G C Sen

Lerner Research Institute, Cleveland, Ohio, United States

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Publications (206)1172.17 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The Type I/III interferon (IFN) system has major roles in regulating viral pathogenesis, usually ameliorating pathogenesis by impairing virus replication through the antiviral actions of one or more IFN-induced proteins. Ifit2 is one such protein which can be induced by IFN or virus infection and is responsible for protecting mice from neuropathogenesis caused by vesicular stomatitis virus. Here, we show that Ifit2 also protects mice from pathogenesis caused by the respirovirus, Sendai virus (SeV). Mice lacking Ifit2 (Ifit2-/-) suffered severe weight loss and succumbed to intranasal infection with SeV strain 52, at a dose that killed only few wild-type mice. Viral RNA was detectable only in lungs and SeV titers were higher in Ifit2-/- mice, compared to wild-type mice. Similar infiltration of immune cells was found in the lungs of both mouse lines, corresponding to similar levels of many induced cytokines and chemokines. In contrast, IFN-β and IFN-λ3 expression were considerably higher in the lungs of Ifit2-/- mice. Surprisingly, type I IFN receptor knock-out (IFNAR-/-) mice were less susceptible to SeV than Ifit2-/- mice, although their pulmonary virus titers were similarly high. To test the intriguing possibility that type I IFN-action enhances pathogenesis in the context of elevated SeV replication in lungs, we generated Ifit2/IFNAR-/- double knock-out mice. These mice were less susceptible to SeV than Ifit2-/- mice, although viral titers in their lungs were even higher. Our results indicate that high SeV replication in the lungs of infected Ifit2-/- mice cooperates with elevated IFN-β induction to cause disease.
    Journal of virology. 09/2014;
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    ABSTRACT: The interferon system provides the first line of host defense against virus infection. Mouse pathogenesis studies have revealed the importance of specific interferon-induced proteins in providing protection against specific viruses. We have previously reported that one such protein, Ifit2, protects neurons of the central nervous system from intranasal infection by the neurotropic rhabdovirus, vesicular stomatitis virus (VSV). Here, we demonstrate that Ifit2 protects the peripheral nervous system from VSV infection as well. In Ifit2-/- mice, VSV, injected subcutaneously into the footpad, entered the proximal lymph node where it replicated and infected the nodal nerve endings. The infection spread to the sciatic nerve, the spinal cord and the brain, causing paralysis. In contrast, in the wild-type mice, although VSV replicated equally well in the lymph node, infection of the sciatic nerve and the rest of the nervous system was impaired, thus preventing paralysis. Ifit2 protected only the nervous system from VSV infection; other tissues were well protected even in Ifit2-/- mice. These results indicate that Ifit2 is the interferon-induced protein that prevents VSV infection of neurons of both the peripheral and the central nervous systems, thus inhibiting the consequent neuropathy; but it is dispensable for protecting the cells of other tissues from VSV infection.
    Journal of virology. 07/2014;
  • Saurabh Chattopadhyay, Ganes C Sen
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    ABSTRACT: Double-stranded (ds) RNA has diverse roles in host defense and disease prevention. dsRNA, produced by viral replication, elicits strong antiviral responses in host; similar protective responses can also be triggered by cellular dsRNA produced by necrotic, apoptotic, or otherwise stressed, uninfected cells. dsRNA is recognized in the cell by a large family of dsRNA-binding proteins, among which are the pattern recognition receptors (PRRs), toll-like receptor 3 (TLR3), and retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs). TLR3 signals from the endosomal membrane where it senses extracellular dsRNA that has been endocytosed, whereas RLRs signal from the cytoplasm using a mitochondrial adaptor protein. In this review, we will summarize the signaling pathways used by these 2 PRRs, which lead to the activation of specific transcription factors and the induction of many proinflammatory and antiviral genes. However, it is becoming increasingly clear that all host responses are not mediated by the products of these induced genes; signal-dependent post-translational modifications of existing proteins can also profoundly change cellular properties. We will discuss how Src activation by TLR3 changes cell migration, adhesion, and proliferation rates and how IRF-3 activation by RLR triggers a gene induction-independent pro-apoptotic pathway that provides strong antiviral protection.
    06/2014; 34(6):427-436.
  • Saurabh Chattopadhyay, Ganes C Sen
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    ABSTRACT: Cellular interferon response to microbial infection is transient. In a recent paper in Immunity, Long et al. (2014) identify protein phosphatase 2A (PP2A) as a deactivator of phospho-interferon regulatory factor 3, the key transcription factor for interferon synthesis, thus providing one basis for the observed transiency.
    Molecular cell 04/2014; 54(2):210-1. · 14.61 Impact Factor
  • Saurabh Chattopadhyay, Ganes C. Sen
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    ABSTRACT: There is a wealth of knowledge about how different Ser/Thr protein kinases participate in Toll-like receptor (TLR) signaling. In many cases, we know the identities of the Ser/Thr residues of various components of the TLR-signaling pathways that are phosphorylated, the functional consequences of the phosphorylation and the responsible protein kinases. In contrast, the analysis of Tyr-phosphorylation of TLRs and their signaling proteins is currently incomplete, because several existing analyses are not systematic or they do not rely on robust experimental data. Nevertheless, it is clear that many TLRs require, for signaling, ligand-dependent phosphorylation of specific Tyr residues in their cytoplasmic domains; the list includes TLR2, TLR3, TLR4, TLR5, TLR8 and TLR9. In this article, we discuss the current status of knowledge on the effect of Tyr-phosphorylation of TLRs and their signaling proteins on their biochemical and biological functions, the possible identities of the relevant protein tyrosine kinases (PTKs) and the nature of regulations of PTK-mediated activation of TLR signaling pathways.
    Cytokine & Growth Factor Reviews. 01/2014;
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    ABSTRACT: Angiotensin-converting enzyme (ACE) regulates normal blood pressure and fluid homeostasis through its action in the renin-angiotensin-system (RAS). Ace-/- mice are smaller in size, have low blood pressure and defective kidney structure and functions. All of these defects are cured by transgenic expression of somatic ACE (sACE) in vascular endothelial cells of Ace-/- mice. sACE is expressed on the surface of vascular endothelial cells and undergoes a natural cleavage secretion process to generate a soluble form in the body fluids. Both the tissue-bound and the soluble forms of ACE are enzymatically active, and generate the vasoactive octapeptide Angiotensin II (Ang II) with equal efficiency. To assess the relative physiological roles of the secreted and the cell-bound forms of ACE, we expressed, in the vascular endothelial cells of Ace-/- mice, the ectodomain of sACE, which corresponded to only the secreted form of ACE. Our results demonstrated that the secreted form of ACE could normalize kidney functions and RAS integrity, growth and development of Ace-/- mice, but not their blood pressure. This study clearly demonstrates that the secreted form of ACE cannot replace the tissue-bound ACE for maintaining normal blood pressure; a suitable balance between the tissue-bound and the soluble forms of ACE is essential for maintaining all physiological functions of ACE.
    PLoS ONE 01/2014; 9(1):e87484. · 3.53 Impact Factor
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    ABSTRACT: Type I interferons (IFNα/β) limit viral dissemination prior to the emergence of adaptive immune responses through the concerted action of interferon stimulated genes (ISGs). Although IFNα/β induction by coronaviruses is modest, it effectively limits viral spread within the central nervous system (CNS) and protects from mortality. The protective roles of specific ISGs against the mouse hepatitis virus (MHV) members of coronaviruses are largely unknown. This study demonstrates a protective role of the ISG Ifit2 in encephalitis induced by the dual hepato- and neuro-tropic MHV-A59. Contrasting the mild encephalitis and 100% survival of infected wild-type (wt) mice, nearly 60% of MHV-A59 infected Ifit2-/- mice exhibited severe encephalitis and succumbed between 6-8 days post infection. Increased clinical disease in Ifit2-/- mice coincided with higher viral loads and enhanced viral spread throughout the CNS parenchyma. Ifit2-/- mice also expressed significantly reduced IFNα/β and downstream ISG mRNAs Ifit1, Isg15 and Pkr, while expression of proinflammatory cytokines and chemokines was only modestly affected in the CNS. Impaired IFNα/β induction in the absence of Ifit2 was confirmed by ex vivo mRNA analysis of microglia and macrophages, the prominent cell types producing IFNα/β following MHV CNS infection. Furthermore, both IFNα/β mRNA and protein production were significantly reduced in MHV infected Ifit2-/- relative to wt bone marrow derived macrophages. Collectively, the data implicate Ifit2 as a positive regulator of IFNα/β expression, rather than direct antiviral mediator, during MHV induced encephalitis.
    Journal of Virology 11/2013; · 5.08 Impact Factor
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    ABSTRACT: PKR is well characterized for its function in antiviral immunity. Using Toxoplasma gondii, we examined if PKR promotes resistance to disease caused by a non-viral pathogen. PKR(-/-) mice infected with T. gondii exhibited higher parasite load and worsened histopathology in the eye and brain compared to wild-type controls. Susceptibility to toxoplasmosis was not due to defective expression of IFN-γ, TNF-α, NOS2 or IL-6 in the retina and brain, differences in IL-10 expression in these organs or to impaired induction of T. gondii-reactive T cells. While macrophages/microglia with defective PKR signaling exhibited unimpaired anti-T. gondii activity in response to IFN-γ/TNF-α, these cells were unable to kill the parasite in response to CD40 stimulation. The TRAF6 binding site of CD40, but not the TRAF2,3 binding sites, was required for PKR phosphorylation in response to CD40 ligation in macrophages. TRAF6 co-immunoprecipitated with PKR upon CD40 ligation. TRAF6-PKR interaction appeared to be indirect, since TRAF6 co-immunoprecipitated with TRAF2 and TRAF2 co-immunoprecipitated with PKR, and deficiency of TRAF2 inhibited TRAF6-PKR co-immunoprecipitation as well as PKR phosphorylation induced by CD40 ligation. PKR was required for stimulation of autophagy, accumulation the autophagy molecule LC3 around the parasite, vacuole-lysosomal fusion and killing of T. gondii in CD40-activated macrophages and microglia. Thus, our findings identified PKR as a mediator of anti-microbial activity and promoter of protection against disease caused by a non-viral pathogen, revealed that PKR is activated by CD40 via TRAF6 and TRAF2, and positioned PKR as a link between CD40-TRAF signaling and stimulation of the autophagy pathway.
    PLoS Pathogens 08/2013; 9(8):e1003557. · 8.14 Impact Factor
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    ABSTRACT: The balance between the innate immunity of the host and the ability of a pathogen to evade it strongly influences pathogenesis and virulence. The two nonstructural (NS) proteins, NS1 and NS2, of respiratory syncytial virus (RSV) are critically required for RSV virulence. Together, they strongly suppress the type I interferon (IFN)-mediated in-nate immunity of the host cells by degrading or inhibiting multiple cellular factors required for either IFN induction or response pathways, including RIG-I, IRF3, IRF7, TBK1 and STAT2. Here, we provide evidence for the existence of a large and heterogeneous degradative complex assembled by the NS proteins, which we named "NS-degradasome" (NSD). The NSD is roughly ~300-750 kD in size, and its degradative activity was enhanced by the addition of purified mitochondria in vitro. Inside the cell, the majority of the NS proteins and the substrates of the NSD translocated to the mitochondria upon RSV infection. Genetic and pharmacological evidence shows that optimal suppression of in-nate immunity requires mitochondrial MAVS and mitochondrial motility. Together, we propose a novel paradigm in which the mitochondria, known to be important for the innate immune activation of the host, are also important for viral suppression of the innate immunity.
    Cell Research 07/2013; 23(23):1025-1042. · 10.53 Impact Factor
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    ABSTRACT: Previous studies have demonstrated that type I interferon (IFN) restricts West Nile virus (WNV) replication and pathogenesis in peripheral and central nervous system (CNS) tissues. However, the in vivo role of specific antiviral genes that are induced by type I IFN against WNV infection remains less well characterized. Here, using Ifit2(-/-) mice we defined the antiviral function of the interferon-stimulated gene (ISG) Ifit2 in limiting infection and disease in vivo by a virulent North American strain of WNV. Compared to congenic wild-type controls, Ifit2(-/-) mice showed enhanced WNV infection in a tissue-restricted manner, with preferential replication in the CNS of animals lacking Ifit2. Virological analysis of cultured macrophages, dendritic cells, fibroblasts, cerebellar granule cell neurons, and cortical neurons revealed cell-type specific antiviral functions of Ifit2 against WNV. In comparison, small effects of Ifit2 were observed on the induction or magnitude of innate or adaptive immune responses. Our results suggest that Ifit2 restricts WNV infection and pathogenesis in different tissues in a cell-type specific manner.
    Journal of Virology 06/2013; · 5.08 Impact Factor
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    ABSTRACT: In Press. DOI and volume not yet received.
    Cell Research 04/2013; XXX(XXX):XXX. · 10.53 Impact Factor
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    ABSTRACT: The primary function of the dsRNA binding protein (dsRBP) PACT/RAX is to activate the dsRNA dependent protein kinase PKR in response to stress signals. Additionally, it has been identified as a component of the small RNA processing pathway. A role for PACT/RAX in this pathway represents an important interplay between two modes of post-transcriptional gene regulation. The function of PACT/RAX in this context is poorly understood. Thus, additional models are required to clarify the mechanism by which PACT/RAX functions. In this study, Drosophila melanogaster was employed to identify functionally orthologous dsRNA-binding proteins. Transgenic Drosophila expressing human PACT were generated to determine whether PACT is capable of functionally substituting for the Drosophila dsRBP R2D2, which has a well-defined role in small RNA biogenesis. Results presented here indicate that PACT is unable to substitute for R2D2 at the whole organism level.
    F1000Research. 01/2013; 2:220.
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    ABSTRACT: ABSTRACT Interferon (IFN) is required for protecting mice from viral pathogenesis; reciprocally, it mediates the deleterious septic shock response to bacterial infection. The critical transcription factor for IFN induction, in both cases, is IRF-3, which is activated by TLR3 or RIG-I signaling in response to virus infection and TLR4 signaling in response to bacterial infection. Here, we report that IRF-3's transcriptional activity required its coactivators, β-catenin and CBP, to be modified by HDAC6-mediated deacetylation and protein kinase C isozyme β (PKC-β)-mediated phosphorylation, respectively, so that activated nuclear IRF-3 could form a stable transcription initiation complex at the target gene promoters. β-Catenin bridges IRF-3 and CBP, and the modifications were required specifically for the interaction between β-catenin and CBP but not β-catenin and IRF-3. Consequently, like IRF-3(-/-) mice, HDAC6(-/-) mice were resistant to bacterial lipopolysaccharide-induced septic shock. Conversely, they were highly susceptible to pathogenesis caused by Sendai virus infection. Thus, HDAC6 is an essential component of the innate immune response to microbial infection. IMPORTANCE It is important to understand how we protect ourselves against microbial infection. Specific receptors present in mammalian cells, called Toll-like receptors, are assigned to sense different microbial chemicals, such as bacterial lipopolysaccharides or viral double-stranded RNA. Activation of these receptors leads to the activation of a critical transcription factor, IRF-3, which drives the induced synthesis of interferon, a secreted protein required for our protection. Here, we report that interferon synthesis is regulated not only by IRF-3 activation but also by activation of two proteins, β-catenin and CBP, which function together with IRF-3. β-Catenin is activated by its deacetylation by HDAC6, and CBP is activated by its phosphorylation by protein kinases C isozyme β (PKC-β). These regulations are operative not only in cell cultures but also in mice.
    mBio 01/2013; 4(2). · 6.88 Impact Factor
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    ABSTRACT: Immunoglobulin A nephropathy (IgAN) is the most common form of glomerulonephritis throughout the world. A majority (approx. 60%) of patients with IgAN experience disease exacerbations associated with an acute respiratory or gastrointestinal illness that appears to represent a viral infection. However, the exact mechanism of the disease exacerbation by viral infection is not understood, especially at the cellular and molecular levels. Here we report that glomerular podocytes express the major sensors for double-stranded RNA (dsRNA), a common byproduct of viral replication. In addition to these receptors, Toll-like receptor 3 (TLR3) and retinoic acid-inducible gene 1 (RIG-I)-like helicases (RLHs), podocytes express the collateral proteins required to support intracellular signaling. The pathways that mediate responses to dsRNA are fully functional in podocytes. The transcription factor interferon regulatory factor 3 (IRF3) and nuclear factor kappa B (NF-ĸB) are phosphorylated and translocate to the nucleus, and dsRNA increases synthesis of proteins driven by IRF3 (P54, P56 and P60) or NF-ĸB (interleukin 8 and A20). Furthermore, dsRNA suppresses podocyte cell migration, alters the expression of a panel of podocyte essential proteins (nephrin, podocin and CD2-associated protein or CD2AP) and changes transepithelial albumin flux. These effects are dsRNA sensor-specific: TLR3-/- podocytes do not respond to extracellular dsRNA, while intracellular dsRNA has no effect on podocytes bearing a dominant negative form of the major active RLH. These results demonstrate that innate responses to viruses can disturb podocyte cell function in vitro.
    Journal of Innate Immunity 12/2012; · 4.46 Impact Factor
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    ABSTRACT: Large parts of mammalian genomes are transcriptionally inactive and enriched with various classes of interspersed and tandem repeats. Here we show that the tumor suppressor protein p53 cooperates with DNA methylation to maintain silencing of a large portion of the mouse genome. Massive transcription of major classes of short, interspersed nuclear elements (SINEs) B1 and B2, both strands of near-centromeric satellite DNAs consisting of tandem repeats, and multiple species of noncoding RNAs was observed in p53-deficient but not in p53 wild-type mouse fibroblasts treated with the DNA demethylating agent 5-aza-2'-deoxycytidine. The abundance of these transcripts exceeded the level of β-actin mRNA by more than 150-fold. Accumulation of these transcripts, which are capable of forming double-stranded RNA (dsRNA), was accompanied by a strong, endogenous, apoptosis-inducing type I IFN response. This phenomenon, which we named "TRAIN" (for "transcription of repeats activates interferon"), was observed in spontaneous tumors in two models of cancer-prone mice, presumably reflecting naturally occurring DNA hypomethylation and p53 inactivation in cancer. These observations suggest that p53 and IFN cooperate to prevent accumulation of cells with activated repeats and provide a plausible explanation for the deregulation of IFN function frequently seen in tumors. Overall, this work reveals roles for p53 and IFN that are key for genetic stability and therefore relevant to both tumorigenesis and the evolution of species.
    Proceedings of the National Academy of Sciences 12/2012; · 9.81 Impact Factor
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    ABSTRACT: Infection of cultured cells by Paramyxoviruses causes cell death, mediated by a newly discovered apoptotic pathway activated by virus infection. The key pro-apoptotic protein in this pathway is IRF-3, which upon activation by virus infection, binds Bax, translocates it to mitochondria and triggers apoptosis. When IRF-3 knockdown cells were infected with Sendai virus (SeV), persistent infection (PI) was established. The PI cells produced infectious SeV continuously and constitutively expressed many innate immune genes. Interferon-signaling was blocked in these cells. The elevated levels of IRF-3-driven genes in the PI cells indicated that the residual IRF-3, activated by endogenous SeV, was high enough to drive the transcriptional effects of IRF3 but too low to trigger its apoptotic activity. We confirmed this IRF-3 'threshold' idea, by generating a tet-off cell line for IRF-3 expression, which enabled us to express varying levels of IRF-3. PI could be established in the tet-off cell line and as expected, when doxycycline was withdrawn, the cells underwent apoptosis. Finally, we tested for PI establishment in twelve mouse embryo fibroblasts by natural selection. Eleven lines became persistently infected; although seven out of them had low IRF-3, four did not. When one of the latter four was further analyzed, we observed that it expressed a very low level of Caspase 3, the final executor protease of the apoptotic pathway. These results demonstrated that SeV PI can arise from infection of normal Wt cells, but only if they can find a way to impair the IRF-3 dependent apoptotic pathway.
    Journal of Virology 10/2012; · 5.08 Impact Factor
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    Ganes C Sen, Volker Fensterl
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    ABSTRACT: Interferon carries out its cellular effects, including its antiviral effects, by inducing the synthesis of many new proteins, amongst which is the IFIT (ISG56) family of proteins. The first crystal structure of an IFIT, reported by Yang et al., revealed several functional properties of the protein that may help us to better understand the biological functions of these proteins.
    Cell Research 09/2012; 22(10):1407-9. · 10.53 Impact Factor
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    ABSTRACT: Prior studies have shown that 2'-O methyltransferase activity of flaviviruses, coronaviruses, and poxviruses promotes viral evasion of Ifit1, an interferon-stimulated innate immune effector protein. Viruses lacking 2'-O methyltransferase activity exhibited attenuation in primary macrophages that was rescued in cells lacking Ifit1 gene expression. Here, we examined the role of Ifit1 in restricting pathogenesis in vivo of wild type WNV (WNV-WT) and a mutant in the NS5 gene (WNV-E218A) lacking 2'-O methylation of the 5' viral RNA cap. While deletion of Ifit1 had marginal effects on WNV-WT pathogenesis, WNV-E218A showed increased replication in peripheral tissues of Ifit1⁻/⁻ mice after subcutaneous infection, yet this failed to correlate with enhanced infection in the brain or lethality. In comparison, WNV-E218A was virulent after intracranial infection as judged by increased infection in different regions of the central nervous system (CNS) and a greater than 16,000-fold decrease in LD(50) values in Ifit1⁻/⁻ compared to wild type mice. Ex vivo infection experiments revealed cell-type specific differences in the ability of an Ifit1 deficiency to complement the replication defect of WNV-E218A. In particular, WNV-E218A infection was impaired in both wild type and Ifit1⁻/⁻ brain microvascular endothelial cells, which are believed to participate in blood-brain barrier (BBB) regulation of virus entry into the CNS. A deficiency of Ifit1 also was associated with increased neuronal death in vivo, which was both cell-intrinsic and mediated by immunopathogenic CD8⁺ T cells. Our results suggest that virulent strains of WNV have largely evaded the antiviral effects of Ifit1, and viral mutants lacking 2'-O methylation are controlled in vivo by Ifit1-dependent and -independent mechanisms in different cell types.
    PLoS Pathogens 05/2012; 8(5):e1002698. · 8.14 Impact Factor
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    ABSTRACT: Interferon protects mice from vesicular stomatitis virus (VSV) infection and pathogenesis; however, it is not known which of the numerous interferon-stimulated genes (ISG) mediate the antiviral effect. A prominent family of ISGs is the interferon-induced with tetratricopeptide repeats (Ifit) genes comprising three members in mice, Ifit1/ISG56, Ifit2/ISG54 and Ifit3/ISG49. Intranasal infection with a low dose of VSV is not lethal to wild-type mice and all three Ifit genes are induced in the central nervous system of the infected mice. We tested their potential contributions to the observed protection of wild-type mice from VSV pathogenesis, by taking advantage of the newly generated knockout mice lacking either Ifit2 or Ifit1. We observed that in Ifit2 knockout (Ifit2(-/-)) mice, intranasal VSV infection was uniformly lethal and death was preceded by neurological signs, such as ataxia and hind limb paralysis. In contrast, wild-type and Ifit1(-/-) mice were highly protected and survived without developing such disease. However, when VSV was injected intracranially, virus replication and survival were not significantly different between wild-type and Ifit2(-/-) mice. When administered intranasally, VSV entered the central nervous system through the olfactory bulbs, where it replicated equivalently in wild-type and Ifit2(-/-) mice and induced interferon-β. However, as the infection spread to other regions of the brain, VSV titers rose several hundred folds higher in Ifit2(-/-) mice as compared to wild-type mice. This was not caused by a broadened cell tropism in the brains of Ifit2(-/-) mice, where VSV still replicated selectively in neurons. Surprisingly, this advantage for VSV replication in the brains of Ifit2(-/-) mice was not observed in other organs, such as lung and liver. Pathogenesis by another neurotropic RNA virus, encephalomyocarditis virus, was not enhanced in the brains of Ifit2(-/-) mice. Our study provides a clear demonstration of tissue-, virus- and ISG-specific antiviral action of interferon.
    PLoS Pathogens 05/2012; 8(5):e1002712. · 8.14 Impact Factor
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    ABSTRACT: dsRNA is a common pathogen-associated molecular pattern that is recognized by cellular TLR3 and used by virus-infected cells to activate specific transcription factors and trigger induction of antiviral genes. In this article, we report a new branch of TLR3 signaling that does not lead to gene induction but affects many cellular properties, such as cell migration, adhesion, and proliferation. We demonstrated that the migration of multiple cell lineages was affected by dsRNA treatment or influenza virus infection in a TLR3-dependent fashion. Surprisingly, for this effect of TLR3 signaling, the adaptor proteins, TRIF and MyD88, were not required. The effects of the new pathway were mediated by the proto-oncoprotein c-Src, which bound to TLR3 after dsRNA stimulation of cells. The response was biphasic: upon dsRNA treatment, we observed an immediate increase in cell motility followed by its strong inhibition. Our results indicate that the first phase was mediated by dsRNA-induced phosphorylation and activation of Src, whereas the second phase resulted from the sequestration of activated Src in lipid rafts, thus decreasing its active cytoplasmic pool. As expected, two other functions of Src, its effect on cell adhesion and cell proliferation, were also inhibited by dsRNA treatment. These results demonstrate that activated TLR3 can engage Src to trigger multiple cellular effects and reveal a possible link between innate immune response and cell growth regulation. This study also provides a rare example of TLR-mediated cellular effects that do not require gene induction and the first example, to our knowledge, of an adaptor-independent effect of any TLR.
    The Journal of Immunology 03/2012; 188(6):2825-33. · 5.52 Impact Factor

Publication Stats

8k Citations
1,172.17 Total Impact Points

Institutions

  • 1998–2014
    • Lerner Research Institute
      Cleveland, Ohio, United States
  • 1992–2013
    • Cleveland Clinic
      • • Department of Molecular Genetics
      • • Department of Molecular Biology
      Cleveland, OH, United States
  • 2012
    • Washington University in St. Louis
      San Luis, Missouri, United States
  • 2011
    • Zhejiang University
      • School of Medicine
      Hangzhou, Zhejiang Sheng, China
  • 2010
    • University of Pittsburgh
      Pittsburgh, Pennsylvania, United States
  • 2001–2010
    • University of Washington Seattle
      • • Department of Medicine
      • • Department of Immunology
      • • Department of Microbiology
      Seattle, WA, United States
  • 2007
    • Case Western Reserve University School of Medicine
      Cleveland, Ohio, United States
  • 2006
    • Monash University (Australia)
      Melbourne, Victoria, Australia
  • 2004
    • University of Toronto
      Toronto, Ontario, Canada
  • 2003
    • Hospital of the University of Pennsylvania
      • Department of Medicine
      Philadelphia, Pennsylvania, United States
  • 2002
    • Case Western Reserve University
      Cleveland, Ohio, United States
  • 1996
    • Roche Institute of Molecular Biology
      Nutley, New Jersey, United States
    • The University of Arizona
      • Department of Pediatrics
      Tucson, AZ, United States
  • 1990
    • New York Blood Center
      New York City, New York, United States
  • 1984–1989
    • Memorial Sloan-Kettering Cancer Center
      • Division of Molecular Biology
      New York City, NY, United States
  • 1983
    • Cornell University
      Ithaca, New York, United States
  • 1975–1978
    • Yale University
      • Department of Molecular Biophysics and Biochemistry
      New Haven, CT, United States