scholarly journals Crosstalk Between Mammalian Antiviral Pathways

2019 ◽  
Vol 5 (1) ◽  
pp. 29 ◽  
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.

scholarly journals A host type I interferon response is induced by cytosolic sensing of the bacterial second messenger cyclic-di-GMP

2009 ◽  
Vol 206 (9) ◽  
pp. 1899-1911 ◽  
Author(s):  
Sarah M. McWhirter ◽  
Roman Barbalat ◽  
Kathryn M. Monroe ◽  
Mary F. Fontana ◽  
Mamoru Hyodo ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Map Kinases ◽  
Second Messenger ◽  
Innate Immune ◽  
Guanosine Monophosphate ◽  
Host Cells ◽  
Type I Interferons ◽  
Interferon Response ◽  
Type I

The innate immune system responds to unique molecular signatures that are widely conserved among microbes but that are not normally present in host cells. Compounds that stimulate innate immune pathways may be valuable in the design of novel adjuvants, vaccines, and other immunotherapeutics. The cyclic dinucleotide cyclic-di–guanosine monophosphate (c-di-GMP) is a recently appreciated second messenger that plays critical regulatory roles in many species of bacteria but is not produced by eukaryotic cells. In vivo and in vitro studies have previously suggested that c-di-GMP is a potent immunostimulatory compound recognized by mouse and human cells. We provide evidence that c-di-GMP is sensed in the cytosol of mammalian cells via a novel immunosurveillance pathway. The potency of cytosolic signaling induced by c-di-GMP is comparable to that induced by cytosolic delivery of DNA, and both nucleic acids induce a similar transcriptional profile, including triggering of type I interferons and coregulated genes via induction of TBK1, IRF3, nuclear factor κB, and MAP kinases. However, the cytosolic pathway that senses c-di-GMP appears to be distinct from all known nucleic acid–sensing pathways. Our results suggest a novel mechanism by which host cells can induce an inflammatory response to a widely produced bacterial ligand.

scholarly journals ALG2 regulates type I interferon responses by inhibiting STING trafficking

2021 ◽  
Author(s):  
Wangsheng Ji ◽  
Lianfei Zhang ◽  
Xiaoyu Xu ◽  
Xinqi Liu
Keyword(s):  
Immune Responses ◽  
Type I Interferon ◽  
Innate Immune ◽  
Type I Interferons ◽  
Interferon Response ◽  
Type I ◽  
Innate Immune Responses ◽  
Downstream Signaling ◽  
Interferon Responses ◽  
Hsv 1

Stimulator of IFN genes (STING), an endoplasmic reticulum (ER) signaling adaptor, is essential for the type I interferon response to cytosolic dsDNA. The translocation from the ER to perinuclear vesicles following binding cGAMP is a critical step for STING to activate downstream signaling molecules, which lead to the production of interferon and pro-inflammatory cytokines. Here we found that apoptosis-linked gene 2 (ALG2) suppressed STING signaling induced by either HSV-1 infection or cGAMP presence. Knockout of ALG2 markedly facilitated the expression of type I interferons upon cGAMP treatment or HSV-1 infection in THP-1 monocytes. Mechanistically, ALG2 associated with the C-terminal tail (CTT) of STING and inhibited its trafficking from ER to perinuclear region. Furthermore, the ability of ALG2 to coordinate calcium was crucial for its regulation of STING trafficking and DNA-induced innate immune responses. This work suggests that ALG2 is involved in DNA-induced innate immune responses by regulating STING trafficking.

scholarly journals SUMO2 and SUMO3 redundantly prevent a noncanonical type I interferon response

2018 ◽  
Vol 115 (26) ◽  
pp. 6798-6803 ◽  
Author(s):  
John T. Crowl ◽  
Daniel B. Stetson
Keyword(s):  
Transcription Factors ◽  
Host Defense ◽  
Unknown Function ◽  
Protein Function ◽  
Type I Interferon ◽  
Innate Immune ◽  
Type I Interferons ◽  
Interferon Response ◽  
Type I ◽  
Negative Regulators

Detection of nucleic acids by innate immune sensors triggers the production of type I interferons (IFNs). While IFNs are essential for host defense against viral infection, dysregulated production of IFNs underlies numerous autoinflammatory diseases. We have found that the loss of sumoylation results in a potent, spontaneous IFN response. Vertebrates possess three small ubiquitin-like modifiers (SUMOs) that can be conjugated onto target proteins and alter protein function in diverse but still poorly characterized ways. We demonstrate that regulation of IFN by sumoylation is redundantly mediated by both SUMO2 and SUMO3, but not SUMO1, revealing a previously unknown function of SUMO2/3. Remarkably, this IFN response is independent of all known IFN-inducing pathways and does not require either of the canonical IFN-associated transcription factors IRF3 or IRF7. Taken together, our findings demonstrate that SUMO2 and SUMO3 are specific and essential negative regulators of a noncanonical mechanism of IFN induction.

scholarly journals Sex-Dependent Intestinal Replication of an Enteric Virus

2017 ◽  
Vol 91 (7) ◽  
Author(s):  
Christopher M. Robinson ◽  
Yao Wang ◽  
Julie K. Pfeiffer
Keyword(s):  
Gastrointestinal Tract ◽  
Viral Replication ◽  
Sex Hormones ◽  
Viral Infections ◽  
Type I Interferon ◽  
Enteric Virus ◽  
Interferon Response ◽  
Sex Bias ◽  
Type I ◽  
Peripheral Tissues

ABSTRACT Coxsackievirus is an enteric virus that initiates infection in the gastrointestinal tract before disseminating to peripheral tissues to cause disease, but intestinal factors that influence viral replication are understudied. Furthermore, a sex bias for severe sequelae from coxsackievirus infections has been observed in humans. While mouse models mimicking human pathogenesis have been well characterized, many of these experiments use intraperitoneal injection of coxsackievirus to infect mice, bypassing the intestine. In light of recent studies identifying intestinal factors, such as the microbiota, that alter enteric viral replication, we sought to investigate coxsackievirus replication within the intestine. Here, we orally infected mice with coxsackievirus B3 (CVB3) and found that CVB3 replication in the intestine is sex dependent. CVB3 replicated efficiently in the intestine of male mice but not female mice. Additionally, we found that the type I interferon response and sex hormones can alter both viral replication and lethality. Overall, these data suggest that sex and the immune response play a vital role in CVB3 replication in the intestine and should be considered in light of the sex bias observed in human disease. IMPORTANCE Sex bias in severe sequelae from enteric viral infections has been observed. Since viruses have evolved to achieve optimal levels of fitness in their environmental niches, it is imperative to study viruses at the site of initial replication. Here, we used an oral inoculation system for CVB3, which follows the natural route of infection in the gastrointestinal tract. We found that sex can influence the replication of CVB3 in the intestine. Additionally, the type I interferon response and sex hormones alter both CVB3 intestinal replication and lethality. Overall this work highlights the fact that sex should be considered in investigations of enteric viral replication and pathogenesis.

scholarly journals Viperin binds STING and enhances the type-I interferon response following dsDNA detection

2018 ◽  
Author(s):  
Keaton M. Crosse ◽  
Ebony A. Monson ◽  
Arti B. Dumbrepatil ◽  
Monique Smith ◽  
Yeu-Yang Tseng ◽  
...  
Keyword(s):  
Type I Interferon ◽  
Innate Immune ◽  
Signalling Pathway ◽  
Interferon Response ◽  
Type I ◽  
Viral Pathogens ◽  
Radical Sam ◽  
Signalling Molecules ◽  
Inducible Protein ◽  
Interferon Inducible Protein

AbstractViperin is an interferon-inducible protein that is pivotal for eliciting an effective immune response against an array of diverse viral pathogens. Here we describe a mechanism of viperin’s broad antiviral activity by demonstrating the protein’s ability to synergistically enhance the innate immune dsDNA signalling pathway to limit viral infection. Viperin co-localised with the key signalling molecules of the innate immune dsDNA sensing pathway, STING and TBK1; binding directly to STING and inducing enhanced K63-linked polyubiquitination of TBK1. Subsequent analysis identified viperin’s necessity to bind the cytosolic iron-sulphur assembly component 2A, to prolong its enhancement of the type-I interferon response to aberrant dsDNA. Here we show that viperin facilitates the formation of a signalling enhanceosome, to coordinate efficient signal transduction following activation of the dsDNA signalling pathway; which results in an enhanced antiviral state. We also provide evidence for viperin’s radical SAM enzymatic activity to self-limit its immunomodulatory functions. This data further defines viperin’s role as a positive regulator of innate immune signalling, offering a mechanism of viperin’s broad antiviral capacity.

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

2017 ◽  
Vol 64 (2) ◽  
Author(s):  
Weronika Ratajczak ◽  
Paulina Niedźwiedzka-Rystwej ◽  
Beata Tokarz-Deptuła ◽  
Wiesław Deptuła
Keyword(s):  
Signaling Pathways ◽  
Crucial Role ◽  
Viral Infections ◽  
Type I Interferon ◽  
Type I Interferons ◽  
Type I ◽  
Interferon Stimulated Genes

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. 

scholarly journals Type I interferon–mediated monogenic autoinflammation: The type I interferonopathies, a conceptual overview

2016 ◽  
Vol 213 (12) ◽  
pp. 2527-2538 ◽  
Author(s):  
Mathieu P. Rodero ◽  
Yanick J. Crow
Keyword(s):  
Lupus Erythematosus ◽  
Clinical Medicine ◽  
Type I Interferon ◽  
Treatment Options ◽  
Clinical Importance ◽  
Innate Immune ◽  
Interferon Response ◽  
Type I ◽  
Monogenic Diseases ◽  
Type I Interferonopathies

Type I interferon is a potent substance. As such, the induction, transmission, and resolution of the type I interferon–mediated immune response are tightly regulated. As defined, the type I interferonopathies represent discrete examples of a disturbance of the homeostatic control of this system caused by Mendelian mutations. Considering the complexity of the interferon response, the identification of further monogenic diseases belonging to this disease grouping seems likely, with the recognition of type I interferonopathies becoming of increasing clinical importance as treatment options are developed based on an understanding of disease pathology and innate immune signaling. Definition of the type I interferonopathies indicates that autoinflammation can be both interferon and noninterferon related, and that a primary disturbance of the innate immune system can “spill over” into autoimmunity in some cases. Indeed, that several non-Mendelian disorders, most particularly systemic lupus erythematosus and dermatomyositis, are also characterized by an up-regulation of type I interferon signaling suggests the possibility that insights derived from this work will have relevance to a broader field of clinical medicine.

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

mBio ◽  
2017 ◽  
Vol 8 (1) ◽  
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.

scholarly journals The brain parenchyma has a type I interferon response that can limit virus spread

2016 ◽  
Vol 114 (1) ◽  
pp. E95-E104 ◽  
Author(s):  
Eugene Drokhlyansky ◽  
Didem Göz Aytürk ◽  
Timothy K. Soh ◽  
Ryan Chrenek ◽  
Elaine O’Loughlin ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Type I Interferon ◽  
Brain Parenchyma ◽  
Innate Immune ◽  
Interferon Response ◽  
Type I ◽  
Virus Spread ◽  
Viral Spread ◽  
The Brain

The brain has a tightly regulated environment that protects neurons and limits inflammation, designated “immune privilege.” However, there is not an absolute lack of an immune response. We tested the ability of the brain to initiate an innate immune response to a virus, which was directly injected into the brain parenchyma, and to determine whether this response could limit viral spread. We injected vesicular stomatitis virus (VSV), a transsynaptic tracer, or naturally occurring VSV-derived defective interfering particles (DIPs), into the caudate–putamen (CP) and scored for an innate immune response and inhibition of virus spread. We found that the brain parenchyma has a functional type I interferon (IFN) response that can limit VSV spread at both the inoculation site and among synaptically connected neurons. Furthermore, we characterized the response of microglia to VSV infection and found that infected microglia produced type I IFN and uninfected microglia induced an innate immune response following virus injection.

scholarly journals When human guanylate-binding proteins meet viral infections

2021 ◽  
Vol 28 (1) ◽  
Author(s):  
Rongzhao Zhang ◽  
Zhixin Li ◽  
Yan-Dong Tang ◽  
Chenhe Su ◽  
Chunfu Zheng
Keyword(s):  
Innate Immunity ◽  
Viral Infection ◽  
Binding Proteins ◽  
Molecular Mechanisms ◽  
Viral Infections ◽  
Innate Immune ◽  
Type I Interferons ◽  
Type I ◽  
Downstream Signaling ◽  
Antiviral Innate Immunity

AbstractInnate immunity is the first line of host defense against viral infection. After invading into the cells, pathogen-associated-molecular-patterns derived from viruses are recognized by pattern recognition receptors to activate the downstream signaling pathways to induce the production of type I interferons (IFN-I) and inflammatory cytokines, which play critical functions in the host antiviral innate immune responses. Guanylate-binding proteins (GBPs) are IFN-inducible antiviral effectors belonging to the guanosine triphosphatases family. In addition to exerting direct antiviral functions against certain viruses, a few GBPs also exhibit regulatory roles on the host antiviral innate immunity. However, our understanding of the underlying molecular mechanisms of GBPs' roles in viral infection and host antiviral innate immune signaling is still very limited. Therefore, here we present an updated overview of the functions of GBPs during viral infection and in antiviral innate immunity, and highlight discrepancies in reported findings and current challenges for future studies, which will advance our understanding of the functions of GBPs and provide a scientific and theoretical basis for the regulation of antiviral innate immunity.

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