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Immunity Apr 2019Type 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... (Comparative Study)
Comparative Study Review
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.
Topics: Adaptive Immunity; Animals; Antiviral Agents; Autoimmune Diseases; Epithelial Cells; Female; Humans; Interferon Type I; Interferons; Male; Maternal-Fetal Exchange; Mice; Neoplasms; Organ Specificity; Pregnancy; Signal Transduction; Transcription, Genetic; Transcriptome; Virus Diseases; Interferon Lambda
PubMed: 30995506
DOI: 10.1016/j.immuni.2019.03.025 -
Nature Microbiology Jun 2019Interferon (IFN)-mediated antiviral responses are central to host defence against viral infection. Despite the existence of at least 20 IFNs, there are only three known... (Review)
Review
Interferon (IFN)-mediated antiviral responses are central to host defence against viral infection. Despite the existence of at least 20 IFNs, there are only three known cell surface receptors. IFN signalling and viral evasion mechanisms form an immensely complex network that differs across species. In this Review, we begin by highlighting some of the advances that have been made towards understanding the complexity of differential IFN signalling inputs and outputs that contribute to antiviral defences. Next, we explore some of the ways viruses can interfere with, or circumvent, these defences. Lastly, we address the largely under-reviewed impact of IFN signalling on host tropism, and we offer perspectives on the future of research into IFN signalling complexity and viral evasion across species.
Topics: Animals; Antiviral Agents; Gene Expression Regulation; Host-Pathogen Interactions; Humans; Immune Evasion; Immunity, Innate; Interferon Type I; Interferons; Signal Transduction; Tropism; Virus Diseases; Viruses; Interferon Lambda
PubMed: 30936491
DOI: 10.1038/s41564-019-0421-x -
Cell Host & Microbe Jul 2021COVID-19 can result in severe disease characterized by significant immunopathology that is spurred by an exuberant, yet dysregulated, innate immune response with a poor... (Review)
Review
COVID-19 can result in severe disease characterized by significant immunopathology that is spurred by an exuberant, yet dysregulated, innate immune response with a poor adaptive response. A limited and delayed interferon I (IFN-I) and IFN-III response results in exacerbated proinflammatory cytokine production and in extensive cellular infiltrates in the respiratory tract, resulting in lung pathology. The development of effective therapeutics for patients with severe COVID-19 depends on our understanding of the pathological elements of this unbalanced innate immune response. Here, we review the mechanisms by which SARS-CoV-2 both activates and antagonizes the IFN and inflammatory response following infection, how a dysregulated cytokine and cellular response contributes to immune-mediated pathology in COVID-19, and therapeutic strategies that target elements of the innate response.
Topics: Animals; Anti-Inflammatory Agents; COVID-19; Cytokines; Disease Models, Animal; Humans; Immune Evasion; Immunity, Innate; Interferon Type I; Interferons; Kinetics; SARS-CoV-2; Interferon Lambda; COVID-19 Drug Treatment
PubMed: 34022154
DOI: 10.1016/j.chom.2021.05.004 -
Frontiers in Immunology 2020Interferons (IFNs) are a family of cytokines with the unique ability to induce cell intrinsic programs that enhance resistance to viral infection. Induction of an... (Review)
Review
Interferons (IFNs) are a family of cytokines with the unique ability to induce cell intrinsic programs that enhance resistance to viral infection. Induction of an antiviral state at the cell, tissue, organ, and organismal level is performed by three distinct IFN families, designated as Type-I, Type-II, and Type-III IFNs. Overall, there are 21 human IFNs, (16 type-I, 12 IFNαs, IFNβ, IFNϵ, IFNκ, and IFNω; 1 type-II, IFNγ; and 4 type-III, IFNλ1, IFNλ2, IFNλ3, and IFNλ4), that induce pleotropic cellular activities essential for innate and adaptive immune responses against virus and other pathogens. IFN signaling is initiated by binding to distinct heterodimeric receptor complexes. The three-dimensional structures of the type-I (IFNα/IFNAR1/IFNAR2), type-II (IFNγ/IFNGR1/IFNGR2), and type-III (IFNλ3/IFNλR1/IL10R2) signaling complexes have been determined. Here, we highlight similar and unique features of the IFNs, their cell surface complexes and discuss their role in inducing downstream IFN signaling responses.
Topics: Animals; Humans; Interferons; Ligands; Mice; Models, Molecular; Protein Conformation; Receptors, Interferon; Signal Transduction; Species Specificity; Structure-Activity Relationship
PubMed: 33281831
DOI: 10.3389/fimmu.2020.606489 -
Clinical Microbiology Reviews Oct 2001Tremendous progress has been made in understanding the molecular basis of the antiviral actions of interferons (IFNs), as well as strategies evolved by viruses to... (Review)
Review
Tremendous progress has been made in understanding the molecular basis of the antiviral actions of interferons (IFNs), as well as strategies evolved by viruses to antagonize the actions of IFNs. Furthermore, advances made while elucidating the IFN system have contributed significantly to our understanding in multiple areas of virology and molecular cell biology, ranging from pathways of signal transduction to the biochemical mechanisms of transcriptional and translational control to the molecular basis of viral pathogenesis. IFNs are approved therapeutics and have moved from the basic research laboratory to the clinic. Among the IFN-induced proteins important in the antiviral actions of IFNs are the RNA-dependent protein kinase (PKR), the 2',5'-oligoadenylate synthetase (OAS) and RNase L, and the Mx protein GTPases. Double-stranded RNA plays a central role in modulating protein phosphorylation and RNA degradation catalyzed by the IFN-inducible PKR kinase and the 2'-5'-oligoadenylate-dependent RNase L, respectively, and also in RNA editing by the IFN-inducible RNA-specific adenosine deaminase (ADAR1). IFN also induces a form of inducible nitric oxide synthase (iNOS2) and the major histocompatibility complex class I and II proteins, all of which play important roles in immune response to infections. Several additional genes whose expression profiles are altered in response to IFN treatment and virus infection have been identified by microarray analyses. The availability of cDNA and genomic clones for many of the components of the IFN system, including IFN-alpha, IFN-beta, and IFN-gamma, their receptors, Jak and Stat and IRF signal transduction components, and proteins such as PKR, 2',5'-OAS, Mx, and ADAR, whose expression is regulated by IFNs, has permitted the generation of mutant proteins, cells that overexpress different forms of the proteins, and animals in which their expression has been disrupted by targeted gene disruption. The use of these IFN system reagents, both in cell culture and in whole animals, continues to provide important contributions to our understanding of the virus-host interaction and cellular antiviral response.
Topics: Antiviral Agents; Apoptosis; Humans; Interferons; Receptors, Interferon; Signal Transduction; Transcriptional Activation; Virus Diseases
PubMed: 11585785
DOI: 10.1128/CMR.14.4.778-809.2001 -
Cold Spring Harbor Perspectives in... Nov 2018Interferons (IFNs) are a broad class of cytokines elicited on challenge to the host defense and are essential for mobilizing immune responses to pathogens. Divided into... (Review)
Review
Interferons (IFNs) are a broad class of cytokines elicited on challenge to the host defense and are essential for mobilizing immune responses to pathogens. Divided into three classes, type I, type II, and type III, all IFNs share in common the ability to evoke antiviral activities initiated by the interaction with their cognate receptors. The nine-member IFN regulatory factor (IRF) family, first discovered in the context of transcriptional regulation of type I IFN genes following viral infection, are pivotal for the regulation of the IFN responses. In this review, we briefly describe cardinal features of the three types of IFNs and then focus on the role of the IRF family members in the regulation of each IFN system.
Topics: Animals; DNA; Gene Expression Regulation; Humans; Interferon Regulatory Factors; Interferons
PubMed: 28963109
DOI: 10.1101/cshperspect.a028423 -
Science (New York, N.Y.) Aug 2020Excessive cytokine signaling frequently exacerbates lung tissue damage during respiratory viral infection. Type I (IFN-α and IFN-β) and III (IFN-λ) interferons are...
Excessive cytokine signaling frequently exacerbates lung tissue damage during respiratory viral infection. Type I (IFN-α and IFN-β) and III (IFN-λ) interferons are host-produced antiviral cytokines. Prolonged IFN-α and IFN-β responses can lead to harmful proinflammatory effects, whereas IFN-λ mainly signals in epithelia, thereby inducing localized antiviral immunity. In this work, we show that IFN signaling interferes with lung repair during influenza recovery in mice, with IFN-λ driving these effects most potently. IFN-induced protein p53 directly reduces epithelial proliferation and differentiation, which increases disease severity and susceptibility to bacterial superinfections. Thus, excessive or prolonged IFN production aggravates viral infection by impairing lung epithelial regeneration. Timing and duration are therefore critical parameters of endogenous IFN action and should be considered carefully for IFN therapeutic strategies against viral infections such as influenza and coronavirus disease 2019 (COVID-19).
Topics: Alveolar Epithelial Cells; Animals; Apoptosis; Bronchoalveolar Lavage Fluid; Cell Differentiation; Cell Proliferation; Cells, Cultured; Cytokines; Female; Influenza A Virus, H3N2 Subtype; Interferon Type I; Interferon-alpha; Interferon-beta; Interferons; Lung; Male; Mice; Orthomyxoviridae Infections; Receptor, Interferon alpha-beta; Receptors, Interferon; Signal Transduction; Tumor Suppressor Protein p53; Interferon Lambda
PubMed: 32527928
DOI: 10.1126/science.abc2061 -
Frontiers in Immunology 2021
Topics: Animals; Asthma; Biomarkers; Disease Management; Disease Susceptibility; Humans; Immunity; Interferon Type I; Interferons; Interferon Lambda
PubMed: 35116044
DOI: 10.3389/fimmu.2021.826363 -
Rheumatic Diseases Clinics of North... Aug 2021Skewing of type I interferon (IFN) production and responses is a hallmark of systemic lupus erythematosus (SLE). Genetic and environmental contributions to IFN... (Review)
Review
Skewing of type I interferon (IFN) production and responses is a hallmark of systemic lupus erythematosus (SLE). Genetic and environmental contributions to IFN production lead to aberrant innate and adaptive immune activation even before clinical development of disease. Basic and translational research in this arena continues to identify contributions of IFNs to disease pathogenesis, and several promising therapeutic options for targeting of type I IFNs and their signaling pathways are in development for treatment of SLE patients.
Topics: Humans; Interferon Type I; Interferons; Lupus Erythematosus, Systemic; Signal Transduction
PubMed: 34215365
DOI: 10.1016/j.rdc.2021.04.001 -
British Medical Journal (Clinical... Mar 1983
Topics: Humans; Interferons; Neoplasms
PubMed: 6186330
DOI: 10.1136/bmj.286.6367.739