Mechanisms of type I interferon action and its role in infections and diseases transmission in mammals

Interferons (IFN) are pivotal regulators of immunological processes. The paper describes mainly type I interferons -α and –β and its recently recounted signaling pathways, especially ISG – interferon stimulated genes, having a crucial role in regulating IFN recruitment. Moreover, the paper shows the data on the role of interferons -α and –β in infections – not only commonly known viral infections, but also bacterial, fungal and parasitic.

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The role of type I interferons in non-viral infections

Immunological Reviews ◽

10.1111/j.0105-2896.2004.00207.x ◽

2004 ◽

Vol 202 (1) ◽

pp. 33-48 ◽

Cited By ~ 110

Author(s):

Christian Bogdan ◽

Jochen Mattner ◽

Ulrike Schleicher

Keyword(s):

Viral Infections ◽

Type I Interferons ◽

Type I

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Role of the transcriptional regulator SP140 in resistance to bacterial infections via repression of type I interferons

10.1101/2020.01.07.897553 ◽

2020 ◽

Cited By ~ 2

Author(s):

Daisy X. Ji ◽

Kristen C. Witt ◽

Dmitri I. Kotov ◽

Shally R. Margolis ◽

Alexander Louie ◽

...

Keyword(s):

Immune Responses ◽

Legionella Pneumophila ◽

Bacterial Infections ◽

Viral Infections ◽

Transcriptional Regulator ◽

Type I Interferons ◽

Type I ◽

Viral Immunity ◽

Type I Ifns

AbstractType I interferons (IFNs) are essential for anti-viral immunity, but often impair protective immune responses during bacterial infections. How type I IFNs are strongly induced during viral infections, and yet are appropriately restrained during bacterial infections, remains poorly understood. The Super susceptibility to tuberculosis 1 (Sst1) locus in mice confers resistance to many bacterial infections. Here we provide evidence that Sp140 is a gene encoded within the Sst1 locus that functions to repress the expression of type I IFNs during bacterial infections. We generated Sp140−/− mice and find they are susceptible to infection by diverse bacteria, including Listeria monocytogenes, Legionella pneumophila, and Mycobacterium tuberculosis. Susceptibility of Sp140−/− mice to bacterial infection was rescued by crosses to mice lacking the type I IFN receptor (Ifnar−/−). Our results implicate Sp140 as an important repressor of type I IFNs that is essential for resistance to bacterial infections.

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FOSL1 Inhibits Type I Interferon Responses to Malaria and Viral Infections by Blocking TBK1 and TRAF3/TRIF Interactions

mBio ◽

10.1128/mbio.02161-16 ◽

2017 ◽

Vol 8 (1) ◽

Cited By ~ 15

Author(s):

Baowei Cai ◽

Jian Wu ◽

Xiao Yu ◽

Xin-zhuan Su ◽

Rong-Fu Wang

Keyword(s):

Immune Responses ◽

Drug Target ◽

Malaria Parasite ◽

Viral Infections ◽

Type I Interferon ◽

Innate Immune ◽

Type I ◽

Potential Drug Target ◽

Chimeric Mice

ABSTRACT Innate immune response plays a critical role in controlling invading pathogens, but such an immune response must be tightly regulated. Insufficient or overactivated immune responses may lead to harmful or even fatal consequences. To dissect the complex host-parasite interactions and the molecular mechanisms underlying innate immune responses to infections, here we investigate the role of FOS-like antigen 1 (FOSL1) in regulating the host type I interferon (IFN-I) response to malaria parasite and viral infections. FOSL1 is known as a component of a transcription factor but was recently implicated in regulating the IFN-I response to malaria parasite infection. Here we show that FOSL1 can act as a negative regulator of IFN-I signaling. Upon stimulation with poly(I:C), malaria parasite-infected red blood cells (iRBCs), or vesicular stomatitis virus (VSV), FOSL1 “translocated” from the nucleus to the cytoplasm, where it inhibited the interactions between TNF receptor-associated factor 3 (TRAF3), TIR domain-containing adapter inducing IFN-β (TRIF), and Tank-binding kinase 1 (TBK1) via impairing K63-linked polyubiquitination of TRAF3 and TRIF. Importantly, FOSL1 knockout chimeric mice had lower levels of malaria parasitemia or VSV titers in peripheral blood and decreased mortality compared with wild-type (WT) mice. Thus, our findings have identified a new role for FOSL1 in negatively regulating the host IFN-I response to malaria and viral infections and have identified a potential drug target for controlling malaria and other diseases. IMPORTANCE Infections of pathogens can trigger vigorous host immune responses, including activation and production of type I interferon (IFN-I). In this study, we investigated the role of FOSL1, a molecule previously known as a transcription factor, in negatively regulating IFN-I responses to malaria and viral infections. We showed that FOSL1 was upregulated and translocated into the cytoplasm of cells after stimulation for IFN-I production. FOSL1 could affect TRAF3 and TRIF ubiquitination and consequently impaired the association of TRAF3, TRIF, and TBK1, leading to inhibition of IFN-I signaling. In vivo experiments with FOSL1 knockout chimeric mice further validated the negative role of FOSL1 in IFN-I production and antimicrobial responses. This report reveals a new functional role for FOSL1 in IFN-I signaling and dissects the mechanism by which FOSL1 regulates IFN-I responses to malaria and viral infections, which can be explored as a potential drug target for disease control and management.

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Role of NLRs in the Regulation of Type I Interferon Signaling, Host Defense and Tolerance to Inflammation

International Journal of Molecular Sciences ◽

10.3390/ijms22031301 ◽

2021 ◽

Vol 22 (3) ◽

pp. 1301

Author(s):

Ioannis Kienes ◽

Tanja Weidl ◽

Nora Mirza ◽

Mathias Chamaillard ◽

Thomas A. Kufer

Keyword(s):

Viral Infections ◽

Type I Interferon ◽

Tissue Injury ◽

Interferon Response ◽

Type I ◽

Interferon Signaling ◽

Microbial Products ◽

Interferon Responses

Type I interferon signaling contributes to the development of innate and adaptive immune responses to either viruses, fungi, or bacteria. However, amplitude and timing of the interferon response is of utmost importance for preventing an underwhelming outcome, or tissue damage. While several pathogens evolved strategies for disturbing the quality of interferon signaling, there is growing evidence that this pathway can be regulated by several members of the Nod-like receptor (NLR) family, although the precise mechanism for most of these remains elusive. NLRs consist of a family of about 20 proteins in mammals, which are capable of sensing microbial products as well as endogenous signals related to tissue injury. Here we provide an overview of our current understanding of the function of those NLRs in type I interferon responses with a focus on viral infections. We discuss how NLR-mediated type I interferon regulation can influence the development of auto-immunity and the immune response to infection.

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Beneficial bacteria activate type-I interferon production via the cytosolic sensors STING and MAVS

10.1101/792523 ◽

2019 ◽

Author(s):

Jorge Gutierrez-Merino ◽

Beatriz Isla ◽

Theo Combes ◽

Fernando Martinez-Estrada ◽

Carlos Maluquer de Motes

Keyword(s):

Type I Interferon ◽

Fermented Food ◽

Innate Immune ◽

Biologically Active ◽

Type I ◽

Beneficial Bacteria ◽

Beneficial Microbes ◽

Interferon Stimulated Genes ◽

Microbial Infections

AbstractType-I interferon (IFN-I) cytokines are produced by innate immune cells in response to microbial infections, cancer and autoimmune diseases. These cytokines trigger protective responses in neighbouring cells through the activation of IFN-I stimulated genes. One of the most predominant pathways associated with IFN-I production is mediated by the cytosolic sensors STING and MAVS, intracellular adaptors that become activated in the presence of microbial nucleic acids in the cytoplasm, leading to IFN-I production via TANK-binding kinase (TBK)-1 and IFN regulatory factors. However, the role of these sensors in responses induced by beneficial microbes has been relatively unexplored. Here we have screened 12 representative strains of lactic acid bacteria (LAB), a group of beneficial microbes found in fermented food and probiotic formulations worldwide, for their ability to trigger IFN-I responses. Two isolates (Lactobacillus plantarum and Pediococcus pentosaceus) induced an IFN-I production that was significantly higher that the rest, both in macrophage cell lines and human primary macrophages. This response correlated with stronger interaction with macrophages and was susceptible to phagocytosis inhibitors, suggesting bacterial internalisation. Accordingly, macrophages deficient for STING and, to a lesser extent, MAVS failed to respond to the two LAB, showing reduced TBK-1 phosphorylation and IFN-I activation. Furthermore, LAB-induced IFN-I was biologically active and resulted in expression of interferon stimulated genes, which was also STING- and MAVS-dependent. Our findings demonstrate a major role for STING in the production of IFN-I by beneficial bacteria and the existence of bacteria-specific immune signatures, which can be exploited to modulate protective responses in the host.

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Poly (I:C) downregulates platelet production and function through type I interferon

Thrombosis and Haemostasis ◽

10.1160/th14-11-0951 ◽

2015 ◽

Vol 114 (11) ◽

pp. 982-993 ◽

Cited By ~ 11

Author(s):

Leonardo Rivadeneyra ◽

Roberto Gabriel Pozner ◽

Roberto Meiss ◽

Carlos Fondevila ◽

Ricardo Martin Gómez ◽

...

Keyword(s):

Bone Marrow ◽

Viral Infections ◽

Type I Interferons ◽

Poly I:C ◽

Synthetic Analogue ◽

Type I ◽

Platelet Production ◽

Underlying Mechanisms ◽

And Function

SummaryThrombocytopenia is a frequent complication of viral infections; the underlying mechanisms appear to depend on the identity of the virus involved. Previous research, including reports from our group, indicates that as well as having antiviral activity type I interferons (IFN I) selectively downregulate platelet production. In this study we extended understanding of the role of endogenous IFN I in megakaryo/ thrombopoiesis by evaluating platelet and megakaryocyte physiology in mice treated with polyinosinic:polycytidylic acid [poly (I:C)], a synthetic analogue of double-stranded RNA, Toll-like receptor-3 ligand and strong IFNp inducer. Mice-treated with poly (I:C) showed thrombocytopaenia, an increase in mean platelet volume and abnormal haemostatic and inflammatory platelet-mediated functionality, indicated by decreased fibrinogen binding and platelet adhesion, prolonged tail bleeding times and impaired P-Selectin externalisation, RANTES release and thrombin-induced platelet-neutrophil aggregate formation. These changes were associated with an increase in size and an abnormal distribution of bone marrow megakaryocytes within the vascular niche and were directly correlated with the plasmatic and bone marrow IFNp levels. All these effects were absent in genetically modified mice lacking the IFN I receptor. Our results suggest that IFN I is the central mediator of poly (I:C)-induced thrombocytopenia and platelet dysfunction and indicate that these abnormalities are due to changes in the last stages of megakaryocyte development. These data provide new evidence for the role of IFN I in megakaryocyte distribution in the bone marrow niches and its influence on thrombopoiesis and haemostasis.

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ILF3 contributes to the establishment of the antiviral type I interferon program

Nucleic Acids Research ◽

10.1093/nar/gkz1060 ◽

2019 ◽

Cited By ~ 1

Author(s):

Samir F Watson ◽

Nicolas Bellora ◽

Sara Macias

Keyword(s):

Viral Infections ◽

Host Factor ◽

Type I Interferons ◽

Type I ◽

Viral Mrnas ◽

Interferon Stimulated Genes ◽

Dsrna Binding ◽

Polysome Profiling ◽

Dsrna Binding Protein ◽

Cellular Mrnas

Abstract Upon detection of viral infections, cells activate the expression of type I interferons (IFNs) and pro-inflammatory cytokines to control viral dissemination. As part of their antiviral response, cells also trigger the translational shutoff response which prevents translation of viral mRNAs and cellular mRNAs in a non-selective manner. Intriguingly, mRNAs encoding for antiviral factors bypass this translational shutoff, suggesting the presence of additional regulatory mechanisms enabling expression of the self-defence genes. Here, we identified the dsRNA binding protein ILF3 as an essential host factor required for efficient translation of the central antiviral cytokine, IFNB1, and a subset of interferon-stimulated genes. By combining polysome profiling and next-generation sequencing, ILF3 was also found to be necessary to establish the dsRNA-induced transcriptional and translational programs. We propose a central role for the host factor ILF3 in enhancing expression of the antiviral defence mRNAs in cellular conditions where cap-dependent translation is compromised.

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Complexities of Type I Interferon Biology: Lessons from LCMV

Viruses ◽

10.3390/v11020172 ◽

2019 ◽

Vol 11 (2) ◽

pp. 172 ◽

Cited By ~ 8

Author(s):

Tamara Suprunenko ◽

Markus Hofer

Keyword(s):

Molecular Mechanisms ◽

Viral Infections ◽

Type I Interferon ◽

Malignant Tumors ◽

Antiviral Immunity ◽

Lymphocytic Choriomeningitis ◽

Type I Interferons ◽

Host Responses ◽

Type I ◽

Novel Treatments

Over the past decades, infection of mice with lymphocytic choriomeningitis virus (LCMV) has provided an invaluable insight into our understanding of immune responses to viruses. In particular, this model has clarified the central roles that type I interferons play in initiating and regulating host responses. The use of different strains of LCMV and routes of infection has allowed us to understand how type I interferons are critical in controlling virus replication and fostering effective antiviral immunity, but also how they promote virus persistence and functional exhaustion of the immune response. Accordingly, these discoveries have formed the foundation for the development of novel treatments for acute and chronic viral infections and even extend into the management of malignant tumors. Here we review the fundamental insights into type I interferon biology gained using LCMV as a model and how the diversity of LCMV strains, dose, and route of administration have been used to dissect the molecular mechanisms underpinning acute versus persistent infection. We also identify gaps in the knowledge regarding LCMV regulation of antiviral immunity. Due to its unique properties, LCMV will continue to remain a vital part of the immunologists’ toolbox.

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Distinct Roles of Type I and Type III Interferons During a Native Murine β Coronavirus Lung Infection

Journal of Virology ◽

10.1128/jvi.01241-21 ◽

2021 ◽

Author(s):

Lokesh Sharma ◽

Xiaohua Peng ◽

Hua Qing ◽

Brandon K. Hilliard ◽

Jooyoung Kim ◽

...

Keyword(s):

Type I Interferon ◽

Lung Infection ◽

Viral Clearance ◽

Type I Interferons ◽

Type I ◽

Interferon Signaling ◽

Type Iii ◽

Coronavirus Infection ◽

Type Iii Interferon

Coronaviruses are a major healthcare threat to humankind. Currently, the host factors that contribute to limit disease severity in healthy young patients are not well defined. Interferons are key antiviral molecules, especially type I and type III interferons. The role of these interferons during coronavirus disease is a subject of debate. Here using mice that are deficient in type I (IFNAR1 -/- ), type III (IFNLR1 -/- ) or both (IFNAR1/LR1 -/- ) interferon signaling pathways and murine adapted coronavirus (MHV-A59) administered through intranasal route, we define the role of interferons in coronavirus infection. We show that type I interferons play a major role in host survival in this model while a minimal role of type III interferons was manifested only in the absence of type I interferons or during a lethal dose of coronavirus. IFNAR1 -/- and IFNAR1/LR1 -/- mice had an uncontrolled viral burden in the airways and lung and increased viral dissemination to other organs. The absence of only type III interferon signaling had no measurable difference in the viral load. The increased viral load in IFNAR1 -/- and IFNAR1/LR1 -/- mice was associated with increased tissue injury, especially evident in the lung and liver. Type I but not type III interferon treatment was able to promote survival if treated during early disease. Further, we show that type I interferon signaling in macrophages contributes to the beneficial effects during coronavirus infection in mice. Importance: The antiviral and pathological potential of type I and type III interferons during coronavirus infection remains poorly defined and opposite findings have been reported. We report that both type I and type III interferons have anti-coronaviral activities, but their potency and organ specificity differ. Type I interferons deficiency rendered the mice susceptible to even a sublethal murine coronavirus infection, while the type III interferon deficiency impaired survival only during a lethal infection or during a sublethal infection in absence of type I interferon signaling. While treatment with both type I and III interferons promoted viral clearance in the airways and lung, only type I interferons promoted the viral clearance in the liver and improved host survival upon early treatment (12 hours post infection). This study demonstrates distinct roles and potency of type I and type III interferons and their therapeutic potential during coronavirus lung infection.

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Crosstalk Between Mammalian Antiviral Pathways

Non-Coding RNA ◽

10.3390/ncrna5010029 ◽

2019 ◽

Vol 5 (1) ◽

pp. 29 ◽

Cited By ~ 1

Author(s):

Samir Watson ◽

Lisanne Knol ◽

Jeroen Witteveldt ◽

Sara Macias

Keyword(s):

Small Rna ◽

Mammalian Cells ◽

Viral Infections ◽

Type I Interferon ◽

Innate Immune ◽

Type I Interferons ◽

Interferon Response ◽

Classical Type ◽

Type I ◽

Rna Biogenesis

As part of their innate immune response against viral infections, mammals activate the expression of type I interferons to prevent viral replication and dissemination. An antiviral RNAi-based response can be also activated in mammals, suggesting that several mechanisms can co-occur in the same cell and that these pathways must interact to enable the best antiviral response. Here, we will review how the classical type I interferon response and the recently described antiviral RNAi pathways interact in mammalian cells. Specifically, we will uncover how the small RNA biogenesis pathway, composed by the nucleases Drosha and Dicer can act as direct antiviral factors, and how the type-I interferon response regulates the function of these. We will also describe how the factors involved in small RNA biogenesis and specific small RNAs impact the activation of the type I interferon response and antiviral activity. With this, we aim to expose the complex and intricate network of interactions between the different antiviral pathways in mammals.

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