scholarly journals Type I Interferons: Distinct Biological Activities and Current Applications for Viral Infection

2018 ◽  
Vol 51 (5) ◽  
pp. 2377-2396 ◽  
Author(s):  
Shi-fang Li ◽  
Mei-jiao Gong ◽  
Fu-rong Zhao ◽  
Jun-jun Shao ◽  
Yin-li Xie ◽  
...  
Keyword(s):  
Biological Activities ◽  
Therapeutic Option ◽  
Influenza Viruses ◽  
Type I Interferons ◽  
Type I ◽  
Virus Infections ◽  
Type I Ifns ◽  
Immunodeficiency Virus ◽  
Potential Applications ◽  
Antiviral Activities

The interferons (IFNs) are a primary defense against pathogens because of the strong antiviral activities they induce. IFNs can be classified into three groups: type I, type II and type III, according to their genetic, structural, and functional characteristics and their receptors on the cell surface. The type I IFNs are the largest group and include IFN-α, IFN-β, IFN-ε, IFN-ω, IFN-κ, IFN-δ, IFN-τ and IFN-ζ. The use of IFNs for the treatment of viral infectious diseases on their antiviral activity may become an important therapeutic option, for example, IFN-α is well known for the successful treatment of hepatitis B and C virus infections, and interest is increasing in the antiviral efficacy of other novel IFN classes and their potential applications. Therefore, in this review, we summarize the recent progress in the study of the biological activities of all the type I IFN classes and their potential applications in the treatment of infections with immunodeficiency virus, hepatitis viruses, and influenza viruses.

Differential expression and activity of the porcine type I interferon family

2010 ◽  
Vol 42 (2) ◽  
pp. 248-258 ◽  
Author(s):  
Yongming Sang ◽  
Raymond R. R. Rowland ◽  
Richard A. Hesse ◽  
Frank Blecha
Keyword(s):  
Antiviral Activity ◽  
Expression Profiles ◽  
Type I Interferons ◽  
Respiratory Syndrome Virus ◽  
Target Cells ◽  
Type I ◽  
Antiviral Responses ◽  
Type I Ifns ◽  
Antiviral Activities ◽  
Vesicular Stomatitis

Type I interferons (IFNs) are central to innate and adaptive immunity, and many have unique developmental and physiological functions. However, in most species, only two subtypes, IFN-α and IFN-β, have been well studied. Because of the increasing importance of zoonotic viral diseases and the use of pigs to address human research questions, it is important to know the complete repertoire and activity of porcine type I IFNs. Here we show that porcine type I IFNs comprise at least 39 functional genes distributed along draft genomic sequences of chromosomes 1 and 10. These functional IFN genes are classified into 17 IFN-α subtypes, 11 IFN-δ subtypes, 7 IFN-ω subtypes, and single-subtype subclasses of IFN-αω, IFN-β, IFN-ε, and IFN-κ. We found that porcine type I IFNs have diverse expression profiles and antiviral activities against porcine reproductive and respiratory syndrome virus (PRRSV) and vesicular stomatitis virus (VSV), with activity ranging from 0 to >105 U·ng−1·ml−1. Whereas most IFN-α subtypes retained the greatest antiviral activity against both PRRSV and VSV in porcine and MARC-145 cells, some IFN-δ and IFN-ω subtypes, IFN-β, and IFN-αω differed in their antiviral activity based on target cells and viruses. Several IFNs, including IFN-α7/11, IFN-δ2/7, and IFN-ω4, exhibited minimal or no antiviral activity in the tested target cell-virus systems. Thus comparative studies showed that antiviral activity of porcine type I IFNs is virus- and cell-dependent, and IFN-αs are positively correlated with induction of MxA, an IFN-stimulated gene. Collectively, these data provide fundamental genomic information for porcine type I IFNs, information that is necessary for understanding porcine physiological and antiviral responses.

scholarly journals Context Is Key: Delineating the Unique Functions of IFNα and IFNβ in Disease

2020 ◽  
Vol 11 ◽  
Author(s):  
Lindsey E. Fox ◽  
Marissa C. Locke ◽  
Deborah J. Lenschow
Keyword(s):  
Viral Infections ◽  
Biological Activities ◽  
Type I Interferons ◽  
Type I ◽  
Disease States ◽  
Type I Ifns ◽  
Wide Range ◽  
Individual Type ◽  
Effector Cytokines ◽  
The Individual

Type I interferons (IFNs) are critical effector cytokines of the immune system and were originally known for their important role in protecting against viral infections; however, they have more recently been shown to play protective or detrimental roles in many disease states. Type I IFNs consist of IFNα, IFNβ, IFNϵ, IFNκ, IFNω, and a few others, and they all signal through a shared receptor to exert a wide range of biological activities, including antiviral, antiproliferative, proapoptotic, and immunomodulatory effects. Though the individual type I IFN subtypes possess overlapping functions, there is growing appreciation that they also have unique properties. In this review, we summarize some of the mechanisms underlying differential expression of and signaling by type I IFNs, and we discuss examples of differential functions of IFNα and IFNβ in models of infectious disease, cancer, and autoimmunity.

scholarly journals An Integrated View of Deubiquitinating Enzymes Involved in Type I Interferon Signaling, Host Defense and Antiviral Activities

2021 ◽  
Vol 12 ◽  
Author(s):  
Guanghui Qian ◽  
Liyan Zhu ◽  
Gen Li ◽  
Ying Liu ◽  
Zimu Zhang ◽  
...  
Keyword(s):  
Immune Responses ◽  
Host Defense ◽  
Critical Role ◽  
Innate Immune ◽  
Type I Interferons ◽  
Future Perspective ◽  
Type I ◽  
Virus Infections ◽  
Deubiquitinating Enzymes ◽  
Antiviral Activities

Viral infectious diseases pose a great challenge to human health around the world. Type I interferons (IFN-Is) function as the first line of host defense and thus play critical roles during virus infection by mediating the transcriptional induction of hundreds of genes. Nevertheless, overactive cytokine immune responses also cause autoimmune diseases, and thus, tight regulation of the innate immune response is needed to achieve viral clearance without causing excessive immune responses. Emerging studies have recently uncovered that the ubiquitin system, particularly deubiquitinating enzymes (DUBs), plays a critical role in regulating innate immune responses. In this review, we highlight recent advances on the diverse mechanisms of human DUBs implicated in IFN-I signaling. These DUBs function dynamically to calibrate host defenses against various virus infections by targeting hub proteins in the IFN-I signaling transduction pathway. We also present a future perspective on the roles of DUB-substrate interaction networks in innate antiviral activities, discuss the promises and challenges of DUB-based drug development, and identify the open questions that remain to be clarified. Our review provides a comprehensive description of DUBs, particularly their differential mechanisms that have evolved in the host to regulate IFN-I-signaling-mediated antiviral responses.

scholarly journals Emerging Connections of S1P-Metabolizing Enzymes with Host Defense and Immunity During Virus Infections

Viruses ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 1097 ◽  
Author(s):  
Jennifer J. Wolf ◽  
Caleb J. Studstill ◽  
Bumsuk Hahm
Keyword(s):  
Therapeutic Option ◽  
Sphingosine Kinase ◽  
Type I ◽  
Virus Infections ◽  
Metabolizing Enzymes ◽  
Host Interactions ◽  
Vital Functions ◽  
Sphingosine 1 Phosphate ◽  
Antiviral Activities ◽  
S1p Lyase

The sphingosine 1-phosphate (S1P) metabolic pathway is a dynamic regulator of multiple cellular and disease processes. Identification of the immune regulatory role of the sphingosine analog FTY720 led to the development of the first oral therapy for the treatment of an autoimmune disease, multiple sclerosis. Furthermore, inhibitors of sphingosine kinase (SphK), which mediate S1P synthesis, are being evaluated as a therapeutic option for the treatment of cancer. In conjunction with these captivating discoveries, S1P and S1P-metabolizing enzymes have been revealed to display vital functions during virus infections. For example, S1P lyase, which is known for metabolizing S1P, inhibits influenza virus replication by promoting antiviral type I interferon innate immune responses. In addition, both isoforms of sphingosine kinase have been shown to regulate the replication or pathogenicity of many viruses. Pro- or antiviral activities of S1P-metabolizing enzymes appear to be dependent on diverse virus–host interactions and viral pathogenesis. This review places an emphasis on summarizing the functions of S1P-metabolizing enzymes during virus infections and discusses the opportunities for designing pioneering antiviral drugs by targeting these host enzymes.

scholarly journals Distinct Roles of Interferon Alpha and Beta in Controlling Chikungunya Virus Replication and Modulating Neutrophil-Mediated Inflammation

2019 ◽  
Vol 94 (1) ◽  
Author(s):  
Lindsey E. Cook ◽  
Marissa C. Locke ◽  
Alissa R. Young ◽  
Kristen Monte ◽  
Matthew L. Hedberg ◽  
...  
Keyword(s):  
Immune Response ◽  
Chikungunya Virus ◽  
Biological Activities ◽  
Neutrophil Infiltration ◽  
Type I Interferons ◽  
Type I ◽  
Functional Variation ◽  
Chikv Infection ◽  
Blocking Antibody ◽  
Type I Ifns

ABSTRACT Type I interferons (IFNs) are key mediators of the innate immune response. Although members of this family of cytokines signal through a single shared receptor, biochemical and functional variation exists in response to different IFN subtypes. While previous work has demonstrated that type I IFNs are essential to control infection by chikungunya virus (CHIKV), a globally emerging alphavirus, the contributions of individual IFN subtypes remain undefined. To address this question, we evaluated CHIKV pathogenesis in mice lacking IFN-β (IFN-β knockout [IFN-β-KO] mice or mice treated with an IFN-β-blocking antibody) or IFN-α (IFN regulatory factor 7 knockout [IRF7-KO] mice or mice treated with a pan-IFN-α-blocking antibody). Mice lacking either IFN-α or IFN-β developed severe clinical disease following infection with CHIKV, with a marked increase in foot swelling compared to wild-type mice. Virological analysis revealed that mice lacking IFN-α sustained elevated infection in the infected ankle and in distant tissues. In contrast, IFN-β-KO mice displayed minimal differences in viral burdens within the ankle or at distal sites and instead had an altered cellular immune response. Mice lacking IFN-β had increased neutrophil infiltration into musculoskeletal tissues, and depletion of neutrophils in IFN-β-KO but not IRF7-KO mice mitigated musculoskeletal disease caused by CHIKV. Our findings suggest disparate roles for the IFN subtypes during CHIKV infection, with IFN-α limiting early viral replication and dissemination and IFN-β modulating neutrophil-mediated inflammation. IMPORTANCE Type I interferons (IFNs) possess a range of biological activity and protect against a number of viruses, including alphaviruses. Despite signaling through a shared receptor, there are established biochemical and functional differences among the IFN subtypes. The significance of our research is in demonstrating that IFN-α and IFN-β both have protective roles during acute chikungunya virus (CHIKV) infection but do so by distinct mechanisms. IFN-α limits CHIKV replication and dissemination, whereas IFN-β protects from CHIKV pathogenesis by limiting inflammation mediated by neutrophils. Our findings support the premise that the IFN subtypes have distinct biological activities in the antiviral response.

scholarly journals AB0042 CYTOKINE NETWORK ELUCIDATED BY THE QUANTIFICATION OF MULTIPLE CYTOKINES IN THE SERUM SEQUENTIALLY SAMPLED FROM RA PATIENTS WHO WERE TREATED WITH BIOLOGIC DMARDS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1323.2-1324
Author(s):  
K. Sato ◽  
S. Mamada ◽  
C. Hayashi ◽  
T. Nagashima ◽  
S. Minota
Keyword(s):  
Bone Erosion ◽  
Feedback System ◽  
Serum Levels ◽  
Type I Interferons ◽  
Type I ◽  
Serum Samples ◽  
Cytokine Network ◽  
Biologic Dmards ◽  
Type I Ifns ◽  
Before And After

Background:Biologic disease modifying anti-rheumatic drugs (DMARDs) have demonstrated that proinflammatory cytokines such as interleukin (IL-) 6 and tumor necrosis factor (TNF) play important roles in the pathogenesis of rheumatoid arthritis (RA). Other cytokines, such as type I interferons (IFNs), are also implicated in its pathogenesis (ref 1). However, the complete picture of the cytokine network involved in RA remains to be elucidated.Objectives:By quantifying sets of cytokines in the serum of RA patients before and after treatment with various biologic DMARDs, we sought to determine the effects of drugs on (A) type I IFNs, (B) soluble IL-6 receptors, and (C) other cytokines.Methods:52 patients with RA were treated with various biologic DMARDs (tocilizumab (TOC): 16, abatacept (ABT): 15, and TNF inhibitors (TNFi): 21). Serum samples were obtained (1) before, (2) approximately 4 weeks after (3) and approximately 12 weeks after the initiation of treatment. A suspension bead-array system was used for analysis; Bio-Plex Human Cytokine 17-plex Assay kits and Express Custom Panels (Bio-Rad), including IFN-β, IFN-α2, soluble IL-6 receptor α (sIL6Rα) and gp130 were used.Results:(1) As expected, the disease activity score 28-joiny count (DAS28) using the erythrocyte sedimentation rate (ESR) significantly decreased in all three groups (TOC, ABT and TNFi) by 12 weeks.(2) IFN-α2 was barely detected in the serum samples. IFN-β seemed to increase slightly in the ABT group, but the increase was not statistically significant.(3) The levels of sIL6Rα did not change substantially. Those of gp130 decreased slightly but significantly in the TOC group by 12 weeks.(4) The levels of IL-6 decreased significantly in the ABT group by 12 weeks. Those in the TNFi group decreased significantly at 4 weeks but not 12 weeks (Fig. 1A).(5) The levels of IL-7 decreased significantly only in the TOC group (Fig. 1B).Conclusion:(1) The biologic DMARDs tested in this study did not significantly affect the serum levels of type I IFNs in this study.(2) The decrease in gp130 in the TOC group may imply that gp130 is induced by IL-6, although whether this level of decrease has physiological significance is open to question.(3) Serum IL-6 was significantly decreased in the TNFi group at 4 weeks but not 12 weeks. TNF has been reported to induce IL-6 (ref 2), but negative feedback loop(s) may be present. Such a feedback system might make the discontinuation of TNFi difficult, even if patients are in remission.(4) IL-7 may be a target of IL-6. A higher level of IL-7 has been reported to be present in the joints of RA patients compared with osteoarthrosis and it is a cytokine implicated in the differentiation of osteoclasts (ref 3). This may partly explain the effect of TOC on preventing bone erosion in RA.References:[1]Ann Rheum Dis. 2007; 66: 1008–14[2]Rheumatology 2007; 46: 920-6[3]Rheumatology 2008; 47: 753-9Acknowledgments:We thank all the members of the Division of Rheumatology and Clinical Immunology, Department of Medicine, Jichi Medical University. We are also grateful to the patients involved in this study.Disclosure of Interests:Kojiro Sato Grant/research support from: Abbie, Pfizer, Chugai, Astellas, Mitsubishi-Tanabe, Ono, Takeda, Sachiko Mamada: None declared, Chiyomi Hayashi: None declared, Takao Nagashima: None declared, Seiji Minota: None declared

scholarly journals Activation of Stimulator of Interferon Genes (STING) and Sjögren Syndrome

2018 ◽  
Vol 97 (8) ◽  
pp. 893-900 ◽  
Author(s):  
J. Papinska ◽  
H. Bagavant ◽  
G.B. Gmyrek ◽  
M. Sroka ◽  
S. Tummala ◽  
...  
Keyword(s):  
Gene Expression ◽  
Viral Infections ◽  
Critical Role ◽  
Autoimmune Disorder ◽  
Sjögren Syndrome ◽  
Lymphoid Cells ◽  
Type I Interferons ◽  
Sjogren Syndrome ◽  
Type I ◽  
Type I Ifns

Sjögren syndrome (SS), a chronic autoimmune disorder causing dry mouth, adversely affects the overall oral health in patients. Activation of innate immune responses and excessive production of type I interferons (IFNs) play a critical role in the pathogenesis of this disorder. Recognition of nucleic acids by cytosolic nucleic acid sensors is a major trigger for the induction of type I IFNs. Upon activation, cytosolic DNA sensors can interact with the stimulator of interferon genes (STING) protein, and activation of STING causes increased expression of type I IFNs. The role of STING activation in SS is not known. In this study, to investigate whether the cytosolic DNA sensing pathway influences SS development, female C57BL/6 mice were injected with a STING agonist, dimethylxanthenone-4-acetic acid (DMXAA). Salivary glands (SGs) were studied for gene expression and inflammatory cell infiltration. SG function was evaluated by measuring pilocarpine-induced salivation. Sera were analyzed for cytokines and autoantibodies. Primary SG cells were used to study the expression and activation of STING. Our data show that systemic DMXAA treatment rapidly induced the expression of Ifnb1, Il6, and Tnfa in the SGs, and these cytokines were also elevated in circulation. In contrast, increased Ifng gene expression was dominantly detected in the SGs. The type I innate lymphoid cells present within the SGs were the major source of IFN-γ, and their numbers increased significantly within 3 d of treatment. STING expression in SGs was mainly observed in ductal and interstitial cells. In primary SG cells, DMXAA activated STING and induced IFN-β production. The DMXAA-treated mice developed autoantibodies, sialoadenitis, and glandular hypofunction. Our study demonstrates that activation of the STING pathway holds the potential to initiate SS. Thus, apart from viral infections, conditions that cause cellular perturbations and accumulation of host DNA within the cytosol should also be considered as possible triggers for SS.

scholarly journals Type I interferons act directly on nociceptors to produce pain sensitization: Implications for viral infection-induced pain

2019 ◽  
Author(s):  
Paulino Barragan-Iglesias ◽  
Úrzula Franco-Enzástiga ◽  
Vivekanand Jeevakumar ◽  
Andi Wangzhou ◽  
Vinicio Granados-Soto ◽  
...  
Keyword(s):  
Viral Infection ◽  
Viral Infections ◽  
Mrna Translation ◽  
Type I Interferons ◽  
Poly I:C ◽  
Type I ◽  
Drg Neurons ◽  
Pain Hypersensitivity ◽  
Type I Ifns ◽  
Pain Sensitization

ABSTRACTOne of the first signs of viral infection is body-wide aches and pain. While this type of pain usually subsides, at the extreme, viral infections can induce painful neuropathies that can last for decades. Neither of these types of pain sensitization are well understood. A key part of the response to viral infection is production of interferons (IFNs), which then activate their specific receptors (IFNRs) resulting in downstream activation of cellular signaling and a variety of physiological responses. We sought to understand how type I IFNs (IFN-α and IFN-β) might act directly on nociceptors in the dorsal root ganglion (DRG) to cause pain sensitization. We demonstrate that type I IFNRs are expressed in small/medium DRG neurons and that their activation produces neuronal hyper-excitability and mechanical pain in mice. Type I IFNs stimulate JAK/STAT signaling in DRG neurons but this does not apparently result in PKR-eIF2α activation that normally induces an anti-viral response by limiting mRNA translation. Rather, type I interferons stimulate MNK-mediated eIF4E phosphorylation in DRG neurons to promote pain hypersensitivity. Endogenous release of type I IFNs with the double stranded RNA mimetic poly(I:C) likewise produces pain hypersensitivity that is blunted in mice lacking MNK-eIF4E signaling. Our findings reveal mechanisms through which type I IFNs cause nociceptor sensitization with implications for understanding how viral infections promote pain and can lead to neuropathies.SIGNIFICANCE STATEMENTIt is increasingly understood that pathogens interact with nociceptors to alert organisms to infection as well as to mount early host defenses. While specific mechanisms have been discovered for diverse bacteria and fungal pathogens, mechanisms engaged by viruses have remained elusive. Here we show that type 1 interferons, one of the first mediators produced by viral infection, act directly on nociceptors to produce pain sensitization. Type I interferons act via a specific signaling pathway (MNK-eIF4E signaling) that is known to produce nociceptor sensitization in inflammatory and neuropathic pain conditions. Our work reveals a mechanism through which viral infections cause heightened pain sensitivity

Adjuvant activity of type I interferons

2008 ◽  
Vol 389 (5) ◽  
Author(s):  
Michael G. Tovey ◽  
Christophe Lallemand ◽  
George Thyphronitis
Keyword(s):  
Immune Response ◽  
Antibody Response ◽  
Antigen Presentation ◽  
Response Characteristic ◽  
Influenza Virus Vaccine ◽  
Type I Interferons ◽  
Type I ◽  
Adjuvant Activity ◽  
Virus Challenge ◽  
Type I Ifns

AbstractType I interferons (IFNs) produced primarily by plasmacytoid dendritic cells (pDCs) as part of the innate immune response to infectious agents induce the maturation of myeloid DCs and enhance antigen presentation. Type I IFNs also enhance apoptosis of virus-infected cells, stimulate cross priming and enhanced presentation of viral peptides. Type I IFNs are powerful polyclonal B-cell activators that induce a strong primary humoral immune response characterized by isotype switching and protection against virus challenge. Type I IFNs stimulate an IgG2a antibody response characteristic of Th1 immunity when ad-mixed with influenza virus vaccine and injected intramuscurarly (i.m.) or administered intranasally. The adjuvant activity of type I IFNs has been shown to involve direct effects of IFN on B-cells, effects on T-cells, as well as effects on antigen presentation. Oromucosal administration of type I IFNs concomitantly with i.m. injection of vaccine alone can also enhance the antibody response to influenza vaccination by enhancing trafficking of antigen-presenting cells towards the site of vaccination. Recombinant IFNs are potent adjuvants that may find application in both parenterally and mucosally administered vaccines.

IFN-κ suppresses the replication of influenza A viruses through the IFNAR-MAPK-Fos-CHD6 axis

2020 ◽  
Vol 13 (626) ◽  
pp. eaaz3381 ◽  
Author(s):  
Yongquan He ◽  
Weihui Fu ◽  
Kangli Cao ◽  
Qian He ◽  
Xiangqing Ding ◽  
...  
Keyword(s):  
Influenza A Virus ◽  
Influenza A ◽  
Influenza Viruses ◽  
Mitogen Activated Protein Kinase ◽  
Type I Interferons ◽  
Type I ◽  
Influenza A Viruses ◽  
Human Lung Cells ◽  
Avian Influenza A Virus ◽  
Factor C

Type I interferons (IFNs) are the first line of defense against viral infection. Using a mouse model of influenza A virus infection, we found that IFN-κ was one of the earliest responding type I IFNs after infection with H9N2, a low-pathogenic avian influenza A virus, whereas this early induction did not occur upon infection with the epidemic-causing H7N9 virus. IFN-κ efficiently suppressed the replication of various influenza viruses in cultured human lung cells, and chromodomain helicase DNA binding protein 6 (CHD6) was the major effector for the antiviral activity of IFN-κ, but not for that of IFN-α or IFN-β. The induction of CHD6 required both of the type I IFN receptor subunits IFNAR1 and IFNAR2, the mitogen-activated protein kinase (MAPK) p38, and the transcription factor c-Fos but was independent of signal transducer and activator of transcription 1 (STAT1) activity. In addition, we showed that pretreatment with IFN-κ protected mice from lethal influenza viral challenge. Together, our findings identify an IFN-κ–specific pathway that constrains influenza A virus and provide evidence that IFN-κ may have potential as a preventative and therapeutic agent against influenza A virus.

Sign in / Sign up

Export Citation Format

Share Document