scholarly journals Viral infection enhances vomocytosis of intracellular fungi via Type I interferons

2019 ◽  
Author(s):  
Paula I Seoane ◽  
Leanne M. Taylor-Smith ◽  
David Stirling ◽  
Lucy C. K. Bell ◽  
Mahdad Noursadeghi ◽  
...  
Keyword(s):  
Viral Infection ◽  
Cryptococcus Neoformans ◽  
Real Life ◽  
Innate Immune ◽  
Type I Interferons ◽  
Multiple Infections ◽  
Interferon Α ◽  
Type I ◽  
Viral Pathogens ◽  
Context Cues

AbstractCryptococcus neoformans is an opportunistic human pathogen, which causes serious disease in immunocompromised hosts. Infection with this pathogen is particularly relevant in HIV+ patients, where it leads to around 200,000 deaths per annum. A key feature of cryptococcal pathogenesis is the ability of the fungus to survive and replicate within the phagosome of macrophages, as well as its ability to escape via a novel non-lytic mechanism known as vomocytosis. We have been exploring whether viral infection affects the interaction between C. neoformans and macrophages. Here we show that viral infection enhances cryptococcal vomocytosis without altering phagocytosis or intracellular proliferation of the fungus. This effect occurs with distinct, unrelated human viral pathogens and is recapitulated when macrophages are stimulated with the anti-viral cytokine interferon alpha (IFNα). Importantly, the effect is abrogated when type-I interferon signalling is blocked, thus underscoring the importance of type-I interferons in this phenomenon. Our results highlight the importance of incorporating specific context cues while studying host-pathogen interactions. By doing so, we found that acute viral infection may trigger the release of latent cryptococci from intracellular compartments, with significant consequences for disease progression.Non-Technical Author SummaryInfectious diseases are typically studied in the laboratory in isolation, but in real life people often encounter multiple infections simultaneously. Here we investigate how the innate immune response to the fatal fungus Cryptococcus neoformans is influenced by viral coinfection. Whilst virally-infected macrophages retain a normal capacity to engulf and kill Cryptococci, they demonstrate a dramatically enhanced propensity to expel them via the process known as non-lytic expulsion or vomocytosis. Activation of vomocytosis is independent of the type of virus encountered, since both HIV and measles (two entirely unrelated viral pathogens) trigger the same effect. Instead it is driven by interferon-α, a generic ‘antiviral’ response, which signals back to the infected macrophage, triggering expulsion of the fungus. We propose that this hitherto unobserved phenomenon represents a ‘reprioritisation’ pathway for innate immune cells, by which they can alter the frequency with which they expel one pathogen (Cryptococcus) depending on the level of threat from a secondary viral infection.

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.

scholarly journals 25-Hydroxycholesterol Production by the Cholesterol-25-Hydroxylase Interferon-Stimulated Gene Restricts Mammalian Reovirus Infection

2018 ◽  
Vol 92 (18) ◽  
Author(s):  
Alexandra Doms ◽  
Tatiana Sanabria ◽  
Jeanne N. Hansen ◽  
Nihal Altan-Bonnet ◽  
Geoffrey H. Holm
Keyword(s):  
Viral Infection ◽  
Infection Type ◽  
Membrane Dynamics ◽  
Innate Immune ◽  
Type I Interferons ◽  
Type I ◽  
Interferon Stimulated Genes ◽  
Endosomal Membrane ◽  
Endosomal Membranes ◽  
Type 3

ABSTRACTFollowing the initial detection of viral infection, innate immune responses trigger the induction of numerous interferon-stimulated genes (ISGs) to inhibit virus replication and dissemination. One such ISG encodes cholesterol-25-hydroxylase (CH25H), an enzyme that catalyzes the oxidation of cholesterol to form a soluble product, 25-hydroxycholesterol (25HC). Recent studies have found that CH25H is broadly antiviral; it inhibits infection by several viruses. For enveloped viruses, 25HC inhibits membrane fusion, likely by altering membrane characteristics such as hydrophobicity or cholesterol aggregation. However, the mechanisms by which 25HC restricts infection of nonenveloped viruses are unknown. We examined whether 25HC restricts infection by mammalian reovirus. Treatment with 25HC restricted infection by reovirus prototype strains type 1 Lang and type 3 Dearing. In contrast to reovirus virions, 25HC did not restrict infection by reovirus infectious subvirion particles (ISVPs), which can penetrate either directly at the cell surface or in early endosomal membranes. Treatment with 25HC altered trafficking of reovirus particles to late endosomes and delayed the kinetics of reovirus uncoating. These results suggest that 25HC inhibits the efficiency of cellular entry of reovirus virions, which may require specific endosomal membrane dynamics for efficient membrane penetration.IMPORTANCEThe innate immune system is crucial for effective responses to viral infection. Type I interferons, central components of innate immunity, induce expression of hundreds of ISGs; however, the mechanisms of action of these antiviral proteins are not well understood. CH25H, encoded by an ISG, represents a significant constituent of these cellular antiviral strategies, as its metabolic product, 25HC, can act in both an autocrine and a paracrine fashion to protect cells from infection and has been shown to limit viral infection in animal models. Further investigation into the mechanism of action of 25HC may inform novel antiviral therapies and influence the use of mammalian reovirus in clinical trials as an oncolytic agent.

scholarly journals Bacterial Cyclic Dinucleotides and the cGAS–cGAMP–STING Pathway: A Role in Periodontitis?

Pathogens ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 675
Author(s):  
Samira Elmanfi ◽  
Mustafa Yilmaz ◽  
Wilson W. S. Ong ◽  
Kofi S. Yeboah ◽  
Herman O. Sintim ◽  
...  
Keyword(s):  
Immune Response ◽  
Periodontal Disease ◽  
Innate Immune ◽  
Host Cells ◽  
Type I Interferons ◽  
Type I ◽  
Vaccine Adjuvants ◽  
Cyclic Dinucleotides ◽  
Sting Pathway

Host cells can recognize cytosolic double-stranded DNAs and endogenous second messengers as cyclic dinucleotides—including c-di-GMP, c-di-AMP, and cGAMP—of invading microbes via the critical and essential innate immune signaling adaptor molecule known as STING. This recognition activates the innate immune system and leads to the production of Type I interferons and proinflammatory cytokines. In this review, we (1) focus on the possible role of bacterial cyclic dinucleotides and the STING/TBK1/IRF3 pathway in the pathogenesis of periodontal disease and the regulation of periodontal immune response, and (2) review and discuss activators and inhibitors of the STING pathway as immune response regulators and their potential utility in the treatment of periodontitis. PubMed/Medline, Scopus, and Web of Science were searched with the terms “STING”, “TBK 1”, “IRF3”, and “cGAS”—alone, or together with “periodontitis”. Current studies produced evidence for using STING-pathway-targeting molecules as part of anticancer therapy, and as vaccine adjuvants against microbial infections; however, the role of the STING/TBK1/IRF3 pathway in periodontal disease pathogenesis is still undiscovered. Understanding the stimulation of the innate immune response by cyclic dinucleotides opens a new approach to host modulation therapies in periodontology.

Type I interferons and the innate immune response—more than just antiviral cytokines

2005 ◽  
Vol 42 (8) ◽  
pp. 869-877 ◽  
Author(s):  
Peter L Smith ◽  
Giovanna Lombardi ◽  
Graham R Foster
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Innate Immune ◽  
Type I Interferons ◽  
Type I

scholarly journals DDX3 directly facilitates IKKα activation and regulates downstream signalling pathways

2018 ◽  
Vol 475 (22) ◽  
pp. 3595-3607 ◽  
Author(s):  
Anthony Fullam ◽  
Lili Gu ◽  
Yvette Höhn ◽  
Martina Schröder
Keyword(s):  
Nuclear Factor Κb ◽  
Innate Immune ◽  
Type I Interferons ◽  
Signalling Pathways ◽  
Type I ◽  
Nuclear Factor ◽  
Toll Like Receptor ◽  
Disease States ◽  
Dead Box ◽  
Iκb Kinase

DDX3 is a DEAD-box RNA helicase that we and others have previously implicated in antiviral immune signalling pathways leading to type I interferon (IFN) induction. We previously demonstrated that it directly interacts with the kinase IKKε (IκB kinase ε), enhances it activation, and then facilitates phosphorylation of the transcription factor IRF3 by IKKε. However, the TLR7/9 (Toll-like receptor 7/9)-mediated pathway, one of the most physiologically relevant IFN induction pathways, proceeds independently of IKKε or the related kinase TBK1 (TANK-binding kinase 1). This pathway induces type I IFN production via the kinases NIK (NF-κB-inducing kinase) and IKKα and is activated when plasmacytoid dendritic cells sense viral nucleic acids. In the present study, we demonstrate that DDX3 also directly interacts with IKKα and enhances its autophosphorylation and -activation. Modulation of DDX3 expression consequently affected NIK/IKKα-mediated IRF7 phosphorylation and induction of type I interferons. In addition, alternative NF-κB (nuclear factor-κB) activation, another pathway regulated by NIK and IKKα, was also down-regulated in DDX3 knockdown cells. This substantially broadens the effects of DDX3 in innate immune signalling to pathways beyond TBK1/IKKε and IFN induction. Dysregulation of these pathways is involved in disease states, and thus, our research might implicate DDX3 as a potential target for their therapeutic manipulation.

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 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.

Detection of Microbial Infections Through Innate Immune Sensing of Nucleic Acids

2018 ◽  
Vol 72 (1) ◽  
pp. 447-478 ◽  
Author(s):  
Xiaojun Tan ◽  
Lijun Sun ◽  
Jueqi Chen ◽  
Zhijian J. Chen
Keyword(s):  
Nucleic Acid ◽  
Nucleic Acids ◽  
Immune Defense ◽  
Innate Immune ◽  
Type I Interferons ◽  
Microbial Pathogens ◽  
Type I ◽  
Immune Recognition ◽  
Microbial Infection ◽  
Microbial Infections

Microbial infections are recognized by the innate immune system through germline-encoded pattern recognition receptors (PRRs). As most microbial pathogens contain DNA and/or RNA during their life cycle, nucleic acid sensing has evolved as an essential strategy for host innate immune defense. Pathogen-derived nucleic acids with distinct features are recognized by specific host PRRs localized in endolysosomes and the cytosol. Activation of these PRRs triggers signaling cascades that culminate in the production of type I interferons and proinflammatory cytokines, leading to induction of an antimicrobial state, activation of adaptive immunity, and eventual clearance of the infection. Here, we review recent progress in innate immune recognition of nucleic acids upon microbial infection, including pathways involving endosomal Toll-like receptors, cytosolic RNA sensors, and cytosolic DNA sensors. We also discuss the mechanisms by which infectious microbes counteract host nucleic acid sensing to evade immune surveillance.

Immune response to dermatomyositis-specific autoantigen, transcriptional intermediary factor 1γ can result in experimental myositis

2021 ◽  
pp. annrheumdis-2020-218661
Author(s):  
Naoko Okiyama ◽  
Yuki Ichimura ◽  
Miwako Shobo ◽  
Ryota Tanaka ◽  
Noriko Kubota ◽  
...  
Keyword(s):  
T Cells ◽  
Lymph Node ◽  
Kinase Inhibitor ◽  
Inflammatory Myopathy ◽  
Janus Kinase ◽  
Type I Interferons ◽  
Interferon Α ◽  
Muscle Fibres ◽  
Type I ◽  
Wild Type

ObjectivesTo investigate whether autoimmunity to transcriptional intermediary factor 1 (TIF1)γ, a ubiquitous nuclear autoantigen for myositis-specific autoantibodies detected in patients with dermatomyositis (DM) is pathogenetic for inflammatory myopathy.MethodsWild-type, β2-microglobulin-null, perforin-null, Igμ‐null and interferon α/β receptor (IFNAR)-null mice were immunised with recombinant human TIF1γ whole protein. A thymidine incorporation assay was performed using lymph node T cells from TIF1γ-immunised mice. Plasma was analysed using immunoprecipitation followed by western blot analysis and enzyme-linked immunosorbent assays. Femoral muscles were histologically and immunohistochemically evaluated. CD8+ or CD4+ T cells isolated from lymph node T cells or IgG purified from plasma were adoptively transferred to naïve mice. TIF1γ-immunised mice were treated with anti-CD8 depleting antibody and a Janus kinase inhibitor, tofacitinib.ResultsImmunisation with TIF1γ-induced experimental myositis presenting with necrosis/atrophy of muscle fibres accompanied by CD8+ T cell infiltration successfully in wild-type mice, in which TIF1γ-specific T cells and antihuman and murine TIF1γ IgG antibodies were detected. The incidence and severity of myositis were significantly lower in β₂-microglobulin-null, perforin-null, CD8-depleted or IFNAR-null mice, while Igμ‐null mice developed myositis normally. Adoptive transfer of CD8+ T cells induced myositis in recipients, while transfer of CD4+ T cells or IgG did not. Treatment with tofacitinib inhibited TIF1γ-induced myositis.ConclusionsHere we show that TIF1γ is immunogenic enough to cause experimental myositis, in which CD8+ T cells and type I interferons, but not CD4+ T cells, B cells or antibodies, are required. This murine model would be a tool for understanding the pathologies of DM.

Sign in / Sign up

Export Citation Format

Share Document