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Early induction of interferon-responsive mRNAs in Creutzfeldt-Jakob disease

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Abstract

Foreign infectious agents typically evoke a host immune response. In scrapie and Creutzfeldt-Jakob disease (CJD), no immune response has been detectable. However, many latent or persistent viruses evade immune recognition but still activate inflammatory pathways. Unique microglial responses in late CJD infection that could be part of a host defense mechanism were previously delineated, although changes secondary to neurodegeneration could not be excluded. Data here show these microglial transcriptional changes are detectable in CJD brain beginning at 30 days after innoculation. In addition, 10 other interferon-sensitive genes were similarly upregulated at very early stages of infection. These responses occurred well before abnormal prion protein (PrP) and clinical signs of CJD were detectable. Further analyses in very pure microglia from CJD brain suggested the CJD agent activated signaling pathways distinct from those induced by amyloidogenic proteins (including abnormal PrP). Although increases in interferon-α or -β transcript levels were not seen in cultures or in whole brain, CJD microglia exhibited a potentiated interferon response when challenged with double-stranded RNA. The induction of interferon-sensitive genes without appreciable interferon synthesis was strikingly similar to that seen in some viral infections. These data suggest the CJD agent is recognized as a foreign virus-like entity. Moreover, the early reactive gene expression profiles described here may be useful in preclinical diagnosis.

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Reference

  • Alexopoulou L, Holt AC, Medzhitov R, Flavell RA (2001). Recognition of double-stranded RNA and activation of NF-kappaB by toll-like receptor 3. Nature 413: 732–738.

    Article  PubMed  CAS  Google Scholar 

  • Antalis TM, Linn ML, Donnan K, Mateo L, Gardner J, Dickinson JL, Buttigieg K, Suhrbier A (1998). The serine proteinase inhibitor (serpin) plasminogen activation inhibitor type 2 protects against viral cytopathic effects by constitutive interferon alpha/beta priming. J Exp Med 187: 1799–1811.

    Article  PubMed  CAS  Google Scholar 

  • Aucouturier P, Geissmann F, Darnotte D, Saborio GP, Meeker HC, Kascsak R, Carp RI, Wisniewski T (2001). Infected splenic dendritic cells are sufficient for prion transmission to the CNS in mouse scrapie. J Clin Invest 108: 703–708.

    PubMed  CAS  Google Scholar 

  • Baca LM, Genis P, Kalvakolanu D, Sen G, Meltzer MS, Zhou A, Silverman R, Gendelman HE (1994). Regulation of interferon-alpha-inducible cellular genes in human immunodeficiency virus-infected monocytes. J Leukoc Biol 55: 299–309.

    PubMed  CAS  Google Scholar 

  • Baker CA, Manuelidis L (2003). Unique inflammatory profiles of microglia in Creutzfeldt-Jakob disease. Proc Natl Acad Sci U S A 100: 675–679.

    Article  PubMed  CAS  Google Scholar 

  • Baker CA, Martin D, Manuelidis L (2002). Microglia from CJD brain are infectious and show specific mRNA activation profiles. J Virol 76: 10905–10913.

    Article  PubMed  CAS  Google Scholar 

  • Barron RM, Thomson V, Jamieson E, Melton DW, Ironside J, Will RG, Manson JC (2001). Changing a single amino acid in the N-terminus of murine PrP alters TSE incubation time across three species barriers. EMBO J 20: 5070–5078.

    Article  PubMed  CAS  Google Scholar 

  • Belardelli F, Vignaux F, Proietti E, Gresser I (1984). Injection of mice with antibody to interferon renders peritoneal macrophages permissive for vesicular stomatitis virus and encephalomyocarditis virus. Proc Natl Acad Sci U S A 81: 602–606.

    Article  PubMed  CAS  Google Scholar 

  • Betmouni S, V.H. P, Gordon JL (1996). Evidence for an early inflammatory response in the central nervous system of mice with scrapie. Neuroscience 74: 1–5.

    Article  PubMed  CAS  Google Scholar 

  • Boyle KA, Pietropaolo RL, Compton T (1999). Engagement of the cellular receptor for glycoprotein B of human cytomegalovirus activates the interferon-responsive pathway. Mol Cell Biol 19: 3607–3613.

    PubMed  CAS  Google Scholar 

  • Brown KL, Stewart K, Ritchie DL, Mabbott NA, Williams A, Fraser H, Morrison WI, Bruce ME (1999). Scrapie repliction in lymphoid tissues depends on prion protein-expressing follicular dendritic cells. Nat Med 5: 1308–1312.

    Article  PubMed  CAS  Google Scholar 

  • Burysek L, Pitha PM (2001). Latently expressed human herpesvirus 8-encoded interferon regulatory factor 2 inhibits double-stranded RNA-activated protein kinase. J Virol 75: 2345–2352.

    Article  PubMed  CAS  Google Scholar 

  • Combs CK, Johnson DE, Cannady SB, Lehman TM, Landreth GE (1999). Identification of microglial signal transduction pathways mediating a neurotoxic response to amyloidogenic fragments of beta-amyloid and prion proteins. J Neurosci 19: 929–939.

    Google Scholar 

  • Combs CK, Karlo JC, Kao SC, Landreth GE (2001). Betaamyloid stimulation of microglia and monocytes results in TNF-alpha dependent expression of inducible nitric oxide synthase and neuronal apoptosis. J Neurosci 21: 1179–1188.

    PubMed  CAS  Google Scholar 

  • Doyle SE, Vaidya SA, O’Connell R, Dadgostar H, Dempsey PW, Wu TT, Rao G, Sun R, Haberland ME, Modlin RL, Cheng G (2002). IRF3 mediates a TLR3/TLR4-specific antiviral gene program. Immunity 17: 251–263.

    Article  PubMed  CAS  Google Scholar 

  • Eisen MB, Spellman PT, Brown PO, Botstein D (1998). Cluster analysis and display of genome-wide expression patterns. Proc Natl Acad Sci U S A 95: 14863–14868.

    Article  PubMed  CAS  Google Scholar 

  • Eklund EA, Jalava A, Kakar R (1998). PU.1, interferon regulatory factor 1, and interferon consensus sequence-binding protein cooperate to increase gp91phox expression. J Biol Chem 273: 13957–13965.

    Article  PubMed  CAS  Google Scholar 

  • Fiebich BL, Lieb K, Engels S, Heinrich M (2002). Inhibition of LPS-induced p42/44 MAP kinase activation and iNOS/NO synthesis by parthenolide in rat primary microglial cells. J Neuroimmunol 132: 18–24.

    Article  PubMed  CAS  Google Scholar 

  • Gotoh B, Takeuchi K, Komatsu T, Yokoo J (2003). The STAT2 activation process is a crucial target of sendai virus C protein for the blockade of alpha interferon signaling. J Virol 77: 3360–3370.

    Article  PubMed  CAS  Google Scholar 

  • Gresser I, Maury C, Chandler RL (1983). Failure to modify scrapie in mice by administration of interferon or anti-interferon globulin. J Gen Virol 64: 1387–1389.

    Article  PubMed  CAS  Google Scholar 

  • Hill A, Antoniou M, Collinge J (1999). Protease-resistant prion protein produced in vitro lacks detectable infectivity. J Gen Virol 80: 11–14.

    PubMed  CAS  Google Scholar 

  • Hsiao KK, Groth D, Scott M, Yang S-L, Serban H, Rapp D, Foster D, Torchia M, DeArmond SJ, Prusiner SB (1994). Serial transmission in rodents of neurodegeneration from transgenic mice expressing mutant prion protein. Proc Natl Acad Sci U S A 91: 9126–9130.

    Article  PubMed  CAS  Google Scholar 

  • Izmailova E, Bertley FMN, Huang Q, Makori N, Miller CJ, Young RA, Aldovini A (2003). HIV-1 Tat reprograms immature dendritic cells to express chemoattractants for activated T cells and macrophages. Nat Med 9: 191–197.

    Article  PubMed  CAS  Google Scholar 

  • Johnson RA, Huong SM, Huang ES (2000). Activation of the mitogen-activated protein kinase p38 by human cytomegalovirus infection through two distinct pathways: a novel mechanism for activation of p38. J Virol 74: 1158–1167.

    Article  PubMed  CAS  Google Scholar 

  • Kim JI, Ju WK, Choi JH, Kim J, Choi EK, Carp RI, Wisniewski HM, Kim YS (1999). Expression of cytokine genes and increased nuclear factor-kappa B activity in the brains of scrapie-infected mice. Mol Brain Res 73: 17–27.

    Article  PubMed  CAS  Google Scholar 

  • Lasmezas CI, Deslys JP, Robain O, Jaegly A, Beringue V, Peyrin JM, Fournier JG, Hauw JJ, Rossier J, Dormont D (1997). Transmission of the BSE agent to mice in the absence of detectable abnormal prion protein. Science 275: 402–405.

    Article  PubMed  CAS  Google Scholar 

  • Lewicki H, Tishon A, Homann D, Mazarguil H, Laval F, Asensio VC, Campbell IL, DeArmond S, Coon B, Teng C, Gairin JE, Oldstone MBA (2003). T cells infiltrate the brain in murine and human transmissible spongiform encephalopathies. J Virol 77: 3799–3808.

    Article  PubMed  CAS  Google Scholar 

  • Lin R, Heylbroeck C, Pitha PM, Hiscott J (1998). Virus-dependent phosphorylation of the IRF-3 transcription factor regulates nuclear translocation, transactivation potential, and proteosome-mediated degredation. Mol Cell Biol 18: 2986–2996.

    PubMed  CAS  Google Scholar 

  • Manuelidis EE, Gorgacs EJ, Manuelidis L (1978). Viremia in experimental Creutzfeldt-Jakob disease. Science 200: 1069–1071.

    Article  PubMed  CAS  Google Scholar 

  • Manuelidis EE, Kim JH, Mericangas JR, Manuelidis L (1985). Transmission to animals of Creutzfeldt-Jakob disease from human blood. Lancet 2: 896–897.

    Article  PubMed  CAS  Google Scholar 

  • Manuelidis L (1997). Beneath the emperor’s clothes: the body of experimental evidence in scrapie and CJD. Ann L’Institut Pasteur 8: 311–326.

    Google Scholar 

  • Manuelidis L (1998). Vaccination with an attenuated Creutzfeldt-Jakob disease strain prevents expression of a virulent agent. Proc Natl Acad Sci U S A 95: 2520–2525.

    Article  PubMed  CAS  Google Scholar 

  • Manuelidis L, Fritch W (1996). Infectivity and host responses in Creutzfeldt-Jakob disease. Virology 216: 46–59.

    Article  PubMed  CAS  Google Scholar 

  • Manuelidis L, Fritch W, Xi YG (1997). Evolution of a strain of CJD that induces BSE-like plaques. Science 277: 94–98.

    Article  PubMed  CAS  Google Scholar 

  • Manuelidis L, Lu ZY (2000). Attenuated Creutzfeldt-Jakob disease agents can hide more virulent infections. Neurosci Lett 293: 163–166.

    Article  PubMed  CAS  Google Scholar 

  • Manuelidis L, Lu ZY (2003). Virus-like interference in the latency and prevention of Creutzfeldt-Jakob disease. Proc Natl Acad Sci U S A 100: 5360–5365.

    Article  PubMed  CAS  Google Scholar 

  • Manuelidis L, Sklaviadis T, Akowitz A, Fritch W (1995). Viral particles are required for infection in neurodegenerative Creutzfeldt-Jakob disease. Proc Natl Acad Sci U S A 92: 5124–5128.

    Article  PubMed  CAS  Google Scholar 

  • Manuelidis L, Zaitsev I, Koni P, Lu ZY, Flavell RA, Fritch W (2000). Follicular dendritic cells and dissemination of Creutzfeldt-Jakob disease. J Virol 74: 8614–8622.

    Article  PubMed  CAS  Google Scholar 

  • Marecki S, Reidneau CJ, Liang MD, Fenton MJ (2001). PU.1 and multiple IFN regulatory factor proteins syngergize to mediate transcriptional activation of the human IL-1 beta gene. J Immunol 166: 6829–6838.

    PubMed  CAS  Google Scholar 

  • Martin M, Romero X, Angel de la Fuente M, Tovar V, Zapater N, Esplugues E, Pizcueta P, Bosch J, Engel P (2001). CD84 functions as a homophilic adhesion molecule and enchances IFN-gamma secretion: adhesion is mediated by Ig-like domain 1. J Immunol 167: 3668–3676.

    PubMed  CAS  Google Scholar 

  • Nakaya T, Sato M, Hata N, Asagiri M, Suemori H, Noguchi S, Tanaka N, Taniguchi T (2001). Gene induction pathways mediated by distinct IRFs during viral infection. Biochem Biophys Res Commun 283: 1150–1156.

    Article  PubMed  CAS  Google Scholar 

  • Navarro L, David M (1999). p38-dependent activation of interferon regulatory factor 3 by lipopolysaccharide. J Biol Chem 274: 35535–35538.

    Article  PubMed  CAS  Google Scholar 

  • Parisien JP, Lau JF, Rodriguez JJ, Sullivan BM, Moscona A, Parks GD, Lamb RA, Horvath CM (2001). The V protein of human parainfluenza virus 2 antagonizes type I interferon responses by destabilizing signal transducer and activator of transcription 2. Virology 283: 230–239.

    Article  PubMed  CAS  Google Scholar 

  • Parisien JP, Lau JF, Rodriguez JJ, Ulane CM, Horvath CM (2002). Selective STAT protein degradation induced by paramyxoviruses requires both STAT1 and STAT2 but is independent of alpha/beta interferon signal transduction. J Virol 76: 4190–4198.

    Article  PubMed  CAS  Google Scholar 

  • Prusiner SB, Scott MR, DeArmond SJ, Cohen FE (1998). Prion protein biology. Cell 93: 337–348.

    Article  PubMed  CAS  Google Scholar 

  • Riemer C, Queck I, Simon D, Kurth R, Baier M (2000). Identification of up-regulated genes in scrapie-infected brain tissue. J Virol 74: 10245–10248.

    Article  PubMed  CAS  Google Scholar 

  • Rodriguez JJ, Parisien JP, Horvath CM (2002). Nipah virus V protein evades alpha and gamma interferons by preventing STAT1 and STAT2 activation and nuclear accumulation. J Virol 76: 11476–11483.

    Article  PubMed  CAS  Google Scholar 

  • Rolle S, De Andrea M, Gioia D, Lembo D, Hertel L, Landolfo S, Gariglio M (2001). The interferon-inducible 204 gene is transcriptionally activated by mouse cytomegalovirus and is required for its replication. Virology 296: 249–255.

    Article  Google Scholar 

  • Ruvolo V, Navarro L, Sample CE, David M, Sung S, Swaminathan S (2003). The Epstein-Barr virus SM protein induces STAT1 and interferon-stimulated gene expression. J Virol 77: 3690–3701.

    Article  PubMed  CAS  Google Scholar 

  • Saborio GP, Permanne B, Soto C (2001). Sensitive detection of pathological prion protein by cyclic amplification of protein misfolding. Nature 411: 810–813.

    Article  PubMed  CAS  Google Scholar 

  • Sato M, Suemori H, Hata N, Asagiri M, Ogasawara K, Nakao K, Nakaya T, Kateuki M, Noguchi S, Tanaka N, Taniguchi T (2000). Distinct and essential roles of transcription factors IRF-3 and IRF-7 in response to viruses for IFN alpha/beta gene induction. Immunity 13: 539–548.

    Article  PubMed  CAS  Google Scholar 

  • Schneider-Schaulies J, ter Meulen V, Schneider-Schaulies S (2001). Measles virus interactions with cellular receptors: consequences for viral pathogenesis. J NeuroVirol 7: 391–399.

    Article  PubMed  CAS  Google Scholar 

  • Servant MJ, ten Oever B, LePage C, Conti L, Gessani S, Julkunen I, Lin R, Hiscott J (2001). Identification of distinct signaling pathways leading to the phosphorylation of interferon regulatory factor 3. J Biol Chem 276: 355–363.

    Article  PubMed  CAS  Google Scholar 

  • Sethi S, Lipford G, Wagner H, Kretzschmar HA (2002). Postexposure prophylaxis against prion disease with a stimulator of innate immunity. Lancet 360: 229–230.

    Article  PubMed  Google Scholar 

  • Sidorenko SP, Clark EA (2003). The dual-function CD150 receptor subfamily: the viral attraction. Nat Immunol 4: 19–24.

    Article  PubMed  CAS  Google Scholar 

  • Takeuchi O, Akira S (2002). Genetic approaches to the study of Toll-like receptor function. Microbes Infect 4: 887–895.

    Article  PubMed  CAS  Google Scholar 

  • Tamura T, Nagamura-Inoue T, Shmeltzer Z, Kuwata T, Ozato K (2002). ICSBP directs bipotential myeloid progenitor cells to differentiate into mature macrophages. Immunity 13: 155–165.

    Article  Google Scholar 

  • Taniguchi T, Takaoka A (2002). The interferon-alpha/beta system in antiviral responses: a multimodal machinery of gene regulation by the IRF family of transcription factors. Curr Opin Immunol 14: 111–116.

    Article  PubMed  CAS  Google Scholar 

  • tenOever BR, Servant MJ, Grandvaux N, Lin R, Hiscott J (2002). Recognition of the measles virus nucleocapsid as a mechanism of IRF-3 activation. J Virol 76: 3659–3669.

    Article  PubMed  CAS  Google Scholar 

  • Wathelet MG, Lin CH, Parekh BS, Ronco LV, Howley PM, Maniatis T (1998). Virus infection induces the assembly of coordinately activated transcription factors on the IFN-beta enchancer in vivo. Mol Cell 1: 507–518.

    Article  PubMed  CAS  Google Scholar 

  • Xi Y-G, Ingrosso L, Ladogana A, Masullo C, Pocchiari M (1992). Amphotericin B treatment dissociates in vivo replication of the scrapie agent from PrP accumulation. Nature 356: 598–601.

    Article  PubMed  CAS  Google Scholar 

  • Xiang Y, Condit RC, Vijaysri S, Jacobs B, Williams BRG, Silverman RH (2002). Blockade of interferon induction and action by the E3L double-stranded RNA binding proteins of vaccinia virus. J Virol 76: 5251–5259.

    Article  PubMed  CAS  Google Scholar 

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  1. Christopher A. Baker

    Present address: Department of Neurobiology, Yale School of Medicine, New Haven, Connecticut, USA

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  1. Section of Neuropathology, Yale School of Medicine, New Haven, Connecticut, USA

    Christopher A. Baker, Zhi Yun Lu & Laura Manuelidis

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  1. Christopher A. Baker
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Correspondence to Laura Manuelidis.

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This work was supported by grants NS12674 and NS34569 from the National Institutes of Health.

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Baker, C.A., Lu, Z.Y. & Manuelidis, L. Early induction of interferon-responsive mRNAs in Creutzfeldt-Jakob disease. Journal of NeuroVirology 10, 29–40 (2004). https://doi.org/10.1080/13550280490261761

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  • DOI: https://doi.org/10.1080/13550280490261761

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