 isoform 2 or 3 partially augmented IFNL-induced ISG expression but did not support proinflammatory gene expression and minimally impacted HBV replication. CONCLUSIONS IFNLR1 isoforms differentially influence IFNL-induced gene expression and HBV replication in hepatocytes. Regulated IFNLR1 expression in vivo could limit the capacity of this pathway to counteract HBV replication.
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Affiliation(s)
- Laura A Novotny
- Division of Infectious Diseases, Department of Medicine, Medical University of South Carolina, Charleston, SC, USA
| | - J Grayson Evans
- Division of Infectious Diseases, Department of Medicine, Medical University of South Carolina, Charleston, SC, USA
| | - Haitao Guo
- Department of Microbiology and Molecular Genetics, Cancer Virology Program, UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Christiana S Kappler
- Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC, USA
| | - Eric G Meissner
- Division of Infectious Diseases, Department of Medicine, Medical University of South Carolina, Charleston, SC, USA; Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, USA.
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Bolin LP, Crane PB, Gunn LH. Exploring Cytokine Networks in Resistant Hypertension. Nurs Res 2024; 73:16-25. [PMID: 37878533 PMCID: PMC10841083 DOI: 10.1097/nnr.0000000000000699] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2023]
Abstract
BACKGROUND Controlling high blood pressure (BP) continues to be a major concern because the associated complications can lead to an increased risk of heart, brain, and kidney disease. Those with hypertension, despite lifestyle and diet modifications and pharmacotherapy, defined as resistant hypertension, are at increased risk for further risk for morbidity and mortality. Understanding inflammation in this population may provide novel avenues for treatment. OBJECTIVES This study aimed to examine a broad range of cytokines in adults with cardiovascular disease and identify specific cytokines associated with resistant hypertension. METHODS A secondary data analysis was conducted. The parent study included 156 adults with a history of myocardial infarction within the past 3-7 years and with a multiplex plasma analysis yielding a cytokine panel. A network analysis with lasso penalization for sparsity was performed to explore associations between cytokines and BP. Associated network centrality measures by cytokine were produced, and a community graph was extracted. A sensitivity analysis BP was also performed. RESULTS Cytokines with larger node strength measures were sTNFR2 and CX3. The graphical network highlighted six cytokines strongly associated with resistant hypertension. Cytokines IL-29 and CCL3 were found to be negatively associated with resistant hypertension, whereas CXCL12, MMP3, sCD163, and sIL6Rb were positively associated with resistant hypertension. DISCUSSION Understanding the network of associations through exploring oxidative stress and vascular inflammation may provide insight into treatment approaches for resistant hypertension.
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de Weerd NA, Ogungbola O, Liu X, Matthews AY, Ismail A, Vivian JP, Lim SS, Tyrrell DL, Putcha N, Skawinski M, Dickensheets H, Lavoie TB, Donnelly RP, Hertzog PJ, Santer DM. Characterization of Monoclonal Antibodies to Measure Cell Surface Protein Levels of Human Interferon-Lambda Receptor 1. J Interferon Cytokine Res 2023; 43:403-413. [PMID: 37499093 DOI: 10.1089/jir.2023.0040] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/29/2023] Open
Abstract
Type III interferons (IFN-lambdas, IFN-λs) are important antiviral cytokines that can also modulate immune responses by acting through a heterodimeric receptor composed of the specific and limited expressed IFN-λR1 chain and the ubiquitous IL-10R2 chain, which is shared with IL-10 family cytokines. Conflicting data have been reported regarding which cells express the IFN-λR1 subunit and directly respond to IFN-λs. This is, in part, owing to transcript levels of the IFN-λR1 gene, IFNLR1, not always correlating with cell surface protein levels. In this study, we tested a panel of novel monoclonal antibodies (mAbs) that specifically recognize human IFN-λR1. Initially, antigen specificity was confirmed by enzyme-linked immunosorbent assay (ELISA), from which a subset of antibodies was selected for additional flow cytometry and neutralization assays. We further characterized two antibodies based on their strong ELISA binding activity (HLR1 and HLR14) and found only HLR14 could reliably detect cell surface IFN-λR1 protein on a variety of cell lines by flow cytometry. HLR14 could also detect IFN-λR1 protein on certain primary human blood cells, including plasmacytoid dendritic cells and B cells from peripheral blood. Availability of the HLR14 mAb will enable the quantification of IFN-λR1 protein levels on cells and better characterization of the cell specificity of the IFN-λ response.
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Affiliation(s)
- Nicole A de Weerd
- Department of Molecular and Translational Science, Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research and Monash University, Clayton, Australia
| | | | - Xinyun Liu
- Department of Immunology, University of Manitoba, Winnipeg, Canada
| | - Antony Y Matthews
- Department of Molecular and Translational Science, Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research and Monash University, Clayton, Australia
| | - Amina Ismail
- Department of Molecular and Translational Science, Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research and Monash University, Clayton, Australia
| | - Julian P Vivian
- St. Vincent's Institute of Medical Research, Fitzroy, Australia
- Department of Medicine, The University of Melbourne, Melbourne, Australia
| | - San S Lim
- Department of Molecular and Translational Science, Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research and Monash University, Clayton, Australia
| | - D Lorne Tyrrell
- Department of Medical Microbiology and Immunology, Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Canada
| | - Niru Putcha
- PBL Assay Science, Piscataway, New Jersey, USA
| | | | - Harold Dickensheets
- Division of Biotechnology Research and Review II, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA
| | - Thomas B Lavoie
- PBL Assay Science, Piscataway, New Jersey, USA
- Strategic Biomarker Deployment, Califon, New Jersey, USA
| | - Raymond P Donnelly
- Division of Biotechnology Research and Review II, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA
| | - Paul J Hertzog
- Department of Molecular and Translational Science, Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research and Monash University, Clayton, Australia
| | - Deanna M Santer
- Department of Immunology, University of Manitoba, Winnipeg, Canada
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Patel P, Nandi A, Verma SK, Kaushik N, Suar M, Choi EH, Kaushik NK. Zebrafish-based platform for emerging bio-contaminants and virus inactivation research. THE SCIENCE OF THE TOTAL ENVIRONMENT 2023; 872:162197. [PMID: 36781138 PMCID: PMC9922160 DOI: 10.1016/j.scitotenv.2023.162197] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 01/23/2023] [Accepted: 02/08/2023] [Indexed: 05/27/2023]
Abstract
Emerging bio-contaminants such as viruses have affected health and environment settings of every country. Viruses are the minuscule entities resulting in severe contagious diseases like SARS, MERS, Ebola, and avian influenza. Recent epidemic like the SARS-CoV-2, the virus has undergone mutations strengthen them and allowing to escape from the remedies. Comprehensive knowledge of viruses is essential for the development of targeted therapeutic and vaccination treatments. Animal models mimicking human biology like non-human primates, rats, mice, and rabbits offer competitive advantage to assess risk of viral infections, chemical toxins, nanoparticles, and microbes. However, their economic maintenance has always been an issue. Furthermore, the redundancy of experimental results due to aforementioned aspects is also in examine. Hence, exploration for the alternative animal models is crucial for risk assessments. The current review examines zebrafish traits and explores the possibilities to monitor emerging bio-contaminants. Additionally, a comprehensive picture of the bio contaminant and virus particle invasion and abatement mechanisms in zebrafish and human cells is presented. Moreover, a zebrafish model to investigate the emerging viruses such as coronaviridae and poxviridae has been suggested.
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Affiliation(s)
- Paritosh Patel
- Plasma Bioscience Research Center, Department of Electrical and Biological Physics, Kwangwoon University, 01897 Seoul, South Korea
| | - Aditya Nandi
- School of Biotechnology, KIIT University, Bhubaneswar 751024, Odisha, India
| | - Suresh K Verma
- School of Biotechnology, KIIT University, Bhubaneswar 751024, Odisha, India; Condensed Matter Theory Group, Materials Theory Division, Department of Physics and Astronomy, Uppsala University, Box 516, SE-751 20 Uppsala, Sweden
| | - Neha Kaushik
- Department of Biotechnology, College of Engineering, The University of Suwon, 18323 Hwaseong, Republic of Korea
| | - Mrutyunjay Suar
- School of Biotechnology, KIIT University, Bhubaneswar 751024, Odisha, India
| | - Eun Ha Choi
- Plasma Bioscience Research Center, Department of Electrical and Biological Physics, Kwangwoon University, 01897 Seoul, South Korea.
| | - Nagendra Kumar Kaushik
- Plasma Bioscience Research Center, Department of Electrical and Biological Physics, Kwangwoon University, 01897 Seoul, South Korea.
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Larsen TV, Daugaard TF, Gad HH, Hartmann R, Nielsen AL. PD-L1 and PD-L2 immune checkpoint protein induction by type III interferon in non-small cell lung cancer cells. Immunobiology 2023; 228:152389. [PMID: 37146414 DOI: 10.1016/j.imbio.2023.152389] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 03/29/2023] [Accepted: 04/16/2023] [Indexed: 05/07/2023]
Abstract
INTRODUCTION Despite the clinical success of PD-1/PD-1-ligand immunotherapy in non-small cell lung cancer (NSCLC), the appearance of primary and acquired therapy resistance is a major challenge reflecting that the mechanisms regulating the expression of the PD-1-ligands PD-L1 and PD-L2 are not fully explored. Type I and II interferons (IFNs) induce PD-L1 and PD-L2 expression. Here, we examined if PD-L1 and PD-L2 expression also can be induced by type III IFN, IFN-λ, which is peculiarly important for airway epithelial surfaces. METHODS In silico mRNA expression analysis of PD-L1 (CD274), PD-L2 (PDCD1LG2), and IFN- λ signaling signature genes in NSCLC tumors and cell lines was performed using RNA sequencing expression data from TCGA, OncoSG, and DepMap portals. IFN-λ-mediated induction of PD-L1 and PD-L2 expression in NSCLC cell lines was examined by real-time quantitative polymerase chain reaction and flow cytometry. RESULTS IFNL genes encoding IFN- λ variants are expressed in the majority of NSCLC tumors and cell lines along with the IFNLR1 and IL10R2 genes encoding the IFN-λ receptor subunits. The expression of PD-L1 and PD-L2 mRNA is higher in NSCLC tumors with IFNL mRNA expression compared to tumors without IFNL expression. In the NSCLC cell line HCC827, stimulation with IFN-λ induced both an increase in PD-L1 and PD-L2 mRNA expression and cell surface abundance of the corresponding proteins. In the NSCLC cell line A427, displaying a low basal expression of PD-L1 and PD-L2 mRNA and corresponding proteins, stimulation with IFN-λ resulted in an induction of the former. CONCLUSION The type III IFN, IFN- λ, is capable of inducing PD-L1 and PD-L2 expression, at least in some NSCLC cells, and this regulation will need acknowledgment in the development of new diagnostic procedures, such as gene expression signature profiles, to improve PD-1/PD-1-ligand immunotherapy in NSCLC.
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Affiliation(s)
| | | | - Hans Henrik Gad
- Department of Molecular Biology and Genetics, Aarhus University, Denmark
| | - Rune Hartmann
- Department of Molecular Biology and Genetics, Aarhus University, Denmark
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Ren J, Antony F, Rouse BT, Suryawanshi A. Role of Innate Interferon Responses at the Ocular Surface in Herpes Simplex Virus-1-Induced Herpetic Stromal Keratitis. Pathogens 2023; 12:437. [PMID: 36986359 PMCID: PMC10058014 DOI: 10.3390/pathogens12030437] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Revised: 03/06/2023] [Accepted: 03/08/2023] [Indexed: 03/14/2023] Open
Abstract
Herpes simplex virus type 1 (HSV-1) is a highly successful pathogen that primarily infects epithelial cells of the orofacial mucosa. After initial lytic replication, HSV-1 enters sensory neurons and undergoes lifelong latency in the trigeminal ganglion (TG). Reactivation from latency occurs throughout the host's life and is more common in people with a compromised immune system. HSV-1 causes various diseases depending on the site of lytic HSV-1 replication. These include herpes labialis, herpetic stromal keratitis (HSK), meningitis, and herpes simplex encephalitis (HSE). HSK is an immunopathological condition and is usually the consequence of HSV-1 reactivation, anterograde transport to the corneal surface, lytic replication in the epithelial cells, and activation of the host's innate and adaptive immune responses in the cornea. HSV-1 is recognized by cell surface, endosomal, and cytoplasmic pattern recognition receptors (PRRs) and activates innate immune responses that include interferons (IFNs), chemokine and cytokine production, as well as the recruitment of inflammatory cells to the site of replication. In the cornea, HSV-1 replication promotes type I (IFN-α/β) and type III (IFN-λ) IFN production. This review summarizes our current understanding of HSV-1 recognition by PRRs and innate IFN-mediated antiviral immunity during HSV-1 infection of the cornea. We also discuss the immunopathogenesis of HSK, current HSK therapeutics and challenges, proposed experimental approaches, and benefits of promoting local IFN-λ responses.
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Affiliation(s)
- Jiayi Ren
- Department of Pathobiology, College of Veterinary Medicine, Auburn University, 240B Greene Hall, Auburn, AL 36849, USA
| | - Ferrin Antony
- Department of Pathobiology, College of Veterinary Medicine, Auburn University, 240B Greene Hall, Auburn, AL 36849, USA
| | - Barry T. Rouse
- College of Veterinary Medicine, University of Tennessee, Knoxville, TN 37996, USA
| | - Amol Suryawanshi
- Department of Pathobiology, College of Veterinary Medicine, Auburn University, 240B Greene Hall, Auburn, AL 36849, USA
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12
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Hao N, Zhou Z, Zhang F, Li Y, Hu R, Zou J, Zheng R, Wang L, Xu L, Tan W, Li C, Wang F. Interleukin-29 Accelerates Vascular Calcification via JAK2/STAT3/BMP2 Signaling. J Am Heart Assoc 2022; 12:e027222. [PMID: 36537334 PMCID: PMC9973608 DOI: 10.1161/jaha.122.027222] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Background Vascular calcification (VC), associated with enhanced cardiovascular morbidity and mortality, is characterized by the osteogenic transdifferentiation of vascular smooth muscle cells. Inflammation promotes VC initiation and progression. Interleukin (IL)-29, a newly discovered member of type III interferon, has recently been implicated in the pathogenesis of autoimmune diseases. Here we evaluated the role of IL-29 in the VC process and underlying inflammatory mechanisms. Methods and Results The mRNA expression of IL-29 was significantly increased and positively associated with an increase in BMP2 (bone morphogenetic protein 2) mRNA level in calcified carotid arteries from patients with coronary artery disease or chronic kidney disease. IL-29 and BMP2 proteins are colocalized in human calcified arteries. IL-29 binding to its specific receptor IL-28Rα (IL-28 receptor α) (IL-29/IL-28Rα) inhibited the proliferation of rat vascular smooth muscle cells without altering cell apoptosis or migration. IL-29 promoted the calcification of rat vascular smooth muscle cells and their osteogenic transdifferentiation in vitro as well as the rat aortic ring calcification ex vivo, induced by the calcification medium or osteogenic medium. The procalcification effect of IL-29 was reduced by pharmacological inhibition of IL-29/IL-28Rα binding as well as suppression of janus kinase 2/signal transducer and activator of transcription pathway activation, accompanied by decreased BMP2 expression in the cultured rat vascular smooth muscle cells. Conclusions These results suggest an important role of IL-29 in VC development, at least partly, via activating the janus kinase 2/signal transducer and activator of transcription 3 signaling. Inhibition of IL-29 or its specific receptor, IL-28Rα, may provide a novel strategy to reduce VC in patients with vascular diseases.
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Affiliation(s)
- Nannan Hao
- Department of CardiologyThe First Affiliated Hospital of Nanjing Medical UniversityNanjingJiangsu ProvinceChina
| | - Zihao Zhou
- Department of CardiologyThe First Affiliated Hospital of Nanjing Medical UniversityNanjingJiangsu ProvinceChina
| | - Feifei Zhang
- Department of CardiologyThe First Affiliated Hospital of Nanjing Medical UniversityNanjingJiangsu ProvinceChina
| | - Yong Li
- Department of CardiologyThe First Affiliated Hospital of Nanjing Medical UniversityNanjingJiangsu ProvinceChina
| | - Rui Hu
- Department of Vascular SurgeryThe First Affiliated Hospital of Nanjing Medical UniversityNanjingJiangsu ProvinceChina
| | - Junjie Zou
- Department of Vascular SurgeryThe First Affiliated Hospital of Nanjing Medical UniversityNanjingJiangsu ProvinceChina
| | - Rui Zheng
- Department of Cardiovascular SurgeryThe First Affiliated Hospital of Nanjing Medical UniversityNanjingJiangsu ProvinceChina
| | - Lei Wang
- Department of RheumatologyThe First Affiliated Hospital of Nanjing Medical UniversityNanjingJiangsu ProvinceChina
| | - Lingxiao Xu
- Department of RheumatologyThe First Affiliated Hospital of Nanjing Medical UniversityNanjingJiangsu ProvinceChina
| | - Wenfeng Tan
- Department of RheumatologyThe First Affiliated Hospital of Nanjing Medical UniversityNanjingJiangsu ProvinceChina
| | - Chunjian Li
- Department of CardiologyThe First Affiliated Hospital of Nanjing Medical UniversityNanjingJiangsu ProvinceChina
| | - Fang Wang
- Department of CardiologyThe First Affiliated Hospital of Nanjing Medical UniversityNanjingJiangsu ProvinceChina
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13
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Huang LY, Chiu CJ, Hsing CH, Hsu YH. Interferon Family Cytokines in Obesity and Insulin Sensitivity. Cells 2022; 11:4041. [PMID: 36552805 PMCID: PMC9776768 DOI: 10.3390/cells11244041] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 12/09/2022] [Accepted: 12/12/2022] [Indexed: 12/15/2022] Open
Abstract
Obesity and its associated complications are global public health concerns. Metabolic disturbances and immune dysregulation cause adipose tissue stress and dysfunction in obese individuals. Immune cell accumulation in the adipose microenvironment is the main cause of insulin resistance and metabolic dysfunction. Infiltrated immune cells, adipocytes, and stromal cells are all involved in the production of proinflammatory cytokines and chemokines in adipose tissues and affect systemic homeostasis. Interferons (IFNs) are a large family of pleiotropic cytokines that play a pivotal role in host antiviral defenses. IFNs are critical immune modulators in response to pathogens, dead cells, and several inflammation-mediated diseases. Several studies have indicated that IFNs are involved in the pathogenesis of obesity. In this review, we discuss the roles of IFN family cytokines in the development of obesity-induced inflammation and insulin resistance.
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Affiliation(s)
- Ling-Yu Huang
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan
| | - Chiao-Juno Chiu
- Department of Medical Research, National Taiwan University Hospital, Taipei 100, Taiwan
| | - Chung-Hsi Hsing
- Department of Anesthesiology, Chi Mei Medical Center, Tainan 710, Taiwan
- Department of Medical Research, Chi Mei Medical Center, Tainan 710, Taiwan
| | - Yu-Hsiang Hsu
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan
- Clinical Medicine Research Center, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan
- Antibody New Drug Research Center, National Cheng Kung University, Tainan 701, Taiwan
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14
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Yang Y, Chen J, Yi C, Yang F, Tang M, Li Z, Bai X. Assessment of serum interleukin-28 as a biomarker to predict mortality in traumatic patients with sepsis. Cytokine 2022; 157:155959. [PMID: 35816926 DOI: 10.1016/j.cyto.2022.155959] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2021] [Revised: 05/11/2022] [Accepted: 07/01/2022] [Indexed: 11/25/2022]
Abstract
BACKGROUND Serious trauma due to various factors is a major global public issue, and sepsis is a major cause of trauma-associated mortality. Timely diagnosis and suitable treatment of post-traumatic sepsis are crucial to improve the hospital outcome of traumatic patients. IL-28 is a newly discovered member of IFN-λ family with multiple functions in inflammatory response. To date, its role in the pathogenic mechanisms of post-traumatic sepsis still remains unknown. METHODS In total, 20 healthy controls, 55 traumatic patients without sepsis and 54 traumatic patients with sepsis were enrolled in this study. Serum IL-28A/B levels were investigated by ELISA. RESULTS IL-28A/B levels were significantly increased in traumatic patients compared to healthy volunteers. Moreover, septic trauma patients displayed a significant increase in IL-28A/B levels compared with non-septic patients. In septic patients, IL-28A/B were negatively correlated with IFN-γ, IL-5, IL-13 and IL-17, and positively associated with IL-10. Moreover, IL-28A (AUC: 0.821, 95 %CI: 0.693-0.949) and IL-28B (AUC: 0.811, 95 %CI: 0.691-0.931) were both beneficial to predict increased mortality risk in septic trauma patients, though there was no statistical difference in the predictive value between them. CONCLUSIONS Early serum levels of IL-28A/B were associated with the development of post-trauma sepsis and could be applied to assess the outcome of traumatic patients with sepsis. Thus, IL-28 may be a potential indicator for post-traumatic sepsis.
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Affiliation(s)
- Yang Yang
- Trauma Center/Department of Emergency and Traumatic Surgery, Tongji Hospital, Tongji Medicine College, Huazhong University of Science and Technology, Wuhan, China
| | - Jiajun Chen
- Trauma Center/Department of Emergency and Traumatic Surgery, Tongji Hospital, Tongji Medicine College, Huazhong University of Science and Technology, Wuhan, China
| | - Chengla Yi
- Trauma Center/Department of Emergency and Traumatic Surgery, Tongji Hospital, Tongji Medicine College, Huazhong University of Science and Technology, Wuhan, China
| | - Fan Yang
- Trauma Center/Department of Emergency and Traumatic Surgery, Tongji Hospital, Tongji Medicine College, Huazhong University of Science and Technology, Wuhan, China
| | - Manli Tang
- Trauma Center/Department of Emergency and Traumatic Surgery, Tongji Hospital, Tongji Medicine College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhanfei Li
- Trauma Center/Department of Emergency and Traumatic Surgery, Tongji Hospital, Tongji Medicine College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiangjun Bai
- Trauma Center/Department of Emergency and Traumatic Surgery, Tongji Hospital, Tongji Medicine College, Huazhong University of Science and Technology, Wuhan, China.
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15
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Guimarães Sousa S, Kleiton de Sousa A, Maria Carvalho Pereira C, Sofia Miranda Loiola Araújo A, de Aguiar Magalhães D, Vieira de Brito T, Barbosa ALDR. SARS-CoV-2 infection causes intestinal cell damage: Role of interferon’s imbalance. Cytokine 2022; 152:155826. [PMID: 35158258 PMCID: PMC8828414 DOI: 10.1016/j.cyto.2022.155826] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Revised: 02/02/2022] [Accepted: 02/04/2022] [Indexed: 12/12/2022]
Abstract
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the causative agent of the newly emerging lung disease pandemic COVID-19. This viral infection causes a series of respiratory disorders, and although this virus mainly infects respiratory cells, the small intestine can also be an important site of entry or interaction, as enterocytes highly express in angiotensin-2 converting enzyme (ACE) receptors. There are countless reports pointing to the importance of interferons (IFNs) with regard to the mediation of the immune system in viral infection by SARS-CoV-2. Thus, this review will focus on the main cells that make up the large intestine, their specific immunology, as well as the function of IFNs in the intestinal mucosa after the invasion of coronavirus-2.
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16
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Sari G, Mulders CE, Zhu J, van Oord GW, Feng Z, Kreeft‐Voermans JJ, Boonstra A, Vanwolleghem T. Treatment induced clearance of hepatitis E viruses by interferon-lambda in liver-humanized mice. Liver Int 2021; 41:2866-2873. [PMID: 34392598 PMCID: PMC9291846 DOI: 10.1111/liv.15033] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Revised: 07/02/2021] [Accepted: 07/28/2021] [Indexed: 01/05/2023]
Abstract
BACKGROUND Hepatitis E viruses (HEV) are an underestimated global cause of enterically transmitted viral hepatitis, which may persist in immunocompromised hosts, posing a risk for progressive liver fibrosis with limited treatment options. We previously established liver-humanized mice as a model for chronic HEV infections, which can be cleared by a 2-week pegylated (peg)-Interferon(IFN)α treatment course. However, severe side effects may hamper the use of IFNα in immunocompromised transplant recipient patients. IFNλ may be a valuable alternative, as its receptor is less ubiquitously expressed. AIMS In this study, we assess the in vitro and in vivo potency of pegIFNλ to induce innate immune signalling in liver cells and to clear a persistent HEV infection in liver-humanized mice. METHODS & RESULTS We found that human liver cells expressed the IFNλ receptor (IFNLR1) and are responsive to pegIFNλ. Treatment with pegIFNλ of liver-humanized mice persistently infected with HEV genotype 3 showed that pegIFNλ was well tolerated. Dose escalation studies showed that although HEV was not cleared at pegIFNλ doses up to 0.12 mg/kg for a maximum of 8 weeks, a dose of 0.3 mg/kg pegIFNλ treatment resulted in complete clearance of HEV antigen and HEV RNA from the liver in 8 out of 9 liver-humanized mice. CONCLUSIONS PegIFNλ is well tolerated in mice and leads to clearance of a persistent HEV infection in liver-humanized mice.
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Affiliation(s)
- Gulce Sari
- Department of Gastroenterology and HepatologyErasmus University Medical CenterRotterdamThe Netherlands
| | - Claudia E. Mulders
- Department of ViroscienceErasmus University Medical CenterRotterdamThe Netherlands
| | - Jingting Zhu
- Center for Vaccines and ImmunityThe Research Institute at Nationwide Children’s HospitalColumbusOhioUSA
| | - Gertine W. van Oord
- Department of Gastroenterology and HepatologyErasmus University Medical CenterRotterdamThe Netherlands
| | - Zongdi Feng
- Center for Vaccines and ImmunityThe Research Institute at Nationwide Children’s HospitalColumbusOhioUSA,Department of PediatricsThe Ohio State University College of MedicineColumbusOhioUSA
| | | | - Andre Boonstra
- Department of Gastroenterology and HepatologyErasmus University Medical CenterRotterdamThe Netherlands
| | - Thomas Vanwolleghem
- Department of Gastroenterology and HepatologyErasmus University Medical CenterRotterdamThe Netherlands,Laboratory of Experimental Medicine and PediatricsFaculty of Medicine and Health SciencesUniversity of AntwerpAntwerpBelgium,Department of Gastroenterology and HepatologyAntwerp University HospitalAntwerpBelgium
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17
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Ye J, Chen J. Interferon and Hepatitis B: Current and Future Perspectives. Front Immunol 2021; 12:733364. [PMID: 34557195 PMCID: PMC8452902 DOI: 10.3389/fimmu.2021.733364] [Citation(s) in RCA: 108] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 08/17/2021] [Indexed: 12/12/2022] Open
Abstract
Chronic hepatitis B virus (HBV) infection remains a major health burden worldwide for which there is still no effective curative treatment. Interferon (IFN) consists of a group of cytokines with antiviral activity and immunoregulatory and antitumor effects, that play crucial roles in both innate and adaptive immune responses. IFN-α and its pegylated form have been used for over thirty years to treat chronic hepatitis B (CHB) with advantages of finite treatment duration and sustained virologic response, however, the efficacy is limited and side effects are common. Here, we summarize the status and unique advantages of IFN therapy against CHB, review the mechanisms of IFN-α action and factors affecting IFN response, and discuss the possible improvement of IFN-based therapy and the rationale of combinations with other antiviral agents in seeking an HBV cure.
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Affiliation(s)
- Jianyu Ye
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Jieliang Chen
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.,Research Unit of Cure of Chronic Hepatitis B Virus Infection, Chinese Academy of Medical Sciences, Shanghai, China
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18
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Plotnikova M, Lozhkov A, Romanovskaya-Romanko E, Baranovskaya I, Sergeeva M, Kаа K, Klotchenko S, Vasin A. IFN-λ1 Displays Various Levels of Antiviral Activity In Vitro in a Select Panel of RNA Viruses. Viruses 2021; 13:1602. [PMID: 34452467 PMCID: PMC8402797 DOI: 10.3390/v13081602] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 08/05/2021] [Accepted: 08/06/2021] [Indexed: 12/25/2022] Open
Abstract
Type III interferons (lambda IFNs) are a quite new, small family of three closely related cytokines with interferon-like activity. Attention to IFN-λ is mainly focused on direct antiviral activity in which, as with IFN-α, viral genome replication is inhibited without the participation of immune system cells. The heterodimeric receptor for lambda interferons is exposed mainly on epithelial cells, which limits its possible action on other cells, thus reducing the likelihood of developing undesirable side effects compared to type I IFN. In this study, we examined the antiviral potential of exogenous human IFN-λ1 in cellular models of viral infection. To study the protective effects of IFN-λ1, three administration schemes were used: 'preventive' (pretreatment); 'preventive/therapeutic' (pre/post); and 'therapeutic' (post). Three IFN-λ1 concentrations (from 10 to 500 ng/mL) were used. We have shown that human IFN-λ1 restricts SARS-CoV-2 replication in Vero cells with all three treatment schemes. In addition, we have shown a decrease in the viral loads of CHIKV and IVA with the 'preventive' and 'preventive/therapeutic' regimes. No significant antiviral effect of IFN-λ1 against AdV was detected. Our study highlights the potential for using IFN-λ as a broad-spectrum therapeutic agent against respiratory RNA viruses.
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Affiliation(s)
- Marina Plotnikova
- Smorodintsev Research Institute of Influenza, Russian Ministry of Health, 197376 St. Petersburg, Russia; (M.P.); (A.L.); (E.R.-R.); (I.B.); (M.S.); (A.V.)
| | - Alexey Lozhkov
- Smorodintsev Research Institute of Influenza, Russian Ministry of Health, 197376 St. Petersburg, Russia; (M.P.); (A.L.); (E.R.-R.); (I.B.); (M.S.); (A.V.)
- Institute of Biomedical Systems and Biotechnologies, Peter the Great St. Petersburg Polytechnic University, 195251 St. Petersburg, Russia
| | - Ekaterina Romanovskaya-Romanko
- Smorodintsev Research Institute of Influenza, Russian Ministry of Health, 197376 St. Petersburg, Russia; (M.P.); (A.L.); (E.R.-R.); (I.B.); (M.S.); (A.V.)
| | - Irina Baranovskaya
- Smorodintsev Research Institute of Influenza, Russian Ministry of Health, 197376 St. Petersburg, Russia; (M.P.); (A.L.); (E.R.-R.); (I.B.); (M.S.); (A.V.)
- Institute of Biomedical Systems and Biotechnologies, Peter the Great St. Petersburg Polytechnic University, 195251 St. Petersburg, Russia
| | - Mariia Sergeeva
- Smorodintsev Research Institute of Influenza, Russian Ministry of Health, 197376 St. Petersburg, Russia; (M.P.); (A.L.); (E.R.-R.); (I.B.); (M.S.); (A.V.)
- Institute of Biomedical Systems and Biotechnologies, Peter the Great St. Petersburg Polytechnic University, 195251 St. Petersburg, Russia
| | - Konstantin Kаа
- Chumakov Federal Scientific Center for Research and Development of Immune-and-Biological Products RAS, 108819 Moscow, Russia;
| | - Sergey Klotchenko
- Smorodintsev Research Institute of Influenza, Russian Ministry of Health, 197376 St. Petersburg, Russia; (M.P.); (A.L.); (E.R.-R.); (I.B.); (M.S.); (A.V.)
| | - Andrey Vasin
- Smorodintsev Research Institute of Influenza, Russian Ministry of Health, 197376 St. Petersburg, Russia; (M.P.); (A.L.); (E.R.-R.); (I.B.); (M.S.); (A.V.)
- Institute of Biomedical Systems and Biotechnologies, Peter the Great St. Petersburg Polytechnic University, 195251 St. Petersburg, Russia
- Scientific and Educational Center for Biophysical Research in The Field of Pharmaceuticals, Saint Petersburg State Chemical Pharmaceutical University, 197022 St. Petersburg, Russia
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19
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De M, Bhushan A, Chinnaswamy S. Monocytes differentiated into macrophages and dendritic cells in the presence of human IFN-λ3 or IFN-λ4 show distinct phenotypes. J Leukoc Biol 2021; 110:357-374. [PMID: 33205487 PMCID: PMC7611425 DOI: 10.1002/jlb.3a0120-001rrr] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2020] [Revised: 10/29/2020] [Accepted: 11/01/2020] [Indexed: 12/13/2022] Open
Abstract
Human IFN-λ4 is expressed by only a subset of individuals who possess the ΔG variant allele at the dinucleotide polymorphism rs368234815. Recent genetic studies have shown an association between rs368234815 and different infectious and inflammatory disorders. It is not known if IFN-λ4 has immunomodulatory activity. The expression of another type III IFN, IFN-λ3, is also controlled by genetic polymorphisms that are strongly linked to rs368234815. Therefore, it is of interest to compare these two IFNs for their effects on immune cells. Herein, using THP-1 cells, it was confirmed that IFN-λ4 could affect the differentiation status of macrophage-like cells and dendritic cells (DCs). The global gene expression changes induced by IFN-λ4 were also characterized in in vitro generated primary macrophages. Next, human PBMC-derived CD14+ monocytes were used to obtain M1 and M2 macrophages and DCs in the presence of IFN-λ3 or IFN-λ4. These DCs were cocultured with CD4+ Th cells derived from allogenic donors and their in vitro cytokine responses were measured. The specific activity of recombinant IFN-λ4 was much lower than that of IFN-λ3, as shown by induction of IFN-stimulated genes. M1 macrophages differentiated in the presence of IFN-λ4 showed higher IL-10 secretion than those differentiated in IFN-λ3. Coculture experiments suggested that IFN-λ4 could confer a Th2-biased phenotype to allogenic Th cells, wherein IFN-λ3, under similar circumstances, did not induce a significant bias toward either a Th1 or Th2 phenotype. This study shows for the first time that IFN-λ4 may influence immune responses by immunomodulation.
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Affiliation(s)
- Manjarika De
- National Institute of Biomedical GenomicsKalyaniWest BengalIndia
| | - Anand Bhushan
- National Institute of Biomedical GenomicsKalyaniWest BengalIndia
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20
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Novotny LA, Evans JG, Su L, Guo H, Meissner EG. Review of Lambda Interferons in Hepatitis B Virus Infection: Outcomes and Therapeutic Strategies. Viruses 2021; 13:1090. [PMID: 34207487 PMCID: PMC8230240 DOI: 10.3390/v13061090] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 05/27/2021] [Accepted: 06/01/2021] [Indexed: 12/27/2022] Open
Abstract
Hepatitis B virus (HBV) chronically infects over 250 million people worldwide and causes nearly 1 million deaths per year due to cirrhosis and liver cancer. Approved treatments for chronic infection include injectable type-I interferons and nucleos(t)ide reverse transcriptase inhibitors. A small minority of patients achieve seroclearance after treatment with type-I interferons, defined as sustained absence of detectable HBV DNA and surface antigen (HBsAg) antigenemia. However, type-I interferons cause significant side effects, are costly, must be administered for months, and most patients have viral rebound or non-response. Nucleos(t)ide reverse transcriptase inhibitors reduce HBV viral load and improve liver-related outcomes, but do not lower HBsAg levels or impart seroclearance. Thus, new therapeutics are urgently needed. Lambda interferons (IFNLs) have been tested as an alternative strategy to stimulate host antiviral pathways to treat HBV infection. IFNLs comprise an evolutionarily conserved innate immune pathway and have cell-type specific activity on hepatocytes, other epithelial cells found at mucosal surfaces, and some immune cells due to restricted cellular expression of the IFNL receptor. This article will review work that examined expression of IFNLs during acute and chronic HBV infection, the impact of IFNLs on HBV replication in vitro and in vivo, the association of polymorphisms in IFNL genes with clinical outcomes, and the therapeutic evaluation of IFNLs for the treatment of chronic HBV infection.
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Affiliation(s)
- Laura A. Novotny
- Division of Infectious Diseases, Medical University of South Carolina, Charleston, SC 29525, USA; (L.A.N.); (J.G.E.)
| | - John Grayson Evans
- Division of Infectious Diseases, Medical University of South Carolina, Charleston, SC 29525, USA; (L.A.N.); (J.G.E.)
| | - Lishan Su
- Division of Virology, Pathogenesis, and Cancer, Institute of Human Virology, Departments of Pharmacology, Microbiology, and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA;
| | - Haitao Guo
- Department of Microbiology and Molecular Genetics, Cancer Virology Program, UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA;
| | - Eric G. Meissner
- Division of Infectious Diseases, Medical University of South Carolina, Charleston, SC 29525, USA; (L.A.N.); (J.G.E.)
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425, USA
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21
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Bibert S, Guex N, Lourenco J, Brahier T, Papadimitriou-Olivgeris M, Damonti L, Manuel O, Liechti R, Götz L, Tschopp J, Quinodoz M, Vollenweider P, Pagani JL, Oddo M, Hügli O, Lamoth F, Erard V, Voide C, Delorenzi M, Rufer N, Candotti F, Rivolta C, Boillat-Blanco N, Bochud PY. Transcriptomic Signature Differences Between SARS-CoV-2 and Influenza Virus Infected Patients. Front Immunol 2021; 12:666163. [PMID: 34135895 PMCID: PMC8202013 DOI: 10.3389/fimmu.2021.666163] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Accepted: 05/10/2021] [Indexed: 12/19/2022] Open
Abstract
The reason why most individuals with COVID-19 have relatively limited symptoms while other develop respiratory distress with life-threatening complications remains unknown. Increasing evidence suggests that COVID-19 associated adverse outcomes mainly rely on dysregulated immunity. Here, we compared transcriptomic profiles of blood cells from 103 patients with different severity levels of COVID-19 with that of 27 healthy and 22 influenza-infected individuals. Data provided a complete overview of SARS-CoV-2-induced immune signature, including a dramatic defect in IFN responses, a reduction of toxicity-related molecules in NK cells, an increased degranulation of neutrophils, a dysregulation of T cells, a dramatic increase in B cell function and immunoglobulin production, as well as an important over-expression of genes involved in metabolism and cell cycle in patients infected with SARS-CoV-2 compared to those infected with influenza viruses. These features also differed according to COVID-19 severity. Overall and specific gene expression patterns across groups can be visualized on an interactive website (https://bix.unil.ch/covid/). Collectively, these transcriptomic host responses to SARS-CoV-2 infection are discussed in the context of current studies, thereby improving our understanding of COVID-19 pathogenesis and shaping the severity level of COVID-19.
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Affiliation(s)
- Stéphanie Bibert
- Infectious Diseases Service, Department of Medicine, University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Nicolas Guex
- Bioinformatics Competence Center, University of Lausanne, Lausanne, Switzerland
| | - Joao Lourenco
- SIB Swiss Institute of Bioinformatics and Department of Fundamenal Oncology, University of Lausanne, Lausanne, Switzerland
| | - Thomas Brahier
- Infectious Diseases Service, Department of Medicine, University Hospital and University of Lausanne, Lausanne, Switzerland
| | | | - Lauro Damonti
- Infectious Diseases Service, Department of Medicine, University Hospital and University of Lausanne, Lausanne, Switzerland
- Department of Infectious Diseases, Bern University Hospital, Bern, Switzerland
| | - Oriol Manuel
- Infectious Diseases Service and Transplantation Center, Department of Medicine, University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Robin Liechti
- Bioinformatics Competence Center, University of Lausanne, Lausanne, Switzerland
- SIB Swiss Institute of Bioinformatics and Department of Fundamenal Oncology, University of Lausanne, Lausanne, Switzerland
| | - Lou Götz
- Bioinformatics Competence Center, University of Lausanne, Lausanne, Switzerland
- SIB Swiss Institute of Bioinformatics and Department of Fundamenal Oncology, University of Lausanne, Lausanne, Switzerland
| | - Jonathan Tschopp
- Infectious Diseases Service, Department of Medicine, University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Mathieu Quinodoz
- Institute of Molecular and Clinical Ophthalmology Basel (IOB), Basel, Switzerland
- Department of Ophthalmology, University Hospital Basel, Basel, Switzerland
- Department of Genetics and Genome Biology, University of Leicester, Leicester, United Kingdom
| | - Peter Vollenweider
- Internal Medicine Service, Department of Medicine, University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Jean-Luc Pagani
- Department of Adult Intensive Care Medicine, University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Mauro Oddo
- Department of Adult Intensive Care Medicine, University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Olivier Hügli
- Emergency Department, University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Frédéric Lamoth
- Infectious Diseases Service, Department of Medicine, University Hospital and University of Lausanne, Lausanne, Switzerland
- Department of Laboratory Medicine, Institute of Microbiology, University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Véronique Erard
- Clinique de Médecine et spécialités, Infectiologie, Hôpital Fribourgeois-Fribourg, Fribourg, Switzerland
| | - Cathy Voide
- Department of Infectious Diseases, Central Institute, Valais Hospital, Sion, Switzerland
| | - Mauro Delorenzi
- SIB Swiss Institute of Bioinformatics and Department of Fundamenal Oncology, University of Lausanne, Lausanne, Switzerland
- Department of Oncology, University Hospital and University of Lausanne, Epalinges, Switzerland
| | - Nathalie Rufer
- Department of Oncology, University Hospital and University of Lausanne, Epalinges, Switzerland
| | - Fabio Candotti
- Division of Immunology and Allergy, University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Carlo Rivolta
- Institute of Molecular and Clinical Ophthalmology Basel (IOB), Basel, Switzerland
- Department of Ophthalmology, University Hospital Basel, Basel, Switzerland
- Department of Genetics and Genome Biology, University of Leicester, Leicester, United Kingdom
| | - Noémie Boillat-Blanco
- Infectious Diseases Service, Department of Medicine, University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Pierre-Yves Bochud
- Infectious Diseases Service, Department of Medicine, University Hospital and University of Lausanne, Lausanne, Switzerland
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22
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Wang SQ, Shen Y, Li J, Liu Y, Cheng LS, Wu SD, She WM, Jiang W. Entecavir-induced interferon-λ1 suppresses type 2 innate lymphoid cells in patients with hepatitis B virus-related liver cirrhosis. J Viral Hepat 2021; 28:795-808. [PMID: 33482039 DOI: 10.1111/jvh.13476] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Accepted: 01/11/2021] [Indexed: 12/09/2022]
Abstract
The immunomodulatory effects of entecavir (ETV) in anti-hepatitis B virus (HBV) therapy have long been recognized. This study aimed to determine the effects of ETV on non-natural killer innate lymphoid cells (non-NK ILCs) in HBV-related liver disease progression. We enrolled treatment-naïve chronic hepatitis B (CHB) and HBV-related liver cirrhosis (LC) patients treated with ETV for 24 months. Before and after therapy, the frequency and cytokine profiles of ILC2s and non-NK ILCs subset homeostasis and their clinical significance were determined, and serial serum interferon (IFN)-λ levels were analysed. Peripheral blood mononuclear cells (PBMCs) of untreated LC patients were cultured with serum from untreated and ETV-treated LC patients in addition to being subject to IFN-λ1 neutralization and stimulation, and the frequency and cytokine production of ILC2s as well as non-NK ILCs subset ratios were calculated. Furthermore, IFN-λ receptor expression on non-NK ILCs and dendritic cells (DCs) was measured. After 24 months of ETV treatment, the frequency and cytokine production of ILC2s (IL-4, IL-13, IFN-γ, TNF-α) decreased with increased ILC1/ILC2 and decreased ILC2/ILC3 ratios, revealing a close association with disease status in LC patients. Long-term ETV administration-induced serum IFN-λ1 levels were negatively correlated with ILC2s. ETV-treated LC serum culture and IFN-λ1 stimulation yielded similar effects on suppression of ILC2s, and IFN-λ1 neutralization in serum culture partly inhibited this effect. The IFN-λ receptor was detected on DCs but not on non-NK ILCs. In conclusion, ETV suppresses the frequency and cytokine profiles of ILC2s by increasing IFN-λ1 in LC patients.
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Affiliation(s)
- Si-Qi Wang
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Institute of Liver Disease, Shanghai, China
| | - Yue Shen
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Institute of Liver Disease, Shanghai, China
| | - Jing Li
- Department of Gastroenterology, Tongji Hospital, Tongji University, Shanghai, China
| | - Yun Liu
- Department of Rheumatology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Li-Sha Cheng
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Institute of Liver Disease, Shanghai, China
| | - Sheng-Di Wu
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Institute of Liver Disease, Shanghai, China
| | - Wei-Min She
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Institute of Liver Disease, Shanghai, China
| | - Wei Jiang
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Institute of Liver Disease, Shanghai, China
- Department of Gastroenterology, Xiamen Branch, Zhongshan Hospital, Fudan University, Xiamen, Fujian, China
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23
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Zhang Z, Urban S. New insights into HDV persistence: The role of interferon response and implications for upcoming novel therapies. J Hepatol 2021; 74:686-699. [PMID: 33276031 DOI: 10.1016/j.jhep.2020.11.032] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Revised: 11/12/2020] [Accepted: 11/22/2020] [Indexed: 02/06/2023]
Abstract
Chronic hepatitis D (CHD), a global health problem, manifests as the most severe form of viral hepatitis. The causative agent, HDV, is the smallest known human virus; it replicates its circular single-stranded RNA genome in the nucleus of hepatocytes. HDV requires HBV-encoded envelope proteins for dissemination and de novo cell entry. However, HDV can also spread through cell division. Following entry into hepatocytes, replicative intermediates of HDV RNA are sensed by the pattern recognition receptor MDA5 (melanoma differentiation antigen 5) resulting in interferon (IFN)-β/λ induction. This IFN response strongly suppresses cell division-mediated spread of HDV genomes, however, it only marginally affects HDV RNA replication in already infected, resting hepatocytes. Monotherapy with IFN-α/λ shows efficacy but rarely results in HDV clearance. Recent molecular insights into key determinants of HDV persistence and the accelerated development of specifically acting antivirals that interfere with the replication cycle have revealed promising new therapeutic perspectives. In this review, we briefly summarise our knowledge on replication/persistence of HDV, the newly discovered HDV-like agents, and the interplay of HDV with the IFN response and its consequences for persistence. Finally, we discuss the possible role of IFNs in combination with upcoming therapies aimed at HDV cure.
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Affiliation(s)
- Zhenfeng Zhang
- Department of Infectious Diseases, Molecular Virology, University Hospital Heidelberg, Heidelberg, Germany
| | - Stephan Urban
- Department of Infectious Diseases, Molecular Virology, University Hospital Heidelberg, Heidelberg, Germany; German Center for Infection Research (DZIF) - Heidelberg Partner Site, Heidelberg, Germany.
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24
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Keshani F, Tabari Z, Hematzadeh S. IL29 expression in gingival tissues of chronic periodontitis and aggressive periodontitis patients: An immunohistochemical analysis. Dent Res J (Isfahan) 2021. [DOI: 10.4103/1735-3327.324025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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25
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Duncan CJA, Randall RE, Hambleton S. Genetic Lesions of Type I Interferon Signalling in Human Antiviral Immunity. Trends Genet 2021; 37:46-58. [PMID: 32977999 PMCID: PMC7508017 DOI: 10.1016/j.tig.2020.08.017] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 08/08/2020] [Accepted: 08/20/2020] [Indexed: 12/13/2022]
Abstract
The concept that type I interferons (IFN-I) are essential to antiviral immunity derives from studies on animal models and cell lines. Virtually all pathogenic viruses have evolved countermeasures to IFN-I restriction, and genetic loss of viral IFN-I antagonists leads to virus attenuation. But just how important is IFN-I to antiviral defence in humans? The recent discovery of genetic defects of IFN-I signalling illuminates this and other questions of IFN biology, including the role of the mucosa-restricted type III IFNs (IFN-III), informing our understanding of the place of the IFN system within the concerted antiviral response. Here we review monogenic lesions of IFN-I signalling pathways and summarise the organising principles which emerge.
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Affiliation(s)
- Christopher J A Duncan
- Translational and Clinical Research Institute, Immunity and Inflammation Theme, Newcastle University, Newcastle upon Tyne NE2 4HH, UK; Royal Victoria Infirmary, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne NE1 4LP, UK.
| | - Richard E Randall
- School of Biology, University of St Andrew's, St Andrew's KY16 9ST, UK
| | - Sophie Hambleton
- Translational and Clinical Research Institute, Immunity and Inflammation Theme, Newcastle University, Newcastle upon Tyne NE2 4HH, UK; Great North Children's Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne NE1 4LP, UK
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26
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Yan B, Gao J, Guo J, Yang D, Li D. Interleukin-28B dampens protease-induced lung inflammation via IL-25 and TSLP inhibition in epithelial cells. Sci Rep 2020; 10:20973. [PMID: 33262394 PMCID: PMC7708501 DOI: 10.1038/s41598-020-77844-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Accepted: 11/10/2020] [Indexed: 11/16/2022] Open
Abstract
Asthma is a chronic respiratory disease with high heterogeneity in human. Different mouse models have been applied for investigation of pathogenesis and treatment of asthma, which target on different cells, receptors and pathways. Interleukin (IL-) 28B, a member of λ-interferons, have been shown to play a protective role in OVA-induced asthma, which is antigen-specific and adaptive immune system dominant. However, the roles of IL-28B in protease-induced asthma, an adaptive immune system independent asthma, are still unclear. Here, we used plant-derived cysteine protease, papain to induce asthma in mice and found that IL-28B was capable of alleviating papain-induced asthma. Papain challenge lead to activation of epithelial cells and production of alarmin, such as IL-25 and thymic stromal lymphopoietin and IL-28B treatment down-regulated their production. Further mechanism was proved to be that IL-28B inhibited the phosphorylation of Erk in epithelial cells via interaction with their receptors. Our results reveal a protective role of IL-28B via regulation of epithelial cells in protease induced asthma.
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Affiliation(s)
- Bailing Yan
- Department of Respiratory Medicine, The First Hospital of Jilin University, 1Xinmin Street, Changchun, 130021, Jilin Province, People's Republic of China
| | - Jinying Gao
- Department of Respiratory Medicine, The First Hospital of Jilin University, 1Xinmin Street, Changchun, 130021, Jilin Province, People's Republic of China
| | - Jia Guo
- Department of Respiratory Medicine, The First Hospital of Jilin University, 1Xinmin Street, Changchun, 130021, Jilin Province, People's Republic of China
| | - Dong Yang
- Department of Gastroenterology, The First Hospital of Jilin University, 1Xinmin Street, Changchun, 130021, Jilin Province, People's Republic of China
| | - Dan Li
- Department of Respiratory Medicine, The First Hospital of Jilin University, 1Xinmin Street, Changchun, 130021, Jilin Province, People's Republic of China.
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27
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Lozhkov AA, Klotchenko SA, Ramsay ES, Moshkoff HD, Moshkoff DA, Vasin AV, Salvato MS. The Key Roles of Interferon Lambda in Human Molecular Defense against Respiratory Viral Infections. Pathogens 2020; 9:pathogens9120989. [PMID: 33255985 PMCID: PMC7760417 DOI: 10.3390/pathogens9120989] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 11/23/2020] [Accepted: 11/24/2020] [Indexed: 12/18/2022] Open
Abstract
Interferons (IFN) are crucial for the innate immune response. Slightly more than two decades ago, a new type of IFN was discovered: the lambda IFN (type III IFN). Like other IFN, the type III IFN display antiviral activity against a wide variety of infections, they induce expression of antiviral, interferon-stimulated genes (MX1, OAS, IFITM1), and they have immuno-modulatory activities that shape adaptive immune responses. Unlike other IFN, the type III IFN signal through distinct receptors is limited to a few cell types, primarily mucosal epithelial cells. As a consequence of their greater and more durable production in nasal and respiratory tissues, they can determine the outcome of respiratory infections. This review is focused on the role of IFN-λ in the pathogenesis of respiratory viral infections, with influenza as a prime example. The influenza virus is a major public health problem, causing up to half a million lethal infections annually. Moreover, the virus has been the cause of four pandemics over the last century. Although IFN-λ are increasingly being tested in antiviral therapy, they can have a negative influence on epithelial tissue recovery and increase the risk of secondary bacterial infections. Therefore, IFN-λ expression deserves increased scrutiny as a key factor in the host immune response to infection.
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Affiliation(s)
- Alexey A. Lozhkov
- Peter the Great St. Petersburg Polytechnic University, 195251 St. Petersburg, Russia; (A.A.L.); (D.A.M.); (A.V.V.)
- Smorodintsev Research Institute of Influenza, Russian Ministry of Health, 196376 St. Petersburg, Russia; (S.A.K.); (E.S.R.)
| | - Sergey A. Klotchenko
- Smorodintsev Research Institute of Influenza, Russian Ministry of Health, 196376 St. Petersburg, Russia; (S.A.K.); (E.S.R.)
| | - Edward S. Ramsay
- Smorodintsev Research Institute of Influenza, Russian Ministry of Health, 196376 St. Petersburg, Russia; (S.A.K.); (E.S.R.)
| | - Herman D. Moshkoff
- Russian Technological University (MIREA), 119454 Moscow, Russia;
- US Pharma Biotechnology, Inc., 5000 Thayer Center, Suite C, Oakland, MD 21550, USA
| | - Dmitry A. Moshkoff
- Peter the Great St. Petersburg Polytechnic University, 195251 St. Petersburg, Russia; (A.A.L.); (D.A.M.); (A.V.V.)
- Smorodintsev Research Institute of Influenza, Russian Ministry of Health, 196376 St. Petersburg, Russia; (S.A.K.); (E.S.R.)
- US Pharma Biotechnology, Inc., 5000 Thayer Center, Suite C, Oakland, MD 21550, USA
- Global Virus Network(GVN), 725 W Lombard St, Baltimore, MD 21201, USA
| | - Andrey V. Vasin
- Peter the Great St. Petersburg Polytechnic University, 195251 St. Petersburg, Russia; (A.A.L.); (D.A.M.); (A.V.V.)
- Smorodintsev Research Institute of Influenza, Russian Ministry of Health, 196376 St. Petersburg, Russia; (S.A.K.); (E.S.R.)
- Global Virus Network(GVN), 725 W Lombard St, Baltimore, MD 21201, USA
- St. Petersburg State Chemical-Pharmaceutical Academy, 197022 St. Petersburg, Russia
| | - Maria S. Salvato
- Global Virus Network(GVN), 725 W Lombard St, Baltimore, MD 21201, USA
- Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
- Correspondence:
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28
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Selective Interferon Responses of Intestinal Epithelial Cells Minimize Tumor Necrosis Factor Alpha Cytotoxicity. J Virol 2020; 94:JVI.00603-20. [PMID: 32847859 DOI: 10.1128/jvi.00603-20] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Accepted: 08/17/2020] [Indexed: 01/21/2023] Open
Abstract
Interferon (IFN) family cytokines stimulate genes (interferon-stimulated genes [ISGs]) that are integral to antiviral host defense. Type I IFNs act systemically, whereas type III IFNs act preferentially at epithelial barriers. Among barrier cells, intestinal epithelial cells (IECs) are particularly dependent on type III IFN for the control and clearance of virus infection, but the physiological basis of this selective IFN response is not well understood. Here, we confirm that type III IFN treatment elicits robust and uniform ISG expression in neonatal mouse IECs and inhibits the replication of IEC-tropic rotavirus. In contrast, type I IFN elicits a marginal ISG response in neonatal mouse IECs and does not inhibit rotavirus replication. In vitro treatment of IEC organoids with type III IFN results in ISG expression that mirrors the in vivo type III IFN response. However, IEC organoids have increased expression of the type I IFN receptor relative to neonate IECs, and the response of IEC organoids to type I IFN is strikingly increased in magnitude and scope relative to type III IFN. The expanded type I IFN-specific response includes proapoptotic genes and potentiates toxicity triggered by tumor necrosis factor alpha (TNF-α). The ISGs stimulated in common by type I and III IFNs have strong interferon-stimulated response element (ISRE) promoter motifs, whereas the expanded set of type I IFN-specific ISGs, including proapoptotic genes, have weak ISRE motifs. Thus, the preferential responsiveness of IECs to type III IFN in vivo enables selective ISG expression during infection that confers antiviral protection but minimizes disruption of intestinal homeostasis.IMPORTANCE Enteric viral infections are a major cause of gastroenteritis worldwide and have the potential to trigger or exacerbate intestinal inflammatory diseases. Prior studies have identified specialized innate immune responses that are active in the intestinal epithelium following viral infection, but our understanding of the benefits of such an epithelium-specific response is incomplete. Here, we show that the intestinal epithelial antiviral response is programmed to enable protection while minimizing epithelial cytotoxicity that can often accompany an inflammatory response. Our findings offer new insight into the benefits of a tailored innate immune response at the intestinal barrier and suggest how dysregulation of this response could promote inflammatory disease.
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29
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Interferon-λ Enhances the Differentiation of Naive B Cells into Plasmablasts via the mTORC1 Pathway. Cell Rep 2020; 33:108211. [DOI: 10.1016/j.celrep.2020.108211] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Revised: 06/24/2020] [Accepted: 09/09/2020] [Indexed: 01/21/2023] Open
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30
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Zhao M, Li L, Zhai L, Yue Q, Liu H, Ren S, Jiang X, Gao F, Bai S, Li H, Zhang Y, Xu H, Zhang L, Liu P, Tan M, Yu Q. Comparative Transcriptomic and Proteomic Analyses Prove that IFN-λ1 is a More Potent Inducer of ISGs than IFN-α against Porcine Epidemic Diarrhea Virus in Porcine Intestinal Epithelial Cells. J Proteome Res 2020; 19:3697-3707. [PMID: 32692179 DOI: 10.1021/acs.jproteome.0c00164] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Type III interferon (IFN-λ) is currently considered to be largely nonredundant to type I interferon (IFN-α) in antivirus infection, especially in epithelial cells. Previous studies reported that, compared with IFN-α, IFN-λ exhibited stronger induction of interferon-stimulated genes (ISGs) at the transcriptional level in intestinal epithelial cells and stronger inhibition of porcine epidemic diarrhea virus (PEDV). In this study, the different mechanisms of ISG upregulation induced by IFN-α and IFN-λ1 were compared at the mRNA and protein levels in the porcine intestinal epithelial cell model (IPEC-J2). It was proved that IFN-λ1 consistently exhibited stronger stimulation effects at both levels. At the mRNA level, 132 genes were significantly upregulated upon IFN-λ1 stimulation, while 42 genes upon IFN-α stimulation. At the protein level, 47 proteins were significantly upregulated upon IFN-λ1 stimulation, but only 8 proteins were upregulated upon IFN-α stimulation. The shared upregulated genes/proteins by IFN-λ1 in both transcriptional and translational omics, especially the regulation factors of ISG15, were involved in the JAK-STAT signaling pathway. Compared to IFN-α, IFN-λ1 could induce more consistent upregulation of the key ISGs (ISG15, USP18, OASL, and RSAD2) at 3-24 h postinduction as measured by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) validation. It was further confirmed through functional analysis that ISG15 and RSAD2 could inhibit PEDV infection in dose-dependent manners. This study provided solid evidence that IFN-λ1 could induce a more unique and higher ISG expression level, which exhibited anti-PEDV effects on porcine intestinal epithelial cells.
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Affiliation(s)
- Mingzhi Zhao
- Beijing Institute of Transfusion Medicine, 27 Taiping Road, Beijing 100850, China.,Prosit Sole Biotechnology, Co., Ltd., Beijing 100085, China
| | - Liang Li
- State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin 150069, China
| | - Linhui Zhai
- Chemical Proteomics Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China
| | - Qi Yue
- Chemical Proteomics Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.,University of Chinese Academy of Sciences, Beijing 100049, China
| | - Hongyu Liu
- Prosit Sole Biotechnology, Co., Ltd., Beijing 100085, China
| | - Suping Ren
- Beijing Institute of Transfusion Medicine, 27 Taiping Road, Beijing 100850, China
| | - Xingwei Jiang
- Beijing Institute of Transfusion Medicine, 27 Taiping Road, Beijing 100850, China
| | - Fenghua Gao
- Beijing Institute of Transfusion Medicine, 27 Taiping Road, Beijing 100850, China
| | - Shanshan Bai
- Beijing Institute of Transfusion Medicine, 27 Taiping Road, Beijing 100850, China
| | - Honghao Li
- Sartorius Stedim (Shanghai) Trading Co., Ltd., Shanghai 201210, China
| | - Ying Zhang
- The General Hospital of the People's Liberation Army, Beijing 100853, China
| | - Hongwei Xu
- Prosit Sole Biotechnology, Co., Ltd., Beijing 100085, China
| | - Liying Zhang
- Prosit Sole Biotechnology, Co., Ltd., Beijing 100085, China
| | - Pinghuang Liu
- State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin 150069, China
| | - Minjia Tan
- Chemical Proteomics Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.,University of Chinese Academy of Sciences, Beijing 100049, China
| | - Qun Yu
- Beijing Institute of Transfusion Medicine, 27 Taiping Road, Beijing 100850, China
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31
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Broggi A, Granucci F, Zanoni I. Type III interferons: Balancing tissue tolerance and resistance to pathogen invasion. J Exp Med 2020; 217:132623. [PMID: 31821443 PMCID: PMC7037241 DOI: 10.1084/jem.20190295] [Citation(s) in RCA: 104] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Revised: 09/23/2019] [Accepted: 10/30/2019] [Indexed: 12/12/2022] Open
Abstract
Type III IFNs, or IFN-λ, are the latest addition to the IFN family. Thanks to a restricted pattern of expression of their receptor and to unique immunomodulatory properties, IFN-λ stimulates pathogen clearance while, at the same time, curbing inflammation to maintain barrier integrity. Type III IFNs, or IFN-λ, are the newest members of the IFN family and were long believed to play roles that were redundant with those of type I IFNs. However, IFN-λ displays unique traits that delineate them as primary protectors of barrier integrity at mucosal sites. This unique role stems both from the restricted expression of IFN-λ receptor, confined to epithelial cells and to a limited pool of immune cells, and from unique immunomodulatory properties of IFN-λ. Here, we discuss recent findings that establish the unique capacity of IFN-λ to act at the barriers of the host to balance tissue tolerance and immune resistance against viral and bacterial challenges.
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Affiliation(s)
- Achille Broggi
- Division of Immunology, Boston Children's Hospital and Harvard Medical School, Boston, MA.,Division of Gastroenterology, Boston Children's Hospital and Harvard Medical School, Boston, MA
| | - Francesca Granucci
- Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy.,National Institute of Molecular Genetics "Romeo ed Enrica Invernizzi", Milan, Italy
| | - Ivan Zanoni
- Division of Immunology, Boston Children's Hospital and Harvard Medical School, Boston, MA.,Division of Gastroenterology, Boston Children's Hospital and Harvard Medical School, Boston, MA.,Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy
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32
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Santer DM, Minty GES, Golec DP, Lu J, May J, Namdar A, Shah J, Elahi S, Proud D, Joyce M, Tyrrell DL, Houghton M. Differential expression of interferon-lambda receptor 1 splice variants determines the magnitude of the antiviral response induced by interferon-lambda 3 in human immune cells. PLoS Pathog 2020; 16:e1008515. [PMID: 32353085 PMCID: PMC7217487 DOI: 10.1371/journal.ppat.1008515] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Revised: 05/12/2020] [Accepted: 04/03/2020] [Indexed: 12/12/2022] Open
Abstract
Type III interferons (IFN-lambdas(λ)) are important cytokines that inhibit viruses and modulate immune responses by acting through a unique IFN-λR1/IL-10RB heterodimeric receptor. Until now, the primary antiviral function of IFN-λs has been proposed to be at anatomical barrier sites. Here, we examine the regulation of IFN-λR1 expression and measure the downstream effects of IFN-λ3 stimulation in primary human blood immune cells, compared with lung or liver epithelial cells. IFN-λ3 directly bound and upregulated IFN-stimulated gene (ISG) expression in freshly purified human B cells and CD8+ T cells, but not monocytes, neutrophils, natural killer cells, and CD4+ T cells. Despite similar IFNLR1 transcript levels in B cells and lung epithelial cells, lung epithelial cells bound more IFN-λ3, which resulted in a 50-fold greater ISG induction when compared to B cells. The reduced response of B cells could be explained by higher expression of the soluble variant of IFN-λR1 (sIFN-λR1), which significantly reduced ISG induction when added with IFN-λ3 to peripheral blood mononuclear cells or liver epithelial cells. T-cell receptor stimulation potently, and specifically, upregulated membrane-bound IFNLR1 expression in CD4+ T cells, leading to greater antiviral gene induction, and inhibition of human immunodeficiency virus type 1 infection. Collectively, our data demonstrate IFN-λ3 directly interacts with the human adaptive immune system, unlike what has been previously shown in published mouse models, and that type III IFNs could be potentially utilized to suppress both mucosal and blood-borne viral infections.
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Affiliation(s)
- Deanna M. Santer
- Li Ka Shing Institute of Virology and Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada
| | - Gillian E. S. Minty
- Li Ka Shing Institute of Virology and Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada
| | - Dominic P. Golec
- Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada
| | - Julia Lu
- Li Ka Shing Institute of Virology and Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada
| | - Julia May
- Li Ka Shing Institute of Virology and Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada
| | - Afshin Namdar
- Li Ka Shing Institute of Virology and Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada
- School of Dentistry, University of Alberta, Edmonton, Alberta, Canada
- Department of Oncology, University of Alberta, Edmonton, Alberta, Canada
| | - Juhi Shah
- Li Ka Shing Institute of Virology and Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada
| | - Shokrollah Elahi
- Li Ka Shing Institute of Virology and Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada
- School of Dentistry, University of Alberta, Edmonton, Alberta, Canada
- Department of Oncology, University of Alberta, Edmonton, Alberta, Canada
| | - David Proud
- Department of Physiology and Pharmacology and Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
| | - Michael Joyce
- Li Ka Shing Institute of Virology and Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada
| | - D. Lorne Tyrrell
- Li Ka Shing Institute of Virology and Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada
| | - Michael Houghton
- Li Ka Shing Institute of Virology and Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada
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33
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Disruption of Type III Interferon (IFN) Genes Ifnl2 and Ifnl3 Recapitulates Loss of the Type III IFN Receptor in the Mucosal Antiviral Response. J Virol 2019; 93:JVI.01073-19. [PMID: 31462571 DOI: 10.1128/jvi.01073-19] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Accepted: 08/20/2019] [Indexed: 12/13/2022] Open
Abstract
Type III interferon (IFN), or IFN lambda (IFN-λ), is an essential component of the innate immune response to mucosal viral infections. In both the intestine and the lung, signaling via the IFN-λ receptor (IFNLR) controls clinically important viral pathogens, including influenza virus, norovirus, and rotavirus. While it is thought that IFN-λ cytokines are the exclusive ligands for signaling through IFNLR, it is not known whether genetic ablation of these cytokines phenotypically recapitulates disruption of the receptor. Here, we report the serendipitous establishment of Ifnl2- / - Ifnl3- / - mice, which lack all known functional murine IFN-λ cytokines. We demonstrate that, like Ifnlr1- / - mice lacking IFNLR signaling, these mice display defective control of murine norovirus, reovirus, and influenza virus and therefore genocopy Ifnlr1- / - mice. Thus, for regulation of viral infections at mucosal sites of both the intestine and lung, signaling via IFNLR can be fully explained by the activity of known cytokines IFN-λ2 and IFN-λ3. Our results confirm the current understanding of ligand-receptor interactions for type III IFN signaling and highlight the importance of this pathway in regulation of mucosal viral pathogens.IMPORTANCE Type III interferons are potent antiviral cytokines important for regulation of viruses that infect at mucosal surfaces. Studies using mice lacking the Ifnlr1 gene encoding the type III interferon receptor have demonstrated that signaling through this receptor is critical for protection against influenza virus, norovirus, and reovirus. Using a genetic approach to disrupt murine type III interferon cytokine genes Ifnl2 and Ifnl3, we found that mice lacking these cytokines fully recapitulate the impaired control of viruses observed in mice lacking Ifnlr1 Our results support the idea of an exclusive role for known type III interferon cytokines in signaling via IFNLR to mediate antiviral effects at mucosal surfaces. These findings emphasize the importance of type III interferons in regulation of a variety of viral pathogens and provide important genetic evidence to support our understanding of the ligand-receptor interactions in this pathway.
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Grzegorzewska AE. Genetic Polymorphisms within Interferon-λ Region and Interferon-λ3 in the Human Pathophysiology: Their Contribution to Outcome, Treatment, and Prevention of Infections with Hepatotropic Viruses. Curr Med Chem 2019; 26:4832-4851. [DOI: 10.2174/0929867325666180719121142] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2017] [Revised: 03/21/2018] [Accepted: 07/09/2018] [Indexed: 12/16/2022]
Abstract
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Genetic polymorphisms within the interferon λ (IFN-λ) chromosomal region,
mainly rs12979860 of IFN-λ4 gene (IFNL4), are known as associated with spontaneous hepatitis
C virus (HCV) resolution and sustained viral response to therapy with pegylated interferon-
α and ribavirin. Strong linkage disequilibrium of IFNL4 rs12979860 with IFNL4
rs368234815, which is casually associated with HCV spontaneous and therapeutical eradication,
at least partially explains favorable HCV outcomes attributed to major homozygosity in
rs12979860. Effects of IFN-based antiviral treatment are associated with pretreatment expression
of the IFN-λ1 receptor, expression of hepatic IFN-stimulated genes, production of IFN-
λ4, and preactivation of the JAK-STAT signaling. Nowadays direct-acting antivirals (DAAs)
became a potent tool in the treatment of hepatitis C, but IFN-λs are still under investigation as
potential antivirals and might be an option in HCV infection (DAA resistance, recurrent viremia,
adverse effects).
:
Patients with altered immunocompetence are especially prone to infections. In uremic subjects,
polymorphisms within the IFN-λ chromosomal region associate with spontaneous HCV
clearance, similarly like in the non-uremic population. Circulating IFN-λ3 shows a positive
correlation with plasma titers of antibodies to surface antigen of hepatitis B virus (anti-HBs),
which are crucial for protection against hepatitis B virus. More efficient anti-HBs production
in the presence of higher IFN-λ3 levels might occur due to IFN-λ3-induced regulation of indoleamine
2,3-dioxygenase (IDO) expression. IFN-stimulated response element is a part of
IDO gene promoter. It is worth further investigation whether IDO gene, circulating IDO, genetic
polymorphisms within the IFN-λ region, and circulating IFN-λ3 act in concordance in
immunological response to hepatotropic viruses.
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Affiliation(s)
- Alicja E. Grzegorzewska
- Chair and Department of Nephrology, Transplantology and Internal Diseases, Poznan University of Medical Sciences, Poznan, Poland
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35
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Interferon-λ orchestrates innate and adaptive mucosal immune responses. Nat Rev Immunol 2019; 19:614-625. [DOI: 10.1038/s41577-019-0182-z] [Citation(s) in RCA: 186] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/16/2019] [Indexed: 02/07/2023]
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Yurdaydin C. New treatment options for delta virus: Is a cure in sight? J Viral Hepat 2019; 26:618-626. [PMID: 30771261 DOI: 10.1111/jvh.13081] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2018] [Accepted: 01/25/2019] [Indexed: 12/12/2022]
Abstract
Current treatment of chronic hepatitis D viral infection with interferons is poorly tolerated and effective only in a minority of patients. Despite delta virus causing the most severe form of chronic viral hepatitis, no other treatments are available. After many years of inactivity, there is now hope for new treatment approaches for delta virus and some are likely to enter clinical practice in the near future. Four new treatment approaches are currently being evaluated in phase 2 studies. These involve the hepatocyte entry inhibitor myrcludex B, the farnesyl transferase inhibitor lonafarnib, the nucleic acid inhibitor REP 2139 Ca and pegylated interferon lambda. Results obtained so far are promising, and phase 3 studies are expected shortly. This review summarizes the available data on the efficacy and safety of these new drugs.
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Affiliation(s)
- Cihan Yurdaydin
- Department of Gastroenterology, Ankara University Medical School, Ankara, Turkey.,Department of Gastroenterology and Hepatology, Koc University, Istanbul, Turkey
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37
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Lazear HM, Schoggins JW, Diamond MS. Shared and Distinct Functions of Type I and Type III Interferons. Immunity 2019; 50:907-923. [PMID: 30995506 PMCID: PMC6839410 DOI: 10.1016/j.immuni.2019.03.025] [Citation(s) in RCA: 769] [Impact Index Per Article: 128.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2019] [Revised: 03/18/2019] [Accepted: 03/25/2019] [Indexed: 12/12/2022]
Abstract
Type I interferons (IFNs) (IFN-α, IFN-β) and type III IFNs (IFN-λ) share many properties, including induction by viral infection, activation of shared signaling pathways, and transcriptional programs. However, recent discoveries have revealed context-specific functional differences. Here, we provide a comprehensive review of type I and type III IFN activities, highlighting shared and distinct features from molecular mechanisms through physiological responses. Beyond discussing canonical antiviral functions, we consider the adaptive immune priming, anti-tumor, and autoimmune functions of IFNs. We discuss a model wherein type III IFNs serve as a front-line defense that controls infection at epithelial barriers while minimizing damaging inflammatory responses, reserving the more potent type I IFN response for when local responses are insufficient. In this context, we discuss current therapeutic applications targeting these cytokine pathways and highlight gaps in understanding of the biology of type I and type III IFNs in health and disease.
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Affiliation(s)
- Helen M Lazear
- Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
| | - John W Schoggins
- Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Michael S Diamond
- Departments of Medicine, Pathology & Immunology, and Molecular Microbiology, and The Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, Saint Louis, MO 63110, USA.
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Xu F, Song H, Xiao Q, Li N, Zhang H, Cheng G, Tan G. Type III interferon-induced CBFβ inhibits HBV replication by hijacking HBx. Cell Mol Immunol 2019; 16:357-366. [PMID: 29523836 PMCID: PMC6461963 DOI: 10.1038/s41423-018-0006-2] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2017] [Revised: 01/12/2018] [Accepted: 01/12/2018] [Indexed: 02/08/2023] Open
Abstract
Hepatitis B virus (HBV) and its associated chronic infection remain serious health threats worldwide. However, there is still no impactful approach for clinical treatment of hepatitis B patients. Therefore, developing a better understanding of the interactions between HBV and its host is particularly important. HBV infection has been reported to induce type-III but not type-I or type-II interferon (IFN). In this study, we identified CBFβ, an HIV enhancer, as an HBV restriction factor that is specifically induced by type-III IFN in the early stages of HBV infection. Type-III IFN-induced IL-10 played an important role in the production of CBFβ. Interestingly, the interaction between CBFβ- and HBV-encoded regulatory protein X (HBx) enhanced the stability of CBFβ, but notably blocked HBx-mediated promotion of HBV replication. CBFβ expression was lower in HBV patients than in healthy persons, and the addition of serum from HBV patients inhibited CBFβ expression in HepG2 cells. On the contrary, HBV via HBsAg inhibited type-III IFN-induced CBFβ expression and decreased the anti-HBV activity of type-III IFN, suggesting that HBV inhibits antiviral interferon-stimulated gene (ISG) expression and induces IFN resistance. Collectively, our results demonstrate that type-III IFN-triggered and IL-10-induced CBFβ are crucial factors for inhibiting HBV replication, and the HBx-CBFβ-HBsAg axis reveals a new molecular mechanism of interaction between HBV and its hosts.
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Affiliation(s)
- Fengchao Xu
- Department of Immunology, Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, Jilin, 130061, China
| | - Hongxiao Song
- Department of Immunology, Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, Jilin, 130061, China
| | - Qingfei Xiao
- Department of Nephrology, The First Hospital, Jilin University, Changchun, Jilin, 130021, China
| | - Na Li
- Department of Obstetrics, The First Hospital of Jilin University, Changchun, Jilin, 130021, China
| | - Hong Zhang
- Phase I Clinical Research Center, The First Hospital of Jilin University, Jilin, 130021, China
| | - Genhong Cheng
- Department of Immunology, Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, Jilin, 130061, China
- Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA, 90095, USA
- Center of Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005; Suzhou Institute of Systems Medicine, Suzhou, Jiangsu, 215123, China
| | - Guangyun Tan
- Department of Immunology, Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, Jilin, 130061, China.
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Yuan WM, Zhang R, Zhang Q, Ma FL, Wang C, Wang YZ, Zeng Y, Zheng LS. The generation and biological activity of a long-lasting recombinant human interferon-λ1. Protein Eng Des Sel 2019; 31:355-360. [PMID: 30496575 DOI: 10.1093/protein/gzy029] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2018] [Accepted: 10/15/2018] [Indexed: 11/15/2022] Open
Abstract
The previously generated recombinant human (rh) interferon (IFN)-λ1 protein has a short half-life, and this feature makes it challenging to conduct studies on potential clinical applications for rhIFN-λ1. In an attempt to overcome this difficulty, we constructed a 'long-life' version of rhIFN-λ1. This modified rhIFN-λ1, named rhIFN-λ1-CTPON, has a human chorionic gonadotropin β subunit carboxyl-terminal peptide (CTP) and an N-glycosylation sequence linked to its C-terminus. We confirmed the sequence of rhIFN-λ1-CTPON by mass spectrometry and then measured its biological activities. The results show that rhIFN-λ1-CTPON had antiviral activity and anti-proliferation activity in vitro that were similar to those of rhIFN-λ1 and that it similarly promoted natural killer cell cytotoxicity. Notably, the in vivo half-life of rhIFN-λ1-CTPON was determined to be 3-fold higher than that of rhIFN-λ1. We also assessed the anti-hepatitis B virus activity of rhIFN-λ1-CTPON; it was able to inhibit the production of the antigens HBs-Ag and HBe-Ag and induce antiviral gene expression. In conclusion, rhIFN-λ1-CTPON has a longer half-life than rhIFN-λ1 and has similar biological activities, so rhIFN-λ1-CTPON is an appropriate substitute for rhIFN-λ1 in the further study of potential clinical applications for rhIFN- λ1.
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Affiliation(s)
- Wu-Mei Yuan
- Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Department of Biochemistry, School of Medicine, Shihezi University, Shihezi, Xinjiang, China.,Key Laboratory for Medical Virology, National Health Commission, National Institute for Viral Disease Control and Prevention, China CDC, Beijing, China
| | - Rui Zhang
- Medical Teaching Experiment Center, School of Medicine, Shihezi University, Shihezi, Xinjiang, China
| | - Qian Zhang
- Key Laboratory for Medical Virology, National Health Commission, National Institute for Viral Disease Control and Prevention, China CDC, Beijing, China
| | - Fen-Lian Ma
- Key Laboratory for Medical Virology, National Health Commission, National Institute for Viral Disease Control and Prevention, China CDC, Beijing, China
| | - Chao Wang
- Key Laboratory for Medical Virology, National Health Commission, National Institute for Viral Disease Control and Prevention, China CDC, Beijing, China
| | - Ying-Zi Wang
- Medical Teaching Experiment Center, School of Medicine, Shihezi University, Shihezi, Xinjiang, China
| | - Yan Zeng
- Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Department of Biochemistry, School of Medicine, Shihezi University, Shihezi, Xinjiang, China
| | - Li-Shu Zheng
- Key Laboratory for Medical Virology, National Health Commission, National Institute for Viral Disease Control and Prevention, China CDC, Beijing, China
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40
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Andreakos E, Zanoni I, Galani IE. Lambda interferons come to light: dual function cytokines mediating antiviral immunity and damage control. Curr Opin Immunol 2019; 56:67-75. [PMID: 30399529 PMCID: PMC6541392 DOI: 10.1016/j.coi.2018.10.007] [Citation(s) in RCA: 77] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2018] [Revised: 10/10/2018] [Accepted: 10/15/2018] [Indexed: 01/22/2023]
Abstract
Lambda interferons (IFNλs, type III IFNs or interleukins-28/29) were described fifteen years ago as novel cytokines sharing structural and functional homology with IL-10 and type I IFNs, respectively. IFNλs engage a unique receptor complex comprising IFNLR1 and IL10R2, nevertheless they share signaling cascade and many functions with type I IFNs, questioning their possible non-redundant roles and overall biological importance. Here, we review the latest evidence establishing the primacy of IFNλs in front line protection at anatomical barriers, mediating antiviral immunity before type I IFNs. We also discuss their emerging role in regulating inflammation and limiting host damage, a major difference to type I IFNs. IFNλs come thus to light as dual function cytokines mediating antiviral immunity and damage control.
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Affiliation(s)
- Evangelos Andreakos
- Laboratory of Immunobiology, Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, 11527 Athens, Greece; Airway Disease Infection Section, National Heart and Lung Institute, Medical Research Council and Asthma UK Centre in Allergic Mechanisms of Asthma, Imperial College London, London W2 1NY, United Kingdom.
| | - Ivan Zanoni
- Division of Gastroenterology, Boston Children's Hospital, Harvard University, Boston, MA 02115, USA; Department of Biotechnology and Biosciences, University of Milano-Bicocca, 20126 Milan, Italy
| | - Ioanna E Galani
- Laboratory of Immunobiology, Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, 11527 Athens, Greece
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41
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Lasfar A, Zloza A, Silk AW, Lee LY, Cohen-Solal KA. Interferon Lambda: Toward a Dual Role in Cancer. J Interferon Cytokine Res 2019; 39:22-29. [DOI: 10.1089/jir.2018.0046] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Affiliation(s)
- Ahmed Lasfar
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey
- Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey
| | - Andrew Zloza
- Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey
- Department of Surgery, Rutgers Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, New Jersey
| | - Ann W. Silk
- Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey
| | - Leonard Y. Lee
- Department of Surgery, Rutgers Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, New Jersey
- Robert Wood Johnson University Hospital, New Brunswick, New Jersey
| | - Karine A. Cohen-Solal
- Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey
- Department of Surgery, Rutgers Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, New Jersey
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42
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Zav'yalov VP, Hämäläinen-Laanaya H, Korpela TK, Wahlroos T. Interferon-Inducible Myxovirus Resistance Proteins: Potential Biomarkers for Differentiating Viral from Bacterial Infections. Clin Chem 2018; 65:739-750. [PMID: 30593466 PMCID: PMC7108468 DOI: 10.1373/clinchem.2018.292391] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2018] [Accepted: 08/29/2018] [Indexed: 12/31/2022]
Abstract
BACKGROUND In 2015, the 68th World Health Assembly declared that effective, rapid, low-cost diagnostic tools were needed for guiding optimal use of antibiotics in medicine. This review is devoted to interferon-inducible myxovirus resistance proteins as potential biomarkers for differentiating viral from bacterial infections. CONTENT After viral infection, a branch of the interferon (IFN)-induced molecular reactions is triggered by the binding of IFNs with their receptors, a process leading to the activation of mx1 and mx2, which produce antiviral Mx proteins (MxA and MxB). We summarize current knowledge of the structures and functions of type I and III IFNs. Antiviral mechanisms of Mx proteins are discussed in reference to their structural and functional data to provide an in-depth picture of protection against viral attacks. Knowing such a mechanism may allow the development of countermeasures and the specific detection of any viral infection. Clinical research data indicate that Mx proteins are biomarkers for many virus infections, with some exceptions, whereas C-reactive protein (CRP) and procalcitonin have established positions as general biomarkers for bacterial infections. SUMMARY Mx genes are not directly induced by viruses and are not expressed constitutively; their expression strictly depends on IFN signaling. MxA protein production in peripheral blood cells has been shown to be a clinically sensitive and specific marker for viral infection. Viral infections specifically increase MxA concentrations, whereas viruses have only a modest increase in CRP or procalcitonin concentrations. Therefore, comparison of MxA and CRP and/or procalcitonin values can be used for the differentiation of infectious etiology.
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Affiliation(s)
| | | | - Timo K Korpela
- Department of Future Technologies, University of Turku, Turku, Finland
| | - Tony Wahlroos
- Laboratory of Clinical Research, Labmaster Ltd., Turku, Finland
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Zhang B, Liu Y, Wang X, Li J, Xu X, Guo L, Ho WZ. TLR3 Activation of Hepatic Stellate Cell Line Suppresses HBV Replication in HepG2 Cells. Front Immunol 2018; 9:2921. [PMID: 30619284 PMCID: PMC6304368 DOI: 10.3389/fimmu.2018.02921] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2018] [Accepted: 11/28/2018] [Indexed: 12/23/2022] Open
Abstract
There is limited information about the role of hepatic stellate cells (HSCs) in the liver innate immunity against hepatitis B virus (HBV) infection. We thus examined whether hepatic stellate cell line (LX-2) can be immunologically activated and produce antiviral factors that inhibit HBV replication in HepG2 cells. We found that LX-2 cells expressed the functional Toll-like receptor 3 (TLR3), activation of which by PolyI:C resulted in the selective induction of interferon-β (IFN-β) and IFN-λs, the phosphorylation of IFN regulatory factor 3 (IRF3) and IRF7. When HepG2 cells were treated with supernatant (SN) from PolyI:C-activated LX-2 cells, HBV replication was significantly inhibited. IFN-β and IFN-λ appeared to contribute to LX-2 SN-mediated HBV inhibition, as the antibodies to IFN-β and IFN-λ receptors could largely block the LX-2 SN action. Mechanistically, LX-2 SN treatment of the HepG2 cells induced a number of antiviral IFN-stimulated genes (ISGs: ISG20, ISG54, ISG56, OAS-1, Trim22, and Trim25) and facilitated the phosphorylation of STATs. These observations support further studies on the role of HSCs in the liver innate immunity against HBV infection.
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Affiliation(s)
- Biao Zhang
- School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Yu Liu
- School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Xu Wang
- Department of Pathology and Laboratory Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
| | - Jieliang Li
- Department of Pathology and Laboratory Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
| | - Xiqiu Xu
- School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Le Guo
- School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Wen-Zhe Ho
- School of Basic Medical Sciences, Wuhan University, Wuhan, China.,Department of Pathology and Laboratory Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
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An information-theoretic framework for deciphering pleiotropic and noisy biochemical signaling. Nat Commun 2018; 9:4591. [PMID: 30389942 PMCID: PMC6214929 DOI: 10.1038/s41467-018-07085-1] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2018] [Accepted: 10/12/2018] [Indexed: 12/24/2022] Open
Abstract
Many components of signaling pathways are functionally pleiotropic, and signaling responses are marked with substantial cell-to-cell heterogeneity. Therefore, biochemical descriptions of signaling require quantitative support to explain how complex stimuli (inputs) are encoded in distinct activities of pathways effectors (outputs). A unique perspective of information theory cannot be fully utilized due to lack of modeling tools that account for the complexity of biochemical signaling, specifically for multiple inputs and outputs. Here, we develop a modeling framework of information theory that allows for efficient analysis of models with multiple inputs and outputs; accounts for temporal dynamics of signaling; enables analysis of how signals flow through shared network components; and is not restricted by limited variability of responses. The framework allows us to explain how identity and quantity of type I and type III interferon variants could be recognized by cells despite activating the same signaling effectors.
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Niwa M, Fujisawa T, Mori K, Yamanaka K, Yasui H, Suzuki Y, Karayama M, Hozumi H, Furuhashi K, Enomoto N, Nakamura Y, Inui N, Suzuki T, Maekawa M, Suda T. IL-17A Attenuates IFN-λ Expression by Inducing Suppressor of Cytokine Signaling Expression in Airway Epithelium. THE JOURNAL OF IMMUNOLOGY 2018; 201:2392-2402. [PMID: 30224514 DOI: 10.4049/jimmunol.1800147] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Accepted: 08/18/2018] [Indexed: 01/09/2023]
Abstract
IFN-λ is a cytokine expressed in epithelial tissues and plays a central role in antiviral mucosal immune response. The expression of IFN-λ in the airway is impaired in chronic airway diseases (e.g., asthma, chronic obstructive pulmonary disease), which renders patients susceptible to viral infection. IL-17A is associated with asthma and chronic obstructive pulmonary disease pathogenesis; however, IL-17A regulation of IFN-λ expression remains unclear. The aim of the current study is to clarify IL-17A-mediated regulatory mechanisms of IFN-λ expression in human airway epithelial cells. In this study, we have shown that polyinosinic:polycytidylic acid (polyI:C) and influenza A virus (IAV) infection increased IFN-λ expression at mRNA and protein levels in primary cultures of normal human bronchial epithelial cells, whereas IL-17A attenuated polyI:C- or IAV-induced IFN-λ expression. IFN-λ receptor 1 knockdown and a JAK inhibitor, ruxolitinib, attenuated polyI:C-induced IFN-λ expression, confirming that a positive autocrine feedback loop, the IFN-λ receptor-JAK-STAT pathway, was involved in IFN-λ expression. In Western blotting analysis, we demonstrated that polyI:C and IAV infection induced STAT1 phosphorylation in normal human bronchial epithelial cells, whereas IL-17A suppressed polyI:C- or IAV-mediated STAT1 phosphorylation. Furthermore, we found that cotreatment with IL-17A and polyI:C or IAV infection synergistically increased suppressor of cytokine signaling (SOCS)1 and SOCS3 expression. SOCS1 small interfering RNA and SOCS3 small interfering RNA negated the inhibitory effect of IL-17A in polyI:C-induced IFN-λ expression by restoring attenuated STAT1 phosphorylation. Taken together, these findings indicate that IL-17A attenuates virus-induced IFN-λ expression by enhancing SOCS1 and SOCS3 expression to inhibit autocrine signaling loops in human airway epithelial cells.
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Affiliation(s)
- Mitsuru Niwa
- Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan
| | - Tomoyuki Fujisawa
- Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan;
| | - Kazutaka Mori
- Department of Respiratory Medicine, Shizuoka City Shimizu Hospital, Shizuoka 424-8636, Japan
| | - Katsumasa Yamanaka
- Department of Laboratory Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan
| | - Hideki Yasui
- Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan
| | - Yuzo Suzuki
- Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan
| | - Masato Karayama
- Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan
| | - Hironao Hozumi
- Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan
| | - Kazuki Furuhashi
- Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan.,Department of Laboratory Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan
| | - Noriyuki Enomoto
- Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan
| | - Yutaro Nakamura
- Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan
| | - Naoki Inui
- Department of Clinical Pharmacology and Therapeutics, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan; and
| | - Tetsuro Suzuki
- Department of Virology and Parasitology, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan
| | - Masato Maekawa
- Department of Laboratory Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan
| | - Takafumi Suda
- Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan
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Chen J, Liang Y, Yi P, Xu L, Hawkins HK, Rossi SL, Soong L, Cai J, Menon R, Sun J. Outcomes of Congenital Zika Disease Depend on Timing of Infection and Maternal-Fetal Interferon Action. Cell Rep 2018; 21:1588-1599. [PMID: 29117563 DOI: 10.1016/j.celrep.2017.10.059] [Citation(s) in RCA: 71] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2017] [Revised: 08/24/2017] [Accepted: 10/11/2017] [Indexed: 10/18/2022] Open
Abstract
Zika virus (ZIKV) infection during pregnancy in humans results in intrauterine growth restriction, spontaneous abortion, and microcephaly. Here, we found that fetus-derived type I interferon (IFN-I) signaling can enhance anti-ZIKV responses and provide clinical benefits to the fetus. Because IFN-λ shares signaling cascades and antiviral functions with IFN-I, we investigated the in vivo effects of IFN-λ in ZIKV-infected pregnant mice. IFN-λ administration during mid-pregnancy reduced ZIKV burden in maternal and fetal organs and alleviated placental injuries and fetal demise. In addition, prophylactic and therapeutic treatment of IFN-λ1 in a human trophoblast line, as well as in primary human amniotic epithelial cells, greatly reduced the ZIKV burden. Our data highlight IFN-λ1 as a potential therapeutic useful for women at risk for congenital Zika disease.
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Affiliation(s)
- Jinling Chen
- Department of Pathogen Biology, School of Medicine, Nantong University, Nantong, Jiangsu 226001, China, University of Texas Medical Branch, Galveston, TX 77555, USA; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Yuejin Liang
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Panpan Yi
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA; Department of Infectious Diseases, Key Laboratory of Viral Hepatitis of Hunan, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Lanman Xu
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA; Department of Infectious Diseases, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang, China
| | - Hal K Hawkins
- Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Shannan L Rossi
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA; Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Lynn Soong
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA; Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA; Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Jiyang Cai
- Department of Ophthalmology and Visual Sciences, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Ramkumar Menon
- Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Jiaren Sun
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA; Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA; Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX 77555, USA.
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Abstract
Interferons (IFNs) are secreted glycoproteins that are produced by cells in response to virus infection and other stimuli and induce an antiviral state in cells bearing IFN receptors. In this way, IFNs restrict virus replication and spread before an adaptive immune response is developed. Viruses are very sensitive to the effects of IFNs and consequently have evolved many strategies to interfere with interferon. This is particularly well illustrated by poxviruses, which have large dsDNA genomes and encode hundreds of proteins. Vaccinia virus is the prototypic poxvirus and expresses many proteins that interfere with IFN and are considered in this review. These proteins act either inside or outside the cell and within the cytoplasm or nucleus. They function by restricting the production of IFN by blocking the signaling pathways leading to transcription of IFN genes, stopping IFNs binding to their receptors, blocking IFN-induced signal transduction leading to expression of interferon-stimulated genes (ISGs), or inhibiting the antiviral activity of ISG products.
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Affiliation(s)
| | | | - Yongxu Lu
- University of Cambridge, Cambridge, United Kingdom
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Circulating Interferon- λ3, Responsiveness to HBV Vaccination, and HBV/HCV Infections in Haemodialysis Patients. BIOMED RESEARCH INTERNATIONAL 2017; 2017:3713025. [PMID: 29226133 PMCID: PMC5684519 DOI: 10.1155/2017/3713025] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 05/29/2017] [Revised: 08/16/2017] [Accepted: 08/30/2017] [Indexed: 02/07/2023]
Abstract
The IFN-λ3 gene (IFNL3) plays a role in HCV clearance. We investigated circulating IFN-λ3 and IFNL3 SNPs in haemodialysis patients who differed in their response to HBV vaccination and their HBV/HCV infection status. In 201 patients, plasma IFN-λ3 was determined using ELISA. IFNL3 SNPs (rs12979860, rs8099917) were genotyped using HRM analysis. Differences in IFN-λ3 levels were shown between responders and nonresponders to HBV vaccination and between HBsAg-positive patients and those who developed anti-HBs after infection and became HBsAg negative. HBV vaccine responders without HCV resolution revealed lower IFN-λ3 than noninfected responders. HBsAg/HCV RNA-positive subjects showed lower IFN-λ3 than patients positive only for HCV RNA or subjects who resolved both infections. Circulating IFN-λ3 correlated positively with anti-HBs and negatively with positive HCV RNA testing in the adjusted regression analyses. HBV vaccine nonresponders, HBsAg-positive patients, and subjects with replicating HCV composed a group with unfavourable outcomes. Responders to HBV vaccination, subjects who became HBsAg negative, and those who cleared HCV were analysed as having favourable outcomes. The latter showed higher IFN-λ3 but did not differ in distribution of IFNL3 SNPs compared with subjects with unfavourable outcomes. Higher IFN-λ3 concentrations are associated with response to HBV vaccination, self-limited HBV infection, and HCV resolution.
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Blumer T, Coto-Llerena M, Duong FHT, Heim MH. SOCS1 is an inducible negative regulator of interferon λ (IFN-λ)-induced gene expression in vivo. J Biol Chem 2017; 292:17928-17938. [PMID: 28900038 PMCID: PMC5663890 DOI: 10.1074/jbc.m117.788877] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2017] [Revised: 09/04/2017] [Indexed: 01/08/2023] Open
Abstract
Type I (α and β) and type III (λ) IFNs are induced upon viral infection through host sensory pathways that activate IFN regulatory factors (IRFs) and nuclear factor κB. Secreted IFNs induce autocrine and paracrine signaling through the JAK-STAT pathway, leading to the transcriptional induction of hundreds of IFN-stimulated genes, among them sensory pathway components such as cGAS, STING, RIG-I, MDA5, and the transcription factor IRF7, which enhance the induction of IFN-αs and IFN-λs. This positive feedback loop enables a very rapid and strong host response that, at some point, has to be controlled by negative regulators to maintain tissue homeostasis. Type I IFN signaling is controlled by the inducible negative regulators suppressor of cytokine signaling 1 (SOCS1), SOCS3, and ubiquitin-specific peptidase 18 (USP18). The physiological role of these proteins in IFN-γ signaling has not been clarified. Here we used knockout cell lines and mice to show that IFN-λ signaling is regulated by SOCS1 but not by SOCS3 or USP18. These differences were the basis for the distinct kinetic properties of type I and III IFNs. We found that IFN-α signaling is transient and becomes refractory after hours, whereas IFN-λ provides a long-lasting IFN-stimulated gene induction.
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Affiliation(s)
- Tanja Blumer
- From the Department of Biomedicine, University of Basel, 4031 Basel, Switzerland and
- the University Hospital Basel, 4031 Basel, Switzerland
| | - Mairene Coto-Llerena
- From the Department of Biomedicine, University of Basel, 4031 Basel, Switzerland and
- the University Hospital Basel, 4031 Basel, Switzerland
| | - Francois H T Duong
- From the Department of Biomedicine, University of Basel, 4031 Basel, Switzerland and
- the University Hospital Basel, 4031 Basel, Switzerland
| | - Markus H Heim
- From the Department of Biomedicine, University of Basel, 4031 Basel, Switzerland and
- the University Hospital Basel, 4031 Basel, Switzerland
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50
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Selvakumar TA, Bhushal S, Kalinke U, Wirth D, Hauser H, Köster M, Hornef MW. Identification of a Predominantly Interferon-λ-Induced Transcriptional Profile in Murine Intestinal Epithelial Cells. Front Immunol 2017; 8:1302. [PMID: 29085367 PMCID: PMC5650613 DOI: 10.3389/fimmu.2017.01302] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2017] [Accepted: 09/27/2017] [Indexed: 01/03/2023] Open
Abstract
Type I (α and β) and type III (λ) interferons (IFNs) induce the expression of a large set of antiviral effector molecules via their respective surface membrane receptors. Whereas most cell types respond to type I IFN, type III IFN preferentially acts on epithelial cells and protects mucosal organs such as the lung and gastrointestinal tract. Despite the engagement of different receptor molecules, the type I and type III IFN-induced signaling cascade and upregulated gene profile is thought to be largely identical. Here, we comparatively analyzed the response of gut epithelial cells to IFN-β and IFN-λ2 and identified a set of genes predominantly induced by IFN-λ2. We confirm the influence of epithelial cell polarization for enhanced type III receptor expression and demonstrate the induction of predominantly IFN-λ2-induced genes in the gut epithelium in vivo. Our results suggest that IFN-λ2 targets the epithelium and induces genes to adjust the antiviral host response to the requirements at mucosal body sites.
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Affiliation(s)
- Tharini A. Selvakumar
- Hannover Medical School, Institute for Medical Microbiology and Hospital Epidemiology, Hannover, Germany
- Research Group Model Systems for Infection and Immunity, Helmholtz Centre for Infection Research (HZI), Braunschweig, Germany
| | - Sudeep Bhushal
- Research Group Model Systems for Infection and Immunity, Helmholtz Centre for Infection Research (HZI), Braunschweig, Germany
| | - Ulrich Kalinke
- Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, A Joint Venture between the Helmholtz Centre for Infection Research and the Hannover Medical School, Hannover, Germany
| | - Dagmar Wirth
- Research Group Model Systems for Infection and Immunity, Helmholtz Centre for Infection Research (HZI), Braunschweig, Germany
- Department of Experimental Hematology, Hannover Medical School, Hannover, Germany
| | - Hansjörg Hauser
- Research Group Model Systems for Infection and Immunity, Helmholtz Centre for Infection Research (HZI), Braunschweig, Germany
| | - Mario Köster
- Research Group Model Systems for Infection and Immunity, Helmholtz Centre for Infection Research (HZI), Braunschweig, Germany
| | - Mathias W. Hornef
- Institute for Medical Microbiology, RWTH Aachen University Hospital, Aachen, Germany
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