scholarly journals Viperin: a radical response to viral infection

2012 ◽  
Vol 3 (3) ◽  
pp. 255-266 ◽  
Author(s):  
Kaitlin S. Duschene ◽  
Joan B. Broderick
Keyword(s):  
Viral Infection ◽  
Bacterial Infections ◽  
Viral Infections ◽  
Vital Role ◽  
Secretory Proteins ◽  
Type I ◽  
Antiviral Protein ◽  
Interferon Stimulated Genes ◽  
Inducible Protein ◽  
Raft Domains

AbstractOne of the first lines of defense of the host immune response to infection is upregulation of interferons, which play a vital role in triggering the early nonspecific antiviral state of the host. Interferons prompt the generation of numerous downstream products, known as interferon-stimulated genes (ISGs). One such ISG found to be either directly induced by type I, II, and III interferons or indirectly through viral infection is the ‘virus inhibitory protein, endoplasmic reticulum-associated, interferon-inducible’ protein, or viperin. Not only is viperin capable of combating a wide array of viral infections but its upregulation is also observed in the presence of endotoxins, various bacterial infections, or even in response to other immune stimuli, such as atherosclerotic lesions. Recent advances in the understanding of possible mechanisms of action of viperin involve, but are perhaps not limited to, interaction with farnesyl pyrophosphate synthase and disruption of lipid raft domains to prevent viral bud release, inhibition of hepatitis C virus secretory proteins, and coordination to lipid droplets and inhibition of viral replication. Unexpectedly, new insight into the human cytomegalovirus induction of this antiviral protein demonstrates that mitochondrial viperin plays a necessary and beneficial role for viral propagation.

scholarly journals Interferon-Inducible Myxovirus Resistance Proteins: Potential Biomarkers for Differentiating Viral from Bacterial Infections

2019 ◽  
Vol 65 (6) ◽  
pp. 739-750 ◽  
Author(s):  
Vladimir P Zav'yalov ◽  
Heli Hämäläinen-Laanaya ◽  
Timo K Korpela ◽  
Tony Wahlroos
Keyword(s):  
Viral Infection ◽  
Bacterial Infections ◽  
Viral Infections ◽  
Current Knowledge ◽  
World Health ◽  
Diagnostic Tools ◽  
Specific Marker ◽  
Type I ◽  
Resistance Proteins ◽  
Potential Biomarkers

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.

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

scholarly journals Mast Cell Responses to Viruses and Pathogen Products

2019 ◽  
Vol 20 (17) ◽  
pp. 4241 ◽  
Author(s):  
Jean S. Marshall ◽  
Liliana Portales-Cervantes ◽  
Edwin Leong
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Immune Responses ◽  
Viral Infection ◽  
Viral Infections ◽  
Inflammatory Responses ◽  
Local Source ◽  
Type I ◽  
Viral Challenge ◽  
Cell Responses

Mast cells are well accepted as important sentinel cells for host defence against selected pathogens. Their location at mucosal surfaces and ability to mobilize multiple aspects of early immune responses makes them critical contributors to effective immunity in several experimental settings. However, the interactions of mast cells with viruses and pathogen products are complex and can have both detrimental and positive impacts. There is substantial evidence for mast cell mobilization and activation of effector cells and mobilization of dendritic cells following viral challenge. These cells are a major and under-appreciated local source of type I and III interferons following viral challenge. However, mast cells have also been implicated in inappropriate inflammatory responses, long term fibrosis, and vascular leakage associated with viral infections. Progress in combating infection and boosting effective immunity requires a better understanding of mast cell responses to viral infection and the pathogen products and receptors we can employ to modify such responses. In this review, we outline some of the key known responses of mast cells to viral infection and their major responses to pathogen products. We have placed an emphasis on data obtained from human mast cells and aim to provide a framework for considering the complex interactions between mast cells and pathogens with a view to exploiting this knowledge therapeutically. Long-lived resident mast cells and their responses to viruses and pathogen products provide excellent opportunities to modify local immune responses that remain to be fully exploited in cancer immunotherapy, vaccination, and treatment of infectious diseases.

scholarly journals Deficiency of the B Cell-Activating Factor Receptor Results in Limited CD169+Macrophage Function during Viral Infection

2015 ◽  
Vol 89 (9) ◽  
pp. 4748-4759 ◽  
Author(s):  
Haifeng C. Xu ◽  
Jun Huang ◽  
Vishal Khairnar ◽  
Vikas Duhan ◽  
Aleksandra A. Pandyra ◽  
...  
Keyword(s):  
B Cells ◽  
Viral Infection ◽  
B Cell ◽  
Viral Infections ◽  
Type I Interferon ◽  
Type I ◽  
Interferon Production ◽  
Immune Priming ◽  
Adaptive Immune ◽  
Deficient Mice

ABSTRACTThe B cell-activating factor (BAFF) is critical for B cell development and humoral immunity in mice and humans. While the role of BAFF in B cells has been widely described, its role in innate immunity remains unknown. Using BAFF receptor (BAFFR)-deficient mice, we characterized BAFFR-related innate and adaptive immune functions following infection with vesicular stomatitis virus (VSV) and lymphocytic choriomeningitis virus (LCMV). We identified a critical role for BAFFR signaling in the generation and maintenance of the CD169+macrophage compartment. Consequently,Baffr−/−mice exhibited limited induction of innate type I interferon production after viral infection. Lack of BAFFR signaling reduced virus amplification and presentation following viral infection, resulting in highly reduced antiviral adaptive immune responses. As a consequence, BAFFR-deficient mice showed exacerbated and fatal disease after viral infection. Mechanistically, transient lack of B cells inBaffr−/−animals resulted in limited lymphotoxin expression, which is critical for maintenance of CD169+cells. In conclusion, BAFFR signaling affects both innate and adaptive immune activation during viral infections.IMPORTANCEViruses cause acute and chronic infections in humans resulting in millions of deaths every year. Innate immunity is critical for the outcome of a viral infection. Innate type I interferon production can limit viral replication, while adaptive immune priming by innate immune cells induces pathogen-specific immunity with long-term protection. Here, we show that BAFFR deficiency not only perturbed B cells, but also resulted in limited CD169+macrophages. These macrophages are critical in amplifying viral particles to trigger type I interferon production and initiate adaptive immune priming. Consequently, BAFFR deficiency resulted in reduced enforced viral replication, limited type I interferon production, and reduced adaptive immunity compared to BAFFR-competent controls. As a result, BAFFR-deficient mice were predisposed to fatal viral infections. Thus, BAFFR expression is critical for innate immune activation and antiviral immunity.

scholarly journals Interferon-Stimulated Gene (ISG)-Expression Screening Reveals the Specific Antibunyaviral Activity of ISG20

2018 ◽  
Vol 92 (13) ◽  
Author(s):  
Junjie Feng ◽  
Arthur Wickenhagen ◽  
Matthew L. Turnbull ◽  
Veronica V. Rezelj ◽  
Felix Kreher ◽  
...  
Keyword(s):  
Viral Infections ◽  
Rhesus Macaques ◽  
Type I ◽  
Emerging Viruses ◽  
Content Type ◽  
Expression Screening ◽  
Interferon Stimulated Genes ◽  
Life Threatening

ABSTRACT Bunyaviruses pose a significant threat to human health, prosperity, and food security. In response to viral infections, interferons (IFNs) upregulate the expression of hundreds of interferon-stimulated genes (ISGs), whose cumulative action can potently inhibit the replication of bunyaviruses. We used a flow cytometry-based method to screen the ability of ∼500 unique ISGs from humans and rhesus macaques to inhibit the replication of Bunyamwera orthobunyavirus (BUNV), the prototype of both the Peribunyaviridae family and the Bunyavirales order. Candidates possessing antibunyaviral activity were further examined using a panel of divergent bunyaviruses. Interestingly, one candidate, ISG20, exhibited potent antibunyaviral activity against most viruses examined from the Peribunyaviridae , Hantaviridae , and Nairoviridae families, whereas phleboviruses ( Phenuiviridae ) largely escaped inhibition. Similar to the case against other viruses known to be targeted by ISG20, the antibunyaviral activity of ISG20 is dependent upon its functional RNase activity. Through use of an infectious virus-like particle (VLP) assay (based on the BUNV minigenome system), we confirmed that gene expression from all 3 viral segments is strongly inhibited by ISG20. Using in vitro evolution, we generated a substantially ISG20-resistant BUNV and mapped the determinants of ISG20 sensitivity/resistance. Taking all the data together, we report that ISG20 is a broad and potent antibunyaviral factor but that some bunyaviruses are remarkably ISG20 resistant. Thus, ISG20 sensitivity/resistance may influence the pathogenesis of bunyaviruses, many of which are emerging viruses of clinical or veterinary significance. IMPORTANCE There are hundreds of bunyaviruses, many of which cause life-threatening acute diseases in humans and livestock. The interferon (IFN) system is a key component of innate immunity, and type I IFNs limit bunyaviral propagation both in vitro and in vivo . Type I IFN signaling results in the upregulation of hundreds of IFN-stimulated genes (ISGs), whose concerted action generates an “antiviral state.” Although IFNs are critical in limiting bunyaviral replication and pathogenesis, much is still unknown about which ISGs inhibit bunyaviruses. Using ISG-expression screening, we examined the ability of ∼500 unique ISGs to inhibit Bunyamwera orthobunyavirus (BUNV), the prototypical bunyavirus. Using this approach, we identified ISG20, an interferon-stimulated exonuclease, as a potent inhibitor of BUNV. Interestingly, ISG20 possesses highly selective antibunyaviral activity, with multiple bunyaviruses being potently inhibited while some largely escape inhibition. We speculate that the ability of some bunyaviruses to escape ISG20 may influence their pathogenesis.

scholarly journals A role for IRF3-dependent RXRα repression in hepatotoxicity associated with viral infections

2006 ◽  
Vol 203 (12) ◽  
pp. 2589-2602 ◽  
Author(s):  
Edward K. Chow ◽  
Antonio Castrillo ◽  
Arash Shahangian ◽  
Liming Pei ◽  
Ryan M. O'Connell ◽  
...  
Keyword(s):  
Viral Infection ◽  
Target Genes ◽  
Metabolic Diseases ◽  
Viral Infections ◽  
Type I ◽  
Reye's Syndrome ◽  
Downstream Target ◽  
Antiviral Responses ◽  
Host Metabolism

Viral infections and antiviral responses have been linked to several metabolic diseases, including Reye's syndrome, which is aspirin-induced hepatotoxicity in the context of a viral infection. We identify an interferon regulatory factor 3 (IRF3)–dependent but type I interferon–independent pathway that strongly inhibits the expression of retinoid X receptor α (RXRα) and suppresses the induction of its downstream target genes, including those involved in hepatic detoxification. Activation of IRF3 by viral infection in vivo greatly enhances bile acid– and aspirin-induced hepatotoxicity. Our results provide a critical link between the innate immune response and host metabolism, identifying IRF3-mediated down-regulation of RXRα as a molecular mechanism for pathogen-associated metabolic diseases.

scholarly journals Differential levels of IFNα subtypes in autoimmunity and viral infection

2021 ◽  
Author(s):  
Vincent Bondet ◽  
Mathieu P Rodero ◽  
Celine Posseme ◽  
Pierre Bost ◽  
Jeremie Decalf ◽  
...  
Keyword(s):  
Viral Infection ◽  
Host Response ◽  
Viral Infections ◽  
High Sensitivity ◽  
Type I Interferons ◽  
Type I ◽  
Effector Functions ◽  
Unusual Phenotype ◽  
Digital Elisa ◽  
Cellular Stimulation

Type I interferons are essential for host response to viral infections, while dysregulation of their response can result in autoinflammation or autoimmunity. Among IFNα (alpha) responses, 13 subtypes exist that signal through the same receptor, but have been reported to have different effector functions. However, the lack of available tools for discriminating these closely related subtypes, in particular at the protein level, has restricted the study of their differential roles in disease. We developed a digital ELISA with specificity and high sensitivity for the IFNα2 subtype. Application of this assay, in parallel with our previously described pan-IFNα assay, allowed us to study different IFNα protein responses following cellular stimulation and in diverse patient cohorts. We observed different ratios of IFNα protein responses between viral infection and autoimmune patients. This analysis also revealed a small percentage of autoimmune patients with high IFNα2 protein measurements but low pan-IFNα measurements. Correlation with an ISG score and functional activity showed that in this small sub group of patients, IFNα2 protein measurements did not reflect its biological activity. This unusual phenotype was partly explained by the presence of anti-IFNα auto-antibodies in a subset of autoimmune patients. This study reports ultrasensitive assays for the study of IFNα proteins in patient samples and highlights the insights that can be obtained from the use of multiple phenotypic readouts in translational and clinical studies.

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

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Daisy X Ji ◽  
Kristen C Witt ◽  
Dmitri I Kotov ◽  
Shally R Margolis ◽  
Alexander Louie ◽  
...  
Keyword(s):  
Legionella Pneumophila ◽  
Bacterial Infections ◽  
Viral Infections ◽  
Negative Regulator ◽  
Type I Interferons ◽  
Type I ◽  
Type I Ifn ◽  
Viral Immunity ◽  
Type I Ifns ◽  
Important Negative Regulator

Type I interferons (IFNs) are essential for anti-viral immunity, but often impair protective immune responses during bacterial infections. An important question is how type I IFNs are strongly induced during viral infections, and yet are appropriately restrained during bacterial infections. The Super susceptibility to tuberculosis 1 (Sst1) locus in mice confers resistance to diverse bacterial infections. Here we provide evidence that Sp140 is a gene encoded within the Sst1 locus that represses type I IFN transcription during bacterial infections. We generated Sp140-/- mice and find they are susceptible to infection by 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 negative regulator of type I IFNs that is essential for resistance to bacterial infections.

scholarly journals IFN-β, but not IFN-α, is Responsible for the Pro-Bacterial Effect of Type I Interferon

2021 ◽  
Vol 55 (3) ◽  
pp. 256-264
Keyword(s):  
Dendritic Cells ◽  
Bacterial Infections ◽  
Type I Interferon ◽  
Cytotoxic T Cells ◽  
Type I ◽  
Interferon Stimulated Genes ◽  
Common Receptor ◽  
Wide Range ◽  
Blocking Antibodies ◽  
Bacterial Effect

BACKGROUND/AIMS: During an immune response, type I interferon (IFN-I) signaling induces a wide range of changes, including those which are required to overcome viral infection and those which suppress cytotoxic T cells to avoid immunopathology. During certain bacterial infections, IFN-I signaling exerts largely detrimental effects. Although the IFN-I family of proteins all share one common receptor, biologic responses to signaling vary depending on IFN-I subtype. Here, we asked if one IFN-I subtype dominates the pro-bacterial effect of IFN-I signaling and found that control of Listeria monocytogenes (L.m.) infection is more strongly suppressed by IFN-β than IFN-α. METHODS: To study this, we measured bacterial titers in IFNAR-/-, IFN-β‑/‑, Stat2-/-, Usp18fl/fl and Usp18fl/fl x CD11c-Cre mice models in addition to IFN-I blocking antibodies. Moreover, we measured interferon stimulated genes in bone marrow derived dendritic cells after treatment with IFN-α4 and IFN-β. RESULTS: Specifically, we show that genetic deletion of IFN-β or antibody-mediated IFN-β neutralization was sufficient to reduce bacterial titers to levels similar to those observed in mice that completely lack IFN-I signaling (IFNAR-/- mice). However, IFN-α blockade failed to significantly reduce L.m. titers, suggesting that IFN-β is the dominant IFN-I subtype responsible for the pro-bacterial effect of IFN-I. Mechanistically, when focusing on IFN-I signals to dendritic cells, we found that IFN-β induces ISGs more robustly than IFN-α, including USP18, the protein we previously identified as driving the pro-bacterial effects of IFN-I. Further, we found that this induction was STAT1/STAT2 heterodimer- or STAT2/STAT2 homodimer-dependent, as STAT2-deficient mice were more resistant to L.m. infection. CONCLUSION: In conclusion, IFN-Β is the principal member of the IFN-I family responsible for driving the pro-bacterial effect of IFN-I.

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

2020 ◽  
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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