Taro Kawai

Icahn School of Medicine at Mount Sinai, Manhattan, New York, United States

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Publications (109)1152.6 Total impact

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    ABSTRACT: Pathological conditions such as epilepsy cause misregulation of adult neural stem/progenitor populations in the adult hippocampus in mice, and the resulting abnormal neurogenesis leads to impairment in learning and memory. However, how animals cope with abnormal neuro-genesis remains unknown. Here we show that microglia in the mouse hippocampus attenuate convulsive seizure-mediated aberrant neurogenesis through the activation of Toll-like receptor 9 (TLR9), an innate immune sensor known to recognize microbial DNA and trigger inflammatory responses. We found that microglia sense self-DNA from degenerating neurons following seizure, and secrete tumour necrosis factor-a, resulting in attenuation of aberrant neurogenesis. Furthermore, TLR9 deficiency exacerbated seizure-induced cognitive decline and recurrent seizure severity. Our findings thus suggest the existence of bidirectional communication between the innate immune and nervous systems for the maintenance of adult brain integrity.
    Full-text · Article · Apr 2015 · Nature Communications
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    ABSTRACT: RIG-I-like receptors (RLRs), including RIG-I and MDA5, constitute a family of cytoplasmic RNA helicases that sense viral RNA and mount antiviral innate immunity by producing type I interferons and inflammatory cytokines. Despite their essential roles in antiviral host defense, RLR signaling is negatively regulated to protect the host from excessive inflammation and autoimmunity. Here, we identified Arl5B, an Arl family small GTPase, as a regulator of RLR signaling through MDA5 but not RIG-I. Overexpression of Arl5B repressed interferon β promoter activation by MDA5 but not RIG-I, and its knockdown enhanced MDA5-mediated responses. Furthermore, Arl5B-deficient mouse embryonic fibroblast cells exhibited increased type I interferon expression in response to MDA5 agonists such as polyI:C and encephalomyocarditis virus. Arl5B-mediated negative regulation of MDA5 signaling does not require its GTP-binding ability, but requires Arl5B binding to the C-terminal domain of MDA5, which prevents interaction between MDA5 and polyI:C. Our results therefore suggest that Arl5B is a negative regulator for MDA5. Copyright © 2014, The American Society for Biochemistry and Molecular Biology.
    No preview · Article · Dec 2014 · Journal of Biological Chemistry
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    Surya Pandey · Taro Kawai · Shizuo Akira
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    ABSTRACT: Recognition of an invading pathogen is critical to elicit protective responses. Certain microbial structures and molecules, which are crucial for their survival and virulence, are recognized by different families of evolutionarily conserved pattern recognition receptors (PRRs). This recognition initiates a signaling cascade that leads to the transcription of inflammatory cytokines and chemokines to eliminate pathogens and attract immune cells, thereby perpetuating further adaptive immune responses. Considerable research on the molecular mechanisms underlying host-pathogen interactions has resulted in the discovery of multifarious PRRs. In this review, we discuss the recent developments in microbial recognition by Toll-like receptors (TLRs) and intracellular nucleic acid sensors and the signaling pathways initiated by them.
    Preview · Article · Oct 2014 · Cold Spring Harbor perspectives in biology
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    Takumi Kawasaki · Taro Kawai
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    ABSTRACT: Toll-like receptors (TLRs) play crucial roles in the innate immune system by recognizing pathogen-associated molecular patterns derived from various microbes. TLRs signal through the recruitment of specific adaptor molecules, leading to activation of the transcription factors NF-κB and IRFs, which dictate the outcome of innate immune responses. During the past decade, the precise mechanisms underlying TLR signaling have been clarified by various approaches involving genetic, biochemical, structural, cell biological, and bioinformatics studies. TLR signaling appears to be divergent and to play important roles in many aspects of the innate immune responses to given pathogens. In this review, we describe recent progress in our understanding of TLR signaling regulation and its contributions to host defense.
    Preview · Article · Sep 2014 · Frontiers in Immunology
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    ABSTRACT: While T-cell responses are directly modulated by Toll-like receptor (TLR) ligands, the mechanism and physiological function of nucleic acids (NAs)-mediated T cell costimulation remains unclear. Here we show that unlike in innate cells, T-cell costimulation is induced even by non-CpG DNA and by self-DNA, which is released from dead cells and complexes with antimicrobial peptides or histones. Such NA complexes are internalized by T cells and induce costimulatory responses independently of known NA sensors, including TLRs, RIG-I-like receptors (RLRs), inflammasomes and STING-dependent cytosolic DNA sensors. Such NA-mediated costimulation crucially induces Th2 differentiation by suppressing T-bet expression, followed by the induction of GATA-3 and Th2 cytokines. These findings unveil the function of NA sensing by T cells to trigger and amplify allergic inflammation.
    No preview · Article · Apr 2014 · Nature Communications
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    ABSTRACT: The RIG-I-like receptors, retinoic acid inducible gene-1 (RIG-I), melanoma differentiation-associated protein 5, and laboratory of genetics and physiology-2, are cytoplasmic sensors for RNA viruses that mediate the antiviral innate immune responses. We demonstrate that really interesting new gene-finger domain- and K homology domain-containing MEX3C regulates RIG-I function. MEX3C colocalizes with RIG-I in the stress granules of virally infected cells, and its overexpression causes the lysine-63-linked ubiquitination of RIG-I and activates IFN-β promoter. Embryonic fibroblast cells, macrophages, and conventional dendritic cells derived from Mex3c-deficient mice showed defective production of type I IFN after infection with RNA viruses that are recognized by RIG-I. These results demonstrate that MEX3C is an E3 ubiquitin ligase that modifies RIG-I in stress granules and plays a critical role in eliciting antiviral immune responses.
    Preview · Article · Mar 2014 · Proceedings of the National Academy of Sciences
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    ABSTRACT: High-dose ionizing radiation induces severe DNA damage in the epithelial stem cells in small intestinal crypts and causes gastrointestinal syndrome (GIS). Although the tumour suppressor p53 is a primary factor inducing death of crypt cells with DNA damage, its essential role in maintaining genome stability means inhibiting p53 to prevent GIS is not a viable strategy. Here we show that the innate immune receptor Toll-like receptor 3 (TLR3) is critical for the pathogenesis of GIS. Tlr3(-/-) mice show substantial resistance to GIS owing to significantly reduced radiation-induced crypt cell death. Despite showing reduced crypt cell death, p53-dependent crypt cell death is not impaired in Tlr3(-/-) mice. p53-dependent crypt cell death causes leakage of cellular RNA, which induces extensive cell death via TLR3. An inhibitor of TLR3-RNA binding ameliorates GIS by reducing crypt cell death. Thus, we propose blocking TLR3 activation as a novel approach to treat GIS.
    Full-text · Article · Mar 2014 · Nature Communications
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    ABSTRACT: ABSTRACT The cytoplasmic helicase RIG-I is an established sensor for viral 5'-triphosphorylated RNA species. Recently, RIG-I was also implicated in the detection of intracellular bacteria. However, little is known about the host cell specificity of this process and the bacterial pathogen-associated molecular pattern (PAMP) that activates RIG-I. Here we show that RNA of Salmonella enterica serovar Typhimurium activates production of beta interferon in a RIG-I-dependent fashion only in nonphagocytic cells. In phagocytic cells, RIG-I is obsolete for detection of Salmonella infection. We further demonstrate that Salmonella mRNA reaches the cytoplasm during infection and is thus accessible for RIG-I. The results from next-generation sequencing analysis of RIG-I-associated RNA suggest that coding bacterial mRNAs represent the activating PAMP. IMPORTANCE S. Typhimurium is a major food-borne pathogen. After fecal-oral transmission, it can infect epithelial cells in the gut as well as immune cells (mainly macrophages, dendritic cells, and M cells). The innate host immune system relies on a growing number of sensors that detect pathogen-associated molecular patterns (PAMPs) to launch a first broad-spectrum response to invading pathogens. Successful detection of a given pathogen depends on colocalization of host sensors and PAMPs as well as potential countermeasures of the pathogen during infection. RIG-I-like helicases were mainly associated with detection of RNA viruses. Our work shows that S. Typhimurium is detected by RIG-I during infection specifically in nonimmune cells.
    Full-text · Article · Feb 2014 · mBio
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    ABSTRACT: The baculovirus Autographa californica nucleopolyhedrovirus (AcNPV) has been widely used to achieve a high level of foreign gene expression in insect cells, as well as for efficient gene transduction into mammalian cells without any replication. In addition to permitting efficient gene delivery, baculovirus has been shown to induce host innate immune responses in various mammalian cells and in mice. In this study, we examined the effects of the innate immune responses on the gene expression by recombinant baculoviruses in cultured cells. The reporter gene expression in IRF3-deficient mouse embryonic fibroblasts (MEFs) by the infection with the recombinant baculovirus was shown to be enhanced in accordance with the suppression of IFN-β production. Furthermore, efficient gene transduction by the recombinant baculovirus was achieved in MEFs deficient for STING, TBK1, IRF3 or IPS-1, but not in those deficient for IRF7, MyD88 or ZBP1/DAI. An enhancement of gene expression by the recombinant baculovirus was also observed in human hepatoma cell lines replicating hepatitis C virus (HCV), in which innate immunity was impaired by the cleavage of IPS-1 by the viral protease. In addition, infection with the recombinant baculovirus expressing the BH3-only protein, BIMS, a potent inducer of apoptosis, resulted in a selective cell death in the HCV replicon cells. These results indicate that innate immune responses induced by infection with baculovirus attenuate transgene expression, and this characteristic might be useful for a selective gene transduction into cells with impaired innate immunity arisen from infection with various viruses.
    Full-text · Article · Dec 2013 · Journal of Virology

  • No preview · Conference Paper · Sep 2013
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    ABSTRACT: Innate immune receptors, notably Toll-like receptors (TLRs) and RIG-I-like receptors (RLRs), sense viral infection and activate transcription factors, including interferon regulatory factor-3 (IRF3), to induce type I interferon (IFN). We demonstrate that the lipid phosphatidylinositol-5-phosphate (PtdIns5P) is increased upon viral infection and facilitates type I IFN production by binding to IRF3 and its upstream kinase TBK1 and promoting TBK1-mediated IRF3 phosphorylation and activation. Additionally, we determine that PtdIns5P is produced through the kinase PIKfyve, which phosphorylates PtdIns to generate PtdIns5P. Accordingly, PIKfyve knockdown or pharamoclogical inhibition decreases PtdIns5P levels and type I IFN production after TLR or RLR stimulation, and results in increased viral replication. A synthetic PtdIns5P, C8-PtdIns5P, promotes IRF3 phosphorylation and cytokine production in dendritic cells and acts as an adjuvant to boost immune responses in immunized mice. Thus, PtdIns5P produced during viral infection is a second messenger that targets the TBK1-IRF3 axis to elicit antiviral immunity.
    Preview · Article · Aug 2013 · Cell host & microbe
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    ABSTRACT: More than 130 million people worldwide chronically infected with hepatitis C virus (HCV) are at risk of developing severe liver disease. Antiviral treatments are only partially effective against HCV infection, and a vaccine is not available. Development of more efficient therapies has been hampered by the lack of a small animal model. Building on the observation that CD81 and occludin (OCLN) comprise the minimal set of human factors required to render mouse cells permissive to HCV entry1, we previously showed that transient expression of these two human genes is sufficient to allow viral uptake into fully immunocompetent inbred mice2. Here we demonstrate that transgenic mice stably expressing human CD81 and OCLN also support HCV entry, but innate and adaptive immune responses restrict HCV infection in vivo. Blunting antiviral immunity in genetically humanized mice infected with HCV results in measurable viraemia over several weeks. In mice lacking the essential cellular co-factor cyclophilin A (CypA), HCV RNA replication is markedly diminished, providing genetic evidence that this process is faithfully recapitulated. Using a cell-based fluorescent reporter activated by the NS3-4A protease we visualize HCV infection in single hepatocytes in vivo. Persistently infected mice produce de novo infectious particles, which can be inhibited with directly acting antiviral drug treatment, thereby providing evidence for the completion of the entire HCV life cycle in inbred mice. This genetically humanized mouse model opens new opportunities to dissect genetically HCV infection in vivo and provides an important preclinical platform for testing and prioritizing drug candidates and may also have utility for evaluating vaccine efficacy.
    Full-text · Article · Jul 2013 · Nature
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    ABSTRACT: RIG-I-like receptors (RLRs) sense virus-derived RNA or polyinosinic-polycytidylic acid (poly IC) to exert antiviral immune responses. Here, we examine the mechanisms underlying the adjuvant effects of poly IC. Poly IC was taken up by dendritic cells (DCs), and it induced lysosomal destabilization, which, in turn, activated an RLR-dependent signaling pathway. Upon poly IC stimulation, cathepsin D was released into the cytoplasm from the lysosome to interact with IPS-1, an adaptor molecule for RLRs. This interaction facilitated cathepsin D cleavage of caspase 8 and the activation of the transcription factor NF-κB, resulting in enhanced cytokine production. Further recruitment of the kinase RIP-1 to this complex initiated the necroptosis of a small number of DCs. HMGB1 released by dying cells enhanced IFN-β production in concert with poly IC. Collectively, these findings suggest that cathepsin D-triggered, IPS-1-dependent necroptosis is a mechanism that propagates the adjuvant efficacy of poly IC.
    Preview · Article · Apr 2013 · Immunity
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    ABSTRACT: Infection of influenza A virus in mammals induces hyper lung pneumonia, which often causes lethal diseases. FasL is a specific ligand of Fas, which is a type-I transmembrane protein to induce cell death. Previously, it has been reported that the hyper induction of gene expression associated with Fas signal is observed in lethal influenza A virus infection. More importantly, it was also reported that functional mutation of the FasL gene protects the host against influenza A virus infection. These observations suggest that induction of FasL signal is functionally associated with the severity of influenza. However, regulation of the induction of FasL or Fas by influenza A virus infection is still unknown. Here, we demonstrated that FasL is induced after the viral infection, and inhibition of the Fas/FasL signal by treatment with a recombinant decoy receptor for FasL (Fas-Fc) increases the survival rate of mice after lethal infection of influenza A virus as well as functional mutation of the FasL gene in gld/gld mice. In addition, the induction level of FasL gene expression in the lung was correlated with the severity of influenza. We also showed that a variety of types of cells in the lung express FasL after the viral infection. Furthermore, type-I interferon induced by the viral infection was shown to be critical for induction of FasL protein expression in the lung. These findings suggested that expression of FasL protein induced by type-I IFN on the lung cell surface is critical to determine the severity of influenza.
    Full-text · Article · Feb 2013 · PLoS ONE
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    ABSTRACT: Double-stranded DNA (dsDNA) derived from pathogen- or host-damaged cells triggers innate immune responses when exposed to cytoplasm. However, the machinery underlying the primary recognition of intracellular dsDNA is obscure. Here we show that the DNA damage sensor, meiotic recombination 11 homolog A (MRE11), serves as a cytosolic sensor for dsDNA. Cells with a mutation of MRE11 gene derived from a patient with ataxia-telangiectasia-like disorder, and cells in which Mre11 was knocked down, had defects in dsDNA-induced type I IFN production. MRE11 physically interacted with dsDNA in the cytoplasm and was required for activation of stimulator of IFN genes (STING) and IRF3. RAD50, a binding protein to MRE11, was also required for dsDNA responses, whereas NBS1, another binding protein to MRE11, was dispensable. Collectively, our results suggest that the MRE11-RAD50 complex plays important roles in recognition of dsDNA and initiation of STING-dependent signaling, in addition to its role in DNA-damage responses.
    Full-text · Article · Feb 2013 · Proceedings of the National Academy of Sciences
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    ABSTRACT: The cytosolic RNA helicases melanoma differentiation-associated gene 5 and retinoic acid-inducible gene-I and their adaptor IFN-β promoter stimulator (IPS-1) have been implicated in the recognition of viral RNA and the production of type I IFN. Complementing the endosomal TLR, melanoma differentiation-associated gene 5, and retinoic acid-inducible gene-I provides alternative mechanisms for viral detection in cells with reduced phagocytosis or autophagy. The infection route of respiratory syncytial virus (RSV)-via fusion of virus particles with the cell membrane-points to IPS-1 signaling as the pathway of choice for downstream antiviral responses. In the current study, viral clearance and inflammation resolution were indeed strongly affected by the absence of an initial IPS-1-mediated IFN-β response. Despite the blunted inflammatory response in IPS-1-deficient alveolar epithelial cells, pulmonary macrophages, and CD11b(+) dendritic cells (DC), the lungs of RSV-infected IPS-1-knockout mice showed augmented recruitment of inflammatory neutrophils, monocytes, and DC. Interestingly, pulmonary CD103(+) DC could functionally compensate for IPS-1 deficiency with the upregulation of certain inflammatory cytokines and chemokines, possibly via TLR3 and TLR7 signaling. The increased inflammation and reduced viral clearance in IPS-1-knockout mice was accompanied by increased T cell activation and IFN-γ production. Experiments with bone marrow chimeras indicated that RSV-induced lung pathology was most severe when IPS-1 expression was lacking in both immune and nonimmune cell populations. Similarly, viral clearance was rescued upon restored IPS-1 signaling in either the nonimmune or the immune compartment. These data support a nonredundant function for IPS-1 in controlling RSV-induced inflammation and viral replication.
    Full-text · Article · Nov 2012 · The Journal of Immunology
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    ABSTRACT: Host protection from infection relies on the recognition of pathogens by innate pattern-recognition receptors such as Toll-like receptors (TLRs). Here, we show that the orphan receptor TLR13 in mice recognizes a conserved 23S ribosomal RNA (rRNA) sequence that is the binding site of macrolide, lincosamide, and streptogramin group (MLS) antibiotics (including erythromycin) in bacteria. Notably, 23S rRNA from clinical isolates of erythromycin-resistant Staphylococcus aureus and synthetic oligoribonucleotides carrying methylated adenosine or a guanosine mimicking a MLS resistance-causing modification failed to stimulate TLR13. Thus, our results reveal both a natural TLR13 ligand and specific mechanisms of antibiotic resistance as potent bacterial immune evasion strategy, avoiding recognition via TLR13.
    Full-text · Article · Jul 2012 · Science
  • Takeshi Kondo · Taro Kawai · Shizuo Akira
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    ABSTRACT: Toll-like receptors (TLRs) sense invading microbial pathogens and play crucial roles in the activation of innate and adaptive immunity. However, excessive TLR activation can disrupt immune homeostasis, and may be responsible for the development of autoimmune and inflammatory diseases. As such, the molecules and pathways that negatively control TLR signaling have been intensively investigated. Here, we discuss recent insights into the negative regulation of TLR signaling, with focus on three major mechanisms: (i) dissociation of adaptor complexes; (ii) degradation of signal proteins; and (iii) transcriptional regulation. We also highlight how pathogens negatively target TLR signaling as a strategy to evade the host immune response.
    No preview · Article · Jun 2012 · Trends in Immunology
  • Shizuo Akira · Tatsuya Saitoh · Taro Kawai
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    ABSTRACT: The innate immune system detects pathogen-derived nucleic acids (DNA and RNA) and induces type I interferon (IFN) and other cytokines, resulting in the host defense against pathogen. We identified interferon-inducible tripartite-motif (TRIM) 56 as a regulator of double-stranded DNA-mediated type I interferon induction. TRIM56 interacted with STING and targeted it for lysine 63-linked ubiquitination. This modification induced STING dimerization, which was a prerequisite for recruitment of the antiviral kinase TBK1 and subsequent induction of IFN-beta. Taken together, these results show that TRIM56 is an interferon-inducible E3 ubiquitin ligase that modulates STING to confer double-stranded DNA-mediated innate immune responses. It is well known that Toll-like receptor 7 (TLR7) and TLR9 sense viral nucleic acids and induce production of type I interferon (IFN) by plasmacytoid dendritic cells (pDCs) to protect the host from virus infection. We showed that the IFN-inducible antiviral protein Viperin promoted TLR7- and TLR9-mediated production of type I IFN by pDCs. Viperin expression was potently induced after TLR7 or TLR9 stimulation and Viperin localized to the cytoplasmic lipid-enriched compartments, lipid bodies, in pDCs. Viperin interacted with the signal mediators IRAK1 and TRAF6 to recruit them to the lipid bodies and facilitated K63-linked ubiquitination of IRAK1 to induce the nuclear translocation of transcription factor IRF7. Thus, besides direct inhibition of viral replication, this finding reveals that Viperin mediates its antiviral function via the regulation of the TLR7 and TLR9-IRAK1 signaling axis in pDCs.
    No preview · Article · Jun 2012 · Uirusu
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    ABSTRACT: The mechanisms of induction of liver injury during chronic infection with hepatitis C virus (HCV) are not well understood. Gamma interferon (IFN-γ)-inducible protein 10 (IP-10), a member of the CXC chemokine family, is expressed in the liver of chronic hepatitis C (CHC) patients and selectively recruits activated T cells to the sites of inflammation. Recently, it was shown that a low plasma concentration of IP-10 in CHC patients was closely associated with the outcome of antiviral therapy. In this study, we examined the role of the Toll-like receptor (TLR) pathway on IP-10 production in cells replicating HCV. Among the CXC chemokines, the expression of IP-10 was specifically increased in cells replicating HCV upon stimulation with conventional TLR2 ligands. The enhancement of IP-10 production upon stimulation with TLR2 ligands in cells replicating HCV induced CD44 expression. CD44 is a broadly distributed type I transmembrane glycoprotein and a receptor for the glycosaminoglycan hyaluronan (HA). In CHC patients, the expression of HA in serum has been shown to increase in accord with the progression of liver fibrosis, and HA also works as a ligand for TLR2. In the present study, IP-10 production upon HA stimulation was dependent on the expression of TLR2 and CD44, and a direct association between TLR2 and CD44 was observed. These results suggest that endogenous expression of HA in hepatocytes in CHC patients participates in IP-10 production through an engagement of TLR2 and CD44.
    Full-text · Article · Apr 2012 · Journal of Virology

Publication Stats

31k Citations
1,152.60 Total Impact Points


  • 2014
    • Icahn School of Medicine at Mount Sinai
      • Division of Infectious Diseases
      Manhattan, New York, United States
    • Nara Institute of Science and Technology
      • Graduate School of Biological Sciences
      Ikuma, Nara, Japan
  • 1999-2014
    • Osaka University
      • • Department of Host Defense
      • • Research Institute for Microbial Diseases
      • • Division of Cellular and Molecular Biology
      Suika, Ōsaka, Japan
  • 2012
    • University of Yamanashi
      • Department of Microbiology
      Kōhu, Yamanashi, Japan
    • Institute of Microbial Chemistry
      Edo, Tokyo, Japan
  • 2011
    • Indian Institute of Science Education and Research Bhopal
      • Department of Biological Sciences
      Bhopal, Madhya Pradesh, India
  • 2008
    • Charité Universitätsmedizin Berlin
      • Department of Neonatology
      Berlín, Berlin, Germany
  • 2005-2008
    • Japan Science and Technology Agency (JST)
      • Exploratory Research for Advanced Technology (ERATO)
      Tokyo, Tokyo-to, Japan
  • 1998-1999
    • Hyogo College of Medicine
      • Department of Biochemistry
      Nishinomiya, Hyōgo, Japan