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. 2012 Aug 4;3(8):590–601. doi: 10.1007/s13238-012-2059-9

Herpesviral infection and Toll-like receptor 2

Ming-sheng Cai 1,2, Mei-li Li 3, Chun-fu Zheng 1,✉
PMCID: PMC4875356  PMID: 22865347

Abstract

In the last decade, substantial progress has been made in understanding the molecular mechanisms involved in the initial host responses to viral infections. Herpesviral infections can provoke an inflammatory cytokine response, however, the innate pathogen-sensing mechanisms that transduce the signal for this response are poorly understood. In recent years, it has become increasingly evident that the Toll-like receptors (TLRs), which are germline-encoded pattern recognition receptors (PRRs), function as potent sensors for infection. TLRs can induce the activation of the innate immunity by recruiting specific intracellular adaptor proteins to initiate signaling pathways, which then culminating in activation of the nuclear factor kappa B (NF-κB) and interferon-regulatory factors (IRFs) that control the transcription of genes encoding type I interferon (IFN I) and other inflammatory cytokines. Furthermore, activation of innate immunity is critical for mounting adaptive immune responses. In parallel, common mechanisms used by viruses to counteract TLR-mediated responses or to actively subvert these pathways that block recognition and signaling through TLRs for their own benefit are emerging. Recent findings have demonstrated that TLR2 plays a crucial role in initiating the inflammatory process, and surprisingly that the response TLR2 triggers might be overzealous in its attempt to counter the attack by the virus. In this review, we summarize and discuss the recent advances about the specific role of TLR2 in triggering inflammatory responses in herpesvirus infection and the consequences of the alarms raised in the host that they are assigned to protect.

Keywords: herpesviruses, innate immune, Toll-like receptor (TLR), TLR2

Footnotes

These authors contributed equally to the work.

References

  1. Akira S., Takeda K. Toll-like receptor signalling. Nat Rev Immunol. 2004;4:499–511. doi: 10.1038/nri1391. [DOI] [PubMed] [Google Scholar]
  2. Akira S., Takeda K., Kaisho T. Toll-like receptors: critical proteins linking innate and acquired immunity. Nat Immunol. 2001;2:675–680. doi: 10.1038/90609. [DOI] [PubMed] [Google Scholar]
  3. Akira S., Uematsu S., Takeuchi O. Pathogen recognition and innate immunity. Cell. 2006;124:783–801. doi: 10.1016/j.cell.2006.02.015. [DOI] [PubMed] [Google Scholar]
  4. Aliprantis A.O., Yang R.B., Mark M.R., Suggett S., Devaux B., Radolf J.D., Klimpel G.R., Godowski P., Zychlinsky A. Cell activation and apoptosis by bacterial lipoproteins through toll-like receptor-2. Science. 1999;285:736–739. doi: 10.1126/science.285.5428.736. [DOI] [PubMed] [Google Scholar]
  5. Aravalli R.N., Hu S., Rowen T.N., Palmquist J.M., Lokensgard J.R. Cutting edge: TLR2-mediated proinflammatory cytokine and chemokine production by microglial cells in response to herpes simplex virus. J Immunol. 2005;175:4189–4193. doi: 10.4049/jimmunol.175.7.4189. [DOI] [PubMed] [Google Scholar]
  6. Ariza M.E., Glaser R., Kaumaya P.T., Jones C., Williams M.V. The EBV-encoded dUTPase activates NF-kappa B through the TLR2 and MyD88-dependent signaling pathway. J Immunol. 2009;182:851–859. doi: 10.4049/jimmunol.182.2.851. [DOI] [PubMed] [Google Scholar]
  7. Armien A.G., Hu S., Little M.R., Robinson N., Lokensgard J.R., Low W.C., Cheeran M.C. Chronic cortical and subcortical pathology with associated neurological deficits ensuing experimental herpes encephalitis. Brain Pathol. 2010;20:738–750. doi: 10.1111/j.1750-3639.2009.00354.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Arvin A.M., Koropchak C.M., Williams B.R., Grumet F.C., Foung S.K. Early immune response in healthy and immunocompromised subjects with primary varicella-zoster virus infection. J Infect Dis. 1986;154:422–429. doi: 10.1093/infdis/154.3.422. [DOI] [PubMed] [Google Scholar]
  9. Barbalat R., Lau L., Locksley R.M., Barton G.M. Toll-like receptor 2 on inflammatory monocytes induces type I interferon in response to viral but not bacterial ligands. Nat Immunol. 2009;10:1200–1207. doi: 10.1038/ni.1792. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Bieback K., Lien E., Klagge I.M., Avota E., Schneider-Schaulies J., Duprex W.P., Wagner H., Kirschning C.J., Ter Meulen V., Schneider-Schaulies S. Hemagglutinin protein of wild-type measles virus activates toll-like receptor 2 signaling. J Virol. 2002;76:8729–8736. doi: 10.1128/JVI.76.17.8729-8736.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Bochud P.Y., Magaret A.S., Koelle D.M., Aderem A., Wald A. Polymorphisms in TLR2 are associated with increased viral shedding and lesional rate in patients with genital herpes simplex virus Type 2 infection. J Infect Dis. 2007;196:505–509. doi: 10.1086/519693. [DOI] [PubMed] [Google Scholar]
  12. Boehme K.W., Guerrero M., Compton T. Human cytomegalovirus envelope glycoproteins B and H are necessary for TLR2 activation in permissive cells. J Immunol. 2006;177:7094–7102. doi: 10.4049/jimmunol.177.10.7094. [DOI] [PubMed] [Google Scholar]
  13. Boivin G., Coulombe Z., Rivest S. Intranasal herpes simplex virus type 2 inoculation causes a profound thymidine kinase dependent cerebral inflammatory response in the mouse hindbrain. Eur J Neurosci. 2002;16:29–43. doi: 10.1046/j.1460-9568.2002.02057.x. [DOI] [PubMed] [Google Scholar]
  14. Bowie A.G., Unterholzner L. Viral evasion and subversion of pattern-recognition receptor signalling. Nat Rev Immunol. 2008;8:911–922. doi: 10.1038/nri2436. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Buwitt-Beckmann U., Heine H., Wiesmuller K.H., Jung G., Brock R., Akira S., Ulmer A.J. Toll-like receptor 6-independent signaling by diacylated lipopeptides. Eur J Immunol. 2005;35:282–289. doi: 10.1002/eji.200424955. [DOI] [PubMed] [Google Scholar]
  16. Chang J.H., McCluskey P.J., Wakefield D. Toll-like receptors in ocular immunity and the immunopathogenesis of inflammatory eye disease. Br J Ophthalmol. 2006;90:103–108. doi: 10.1136/bjo.2005.072686. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Chuang T., Ulevitch R.J. Identification of hTLR10: a novel human Toll-like receptor preferentially expressed in immune cells. Biochim Biophys Acta. 2001;1518:157–161. doi: 10.1016/s0167-4781(00)00289-x. [DOI] [PubMed] [Google Scholar]
  18. Chuang T.H., Ulevitch R.J. Cloning and characterization of a sub-family of human toll-like receptors: hTLR7, hTLR8 and hTLR9. Eur Cytokine Netw. 2000;11:372–378. [PubMed] [Google Scholar]
  19. Compton T., Kurt-Jones E.A., Boehme K.W., Belko J., Latz E., Golenbock D.T., Finberg R.W. Human cytomegalovirus activates inflammatory cytokine responses via CD14 and Toll-like receptor 2. J Virol. 2003;77:4588–4596. doi: 10.1128/JVI.77.8.4588-4596.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Cooper A., Tal G., Lider O., Shaul Y. Cytokine induction by the hepatitis B virus capsid in macrophages is facilitated by membrane heparan sulfate and involves TLR2. J Immunol. 2005;175:3165–3176. doi: 10.4049/jimmunol.175.5.3165. [DOI] [PubMed] [Google Scholar]
  21. Crumpacker C. W.S. Cytomegalovirus. In: Mandell B.J., Dolin R., editors. Principles and Practice of Infectious Diseases. New York: Churchill Livingstone; 2005. pp. 1786–1801. [Google Scholar]
  22. Dolganiuc A., Oak S., Kodys K., Golenbock D.T., Finberg R.W., Kurt-Jones E., Szabo G. Hepatitis C core and nonstructural 3 proteins trigger toll-like receptor 2-mediated pathways and inflammatory activation. Gastroenterology. 2004;127:1513–1524. doi: 10.1053/j.gastro.2004.08.067. [DOI] [PubMed] [Google Scholar]
  23. Du X., Poltorak A., Wei Y., Beutler B. Three novel mammalian toll-like receptors: gene structure, expression, and evolution. Eur Cytokine Netw. 2000;11:362–371. [PubMed] [Google Scholar]
  24. Duesberg U., von dem Bussche A., Kirschning C., Miyake K., Sauerbruch T., Spengler U. Cell activation by synthetic lipopeptides of the hepatitis C virus (HCV)-core protein is mediated by toll like receptors (TLRs) 2 and 4. Immunol Lett. 2002;84:89–95. doi: 10.1016/s0165-2478(02)00178-5. [DOI] [PubMed] [Google Scholar]
  25. Dziarski R., Tapping R.I., Tobias P.S. Binding of bacterial peptidoglycan to CD14. J Biol Chem. 1998;273:8680–8690. doi: 10.1074/jbc.273.15.8680. [DOI] [PubMed] [Google Scholar]
  26. Elsawa S.F., Bost K.L. Murine gamma-herpesvirus-68-induced IL-12 contributes to the control of latent viral burden, but also contributes to viral-mediated leukocytosis. J Immunol. 2004;172:516–524. doi: 10.4049/jimmunol.172.1.516. [DOI] [PubMed] [Google Scholar]
  27. Espevik T., Otterlei M., Skjak-Braek G., Ryan L., Wright S.D., Sundan A. The involvement of CD14 in stimulation of cytokine production by uronic acid polymers. Eur J Immunol. 1993;23:255–261. doi: 10.1002/eji.1830230140. [DOI] [PubMed] [Google Scholar]
  28. Feire A.L., Koss H., Compton T. Cellular integrins function as entry receptors for human cytomegalovirus via a highly conserved disintegrin-like domain. Proc Natl Acad Sci U S A. 2004;101:15470–15475. doi: 10.1073/pnas.0406821101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Fitch M.T., van de Beek D. Drug Insight: steroids in CNS infectious diseases-new indications for an old therapy. Nat Clin Pract Neurol. 2008;4:97–104. doi: 10.1038/ncpneuro0713. [DOI] [PubMed] [Google Scholar]
  30. Gaudreault E., Fiola S., Olivier M., Gosselin J. Epstein-Barr virus induces MCP-1 secretion by human monocytes via TLR2. J Virol. 2007;81:8016–8024. doi: 10.1128/JVI.00403-07. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Gay N.J., Gangloff M. Structure and function of Toll receptors and their ligands. Annu Rev Biochem. 2007;76:141–165. doi: 10.1146/annurev.biochem.76.060305.151318. [DOI] [PubMed] [Google Scholar]
  32. Glaser R., Litsky M.L., Padgett D.A., Baiocchi R.A., Yang E.V., Chen M., Yeh P.E., Green-Church K.B., Caligiuri M.A., Williams M.V. EBV-encoded dUTPase induces immune dysregulation: Implications for the pathophysiology of EBV-associated disease. Virology. 2006;346:205–218. doi: 10.1016/j.virol.2005.10.034. [DOI] [PubMed] [Google Scholar]
  33. Gordon S. Pattern recognition receptors: doubling up for the innate immune response. Cell. 2002;111:927–930. doi: 10.1016/s0092-8674(02)01201-1. [DOI] [PubMed] [Google Scholar]
  34. Guo W., Giancotti F.G. Integrin signalling during tumour progression. Nat Rev Mol Cell Biol. 2004;5:816–826. doi: 10.1038/nrm1490. [DOI] [PubMed] [Google Scholar]
  35. Haller O., Kochs G., Weber F. The interferon response circuit: induction and suppression by pathogenic viruses. Virology. 2006;344:119–130. doi: 10.1016/j.virol.2005.09.024. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Harwani S.C., Lurain N.S., Zariffard M.R., Spear G.T. Differential inhibition of human cytomegalovirus (HCMV) by toll-like receptor ligands mediated by interferon-beta in human foreskin fibroblasts and cervical tissue. Virol J. 2007;4:133. doi: 10.1186/1743-422X-4-133. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Haziot A., Ferrero E., Kontgen F., Hijiya N., Yamamoto S., Silver J., Stewart C.L., Goyert S.M. Resistance to endotoxin shock and reduced dissemination of gram-negative bacteria in CD14-deficient mice. Immunity. 1996;4:407–414. doi: 10.1016/s1074-7613(00)80254-x. [DOI] [PubMed] [Google Scholar]
  38. Heise M.T., Virgin H.W.t. The T-cell-independent role of gamma interferon and tumor necrosis factor alpha in macrophage activation during murine cytomegalovirus and herpes simplex virus infections. J Virol. 1995;69:904–909. doi: 10.1128/jvi.69.2.904-909.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Hellman J., Tehan M.M., Warren H.S. Murein lipoprotein, peptidoglycan-associated lipoprotein, and outer membrane protein A are present in purified rough and smooth lipopolysaccharides. J Infect Dis. 2003;188:286–289. doi: 10.1086/376453. [DOI] [PubMed] [Google Scholar]
  40. Herbst-Kralovetz M., Pyles R. Toll-like receptors, innate immunity and HSV pathogenesis. Herpes. 2006;13:37–41. [PubMed] [Google Scholar]
  41. Hiscott J., Nguyen T.L., Arguello M., Nakhaei P., Paz S. Manipulation of the nuclear factor-kappaB pathway and the innate immune response by viruses. Oncogene. 2006;25:6844–6867. doi: 10.1038/sj.onc.1209941. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Horng T., Barton G.M., Flavell R.A., Medzhitov R. The adaptor molecule TIRAP provides signalling specificity for Toll-like receptors. Nature. 2002;420:329–333. doi: 10.1038/nature01180. [DOI] [PubMed] [Google Scholar]
  43. Hornung V., Rothenfusser S., Britsch S., Krug A., Jahrsdorfer B., Giese T., Endres S., Hartmann G. Quantitative expression of toll-like receptor 1–10 mRNA in cellular subsets of human peripheral blood mononuclear cells and sensitivity to CpG oligodeoxynucleotides. J Immunol. 2002;168:4531–4537. doi: 10.4049/jimmunol.168.9.4531. [DOI] [PubMed] [Google Scholar]
  44. Ingalls R.R., Heine H., Lien E., Yoshimura A., Golenbock D. Lipopolysaccharide recognition, CD14, and lipopolysaccharide receptors. Infect Dis Clin North Am. 1999;13:341–353. doi: 10.1016/s0891-5520(05)70078-7. [DOI] [PubMed] [Google Scholar]
  45. Janeway C.A., Jr. Approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harb Symp Quant Biol. 1989;54(Pt1):1–13. doi: 10.1101/sqb.1989.054.01.003. [DOI] [PubMed] [Google Scholar]
  46. Jiang Z., Georgel P., Du X., Shamel L., Sovath S., Mudd S., Huber M., Kalis C., Keck S., Galanos C., et al. CD14 is required for MyD88-independent LPS signaling. Nat Immunol. 2005;6:565–570. doi: 10.1038/ni1207. [DOI] [PubMed] [Google Scholar]
  47. Kawai T., Akira S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol. 2010;11:373–384. doi: 10.1038/ni.1863. [DOI] [PubMed] [Google Scholar]
  48. Kawai T., Akira S. Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity. 2011;34:637–650. doi: 10.1016/j.immuni.2011.05.006. [DOI] [PubMed] [Google Scholar]
  49. Kijpittayarit S., Eid A.J., Brown R.A., Paya C.V., Razonable R.R. Relationship between Toll-like receptor 2 polymorphism and cytomegalovirus disease after liver transplantation. Clin Infect Dis. 2007;44:1315–1320. doi: 10.1086/514339. [DOI] [PubMed] [Google Scholar]
  50. Kinashi T. Intracellular signalling controlling integrin activation in lymphocytes. Nat Rev Immunol. 2005;5:546–559. doi: 10.1038/nri1646. [DOI] [PubMed] [Google Scholar]
  51. Kirschning C.J., Wesche H., Merrill Ayres T., Rothe M. Human toll-like receptor 2 confers responsiveness to bacterial lipopolysaccharide. J Exp Med. 1998;188:2091–2097. doi: 10.1084/jem.188.11.2091. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Koenig A., Wolff M.H. Infectibility of separated peripheral blood mononuclear cell subpopulations by varicella-zoster virus (VZV) J Med Virol. 2003;70(Suppl1):S59–63. doi: 10.1002/jmv.10323. [DOI] [PubMed] [Google Scholar]
  53. Ku C.L., Yang K., Bustamante J., Puel A., von Bernuth H., Santos O.F., Lawrence T., Chang H.H., Al-Mousa H., Picard C., et al. Inherited disorders of human Toll-like receptor signaling: immunological implications. Immunol Rev. 2005;203:10–20. doi: 10.1111/j.0105-2896.2005.00235.x. [DOI] [PubMed] [Google Scholar]
  54. Kurt-Jones E.A., Belko J., Yu C., Newburger P.E., Wang J., Chan M., Knipe D.M., Finberg R.W. The role of toll-like receptors in herpes simplex infection in neonates. J Infect Dis. 2005;191:746–748. doi: 10.1086/427339. [DOI] [PubMed] [Google Scholar]
  55. Kurt-Jones E.A., Chan M., Zhou S., Wang J., Reed G., Bronson R., Arnold M.M., Knipe D.M., Finberg R.W. Herpes simplex virus 1 interaction with Toll-like receptor 2 contributes to lethal encephalitis. Proc Natl Acad Sci U S A. 2004;101:1315–1320. doi: 10.1073/pnas.0308057100. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. L C. Herpes Simplex Virus. In: Mandell G.L., Dolin R., editors. Principles and Practice of Infectious Diseases, B.J. New York: Churchill Livingstone; 2005. pp. 1762–1780. [Google Scholar]
  57. Lee H.K., Lee J., Tobias P.S. Two lipoproteins extracted from Escherichia coli K-12 LCD25 lipopolysaccharide are the major components responsible for Toll-like receptor 2-mediated signaling. J Immunol. 2002;168:4012–4017. doi: 10.4049/jimmunol.168.8.4012. [DOI] [PubMed] [Google Scholar]
  58. Lee R.M., White M.R., Hartshorn K.L. Influenza a viruses upregulate neutrophil toll-like receptor 2 expression and function. Scand J Immunol. 2006;63:81–89. doi: 10.1111/j.1365-3083.2005.01714.x. [DOI] [PubMed] [Google Scholar]
  59. Lorenz E., Mira J.P., Cornish K.L., Arbour N.C., Schwartz D.A. A novel polymorphism in the toll-like receptor 2 gene and its potential association with staphylococcal infection. Infect Immun. 2000;68:6398–6401. doi: 10.1128/iai.68.11.6398-6401.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Lundberg P., Ramakrishna C., Brown J., Tyszka J.M., Hamamura M., Hinton D.R., Kovats S., Nalcioglu O., Weinberg K., Openshaw H., et al. The immune response to herpes simplex virus type 1 infection in susceptible mice is a major cause of central nervous system pathology resulting in fatal encephalitis. J Virol. 2008;82:7078–7088. doi: 10.1128/JVI.00619-08. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. Marques C.P., Cheeran M.C., Palmquist J.M., Hu S., Lokensgard J.R. Microglia are the major cellular source of inducible nitric oxide synthase during experimental herpes encephalitis. J Neurovirol. 2008;14:229–238. doi: 10.1080/13550280802093927. [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Marques C.P., Cheeran M.C., Palmquist J.M., Hu S., Urban S.L., Lokensgard J.R. Prolonged microglial cell activation and lymphocyte infiltration following experimental herpes encephalitis. J Immunol. 2008;181:6417–6426. doi: 10.4049/jimmunol.181.9.6417. [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. Marques C.P., Hu S., Sheng W., Lokensgard J.R. Microglial cells initiate vigorous yet non-protective immune responses during HSV-1 brain infection. Virus Res. 2006;121:1–10. doi: 10.1016/j.virusres.2006.03.009. [DOI] [PubMed] [Google Scholar]
  64. McGeoch D.J., Dolan A., Ralph A.C. Toward a comprehensive phylogeny for mammalian and avian herpesviruses. J Virol. 2000;74:10401–10406. doi: 10.1128/jvi.74.22.10401-10406.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. McGettrick A.F., O’Neill L.A. The expanding family of MyD88-like adaptors in Toll-like receptor signal transduction. Mol Immunol. 2004;41:577–582. doi: 10.1016/j.molimm.2004.04.006. [DOI] [PubMed] [Google Scholar]
  66. Means T.K., Lien E., Yoshimura A., Wang S., Golenbock D.T., Fenton M.J. The CD14 ligands lipoarabinomannan and lipopolysaccharide differ in their requirement for Toll-like receptors. J Immunol. 1999;163:6748–6755. [PubMed] [Google Scholar]
  67. Medzhitov R. Toll-like receptors and innate immunity. Nat Rev Immunol. 2001;1:135–145. doi: 10.1038/35100529. [DOI] [PubMed] [Google Scholar]
  68. Medzhitov R., Preston-Hurlburt P., Janeway C.A., Jr. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature. 1997;388:394–397. doi: 10.1038/41131. [DOI] [PubMed] [Google Scholar]
  69. Melchjorsen J., Pedersen F.S., Mogensen S.C., Paludan S.R. Herpes simplex virus selectively induces expression of the CC chemokine RANTES/CCL5 in macrophages through a mechanism dependent on PKR and ICP0. J Virol. 2002;76:2780–2788. doi: 10.1128/JVI.76.6.2780-2788.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  70. Michaud F., Coulombe F., Gaudreault E., Kriz J., Gosselin J. Involvement of TLR2 in recognition of acute gammaherpesvirus-68 infection. PLoS One. 2010;5:e13742. doi: 10.1371/journal.pone.0013742. [DOI] [PMC free article] [PubMed] [Google Scholar]
  71. Mogensen T.H., Paludan S.R. Reading the viral signature by Toll-like receptors and other pattern recognition receptors. J Mol Med (Berl) 2005;83:180–192. doi: 10.1007/s00109-004-0620-6. [DOI] [PubMed] [Google Scholar]
  72. Morrison L.A. The Toll of herpes simplex virus infection. Trends Microbiol. 2004;12:353–356. doi: 10.1016/j.tim.2004.06.001. [DOI] [PubMed] [Google Scholar]
  73. Ogawa T., Asai Y., Hashimoto M., Uchida H. Bacterial fimbriae activate human peripheral blood monocytes utilizing TLR2, CD14 and CD11a/CD18 as cellular receptors. Eur J Immunol. 2002;32:2543–2550. doi: 10.1002/1521-4141(200209)32:9<2543::AID-IMMU2543>3.0.CO;2-2. [DOI] [PubMed] [Google Scholar]
  74. Ogus A.C., Yoldas B., Ozdemir T., Uguz A., Olcen S., Keser I., Coskun M., Cilli A., Yegin O. The Arg753GLn polymorphism of the human toll-like receptor 2 gene in tuberculosis disease. Eur Respir J. 2004;23:219–223. doi: 10.1183/09031936.03.00061703. [DOI] [PubMed] [Google Scholar]
  75. Olson J.K., Miller S.D. Microglia initiate central nervous system innate and adaptive immune responses through multiple TLRs. J Immunol. 2004;173:3916–3924. doi: 10.4049/jimmunol.173.6.3916. [DOI] [PubMed] [Google Scholar]
  76. Paludan S.R. Requirements for the induction of interleukin-6 by herpes simplex virus-infected leukocytes. J Virol. 2001;75:8008–8015. doi: 10.1128/JVI.75.17.8008-8015.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  77. Pellett P. R.B. The family Herpesviridae: a brief introduction. In: Knipe H.P., editor. Fields virology. Philadelphia: Lippincott Williams and Wilkins; 2007. pp. 2479–2500. [Google Scholar]
  78. Randall R.E., Goodbourn S. Interferons and viruses: an interplay between induction, signalling, antiviral responses and virus countermeasures. J Gen Virol. 2008;89:1–47. doi: 10.1099/vir.0.83391-0. [DOI] [PubMed] [Google Scholar]
  79. Reske A., Pollara G., Krummenacher C., Katz D.R., Chain B.M. Glycoprotein-dependent and TLR2-independent innate immune recognition of herpes simplex virus-1 by dendritic cells. J Immunol. 2008;180:7525–7536. doi: 10.4049/jimmunol.180.11.7525. [DOI] [PubMed] [Google Scholar]
  80. Rock F.L., Hardiman G., Timans J.C., Kastelein R.A., Bazan J.F. A family of human receptors structurally related to Drosophila Toll. Proc Natl Acad Sci U S A. 1998;95:588–593. doi: 10.1073/pnas.95.2.588. [DOI] [PMC free article] [PubMed] [Google Scholar]
  81. Roizman B. K.D., Whitley R.J. Herpes simplex viruses. In: Knipe H.P., editor. Fields Virology. Philadelphia: Lippincott Williams and Wilkins; 2007. pp. 2501–2602. [Google Scholar]
  82. Roy C.R., Mocarski E.S. Pathogen subversion of cell-intrinsic innate immunity. Nat Immunol. 2007;8:1179–1187. doi: 10.1038/ni1528. [DOI] [PubMed] [Google Scholar]
  83. Sabroe I., Read R.C., Whyte M.K., Dockrell D.H., Vogel S.N., Dower S.K. Toll-like receptors in health and disease: complex questions remain. J Immunol. 2003;171:1630–1635. doi: 10.4049/jimmunol.171.4.1630. [DOI] [PubMed] [Google Scholar]
  84. Sarangi P.P., Kim B., Kurt-Jones E., Rouse B.T. Innate recognition network driving herpes simplex virus-induced corneal immunopathology: role of the toll pathway in early inflammatory events in stromal keratitis. J Virol. 2007;81:11128–11138. doi: 10.1128/JVI.01008-07. [DOI] [PMC free article] [PubMed] [Google Scholar]
  85. Sarawar S.R., Cardin R.D., Brooks J.W., Mehrpooya M., Tripp R.A., Doherty P.C. Cytokine production in the immune response to murine gammaherpesvirus 68. J Virol. 1996;70:3264–3268. doi: 10.1128/jvi.70.5.3264-3268.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  86. Sarawar S.R., Lee B.J., Giannoni F. Cytokines and costimulatory molecules in the immune response to murine gammaherpesvirus-68. Viral Immunol. 2004;17:3–11. doi: 10.1089/088282404322875412. [DOI] [PubMed] [Google Scholar]
  87. Sato A., Linehan M.M., Iwasaki A. Dual recognition of herpes simplex viruses by TLR2 and TLR9 in dendritic cells. Proc Natl Acad Sci U S A. 2006;103:17343–17348. doi: 10.1073/pnas.0605102103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  88. Schroder N.W., Morath S., Alexander C., Hamann L., Hartung T., Zahringer U., Gobel U.B., Weber J.R., Schumann R.R. Lipoteichoic acid (LTA) of Streptococcus pneumoniae and Staphylococcus aureus activates immune cells via Toll-like receptor (TLR)-2, lipopolysaccharide-binding protein (LBP), and CD14, whereas TLR-4 and MD-2 are not involved. J Biol Chem. 2003;278:15587–15594. doi: 10.1074/jbc.M212829200. [DOI] [PubMed] [Google Scholar]
  89. Schwandner R., Dziarski R., Wesche H., Rothe M., Kirschning C.J. Peptidoglycan- and lipoteichoic acid-induced cell activation is mediated by toll-like receptor 2. J Biol Chem. 1999;274:17406–17409. doi: 10.1074/jbc.274.25.17406. [DOI] [PubMed] [Google Scholar]
  90. Schwartz D.A., Cook D.N. Polymorphisms of the Toll-like receptors and human disease. Clin Infect Dis. 2005;41(Suppl7):S403–407. doi: 10.1086/431985. [DOI] [PubMed] [Google Scholar]
  91. Sergerie Y., Boivin G., Gosselin D., Rivest S. Delayed but not early glucocorticoid treatment protects the host during experimental herpes simplex virus encephalitis in mice. J Infect Dis. 2007;195:817–825. doi: 10.1086/511987. [DOI] [PubMed] [Google Scholar]
  92. Simmen K.A., Singh J., Luukkonen B.G., Lopper M., Bittner A., Miller N.E., Jackson M.R., Compton T., Fruh K. Global modulation of cellular transcription by human cytomegalovirus is initiated by viral glycoprotein B. Proc Natl Acad Sci U S A. 2001;98:7140–7145. doi: 10.1073/pnas.121177598. [DOI] [PMC free article] [PubMed] [Google Scholar]
  93. Soderberg-Naucler C., Nelson J.Y. Human cytomegalovirus latency and reactivation — a delicate balance between the virus and its host’s immune system. Intervirology. 1999;42:314–321. doi: 10.1159/000053966. [DOI] [PubMed] [Google Scholar]
  94. Sorensen L.N., Reinert L.S., Malmgaard L., Bartholdy C., Thomsen A.R., Paludan S.R. TLR2 and TLR9 synergistically control herpes simplex virus infection in the brain. J Immunol. 2008;181:8604–8612. doi: 10.4049/jimmunol.181.12.8604. [DOI] [PubMed] [Google Scholar]
  95. Szomolanyi-Tsuda E., Liang X., Welsh R.M., Kurt-Jones E.A., Finberg R.W. Role for TLR2 in NK cell-mediated control of murine cytomegalovirus in vivo. J Virol. 2006;80:4286–4291. doi: 10.1128/JVI.80.9.4286-4291.2006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  96. Takeda K., Akira S. Toll receptors and pathogen resistance. Cell Microbiol. 2003;5:143–153. doi: 10.1046/j.1462-5822.2003.00264.x. [DOI] [PubMed] [Google Scholar]
  97. Takeda K., Kaisho T., Akira S. Toll-like receptors. Annu Rev Immunol. 2003;21:335–376. doi: 10.1146/annurev.immunol.21.120601.141126. [DOI] [PubMed] [Google Scholar]
  98. Takeuchi O., Kawai T., Sanjo H., Copeland N.G., Gilbert D.J., Jenkins N.A., Takeda K., Akira S. TLR6: A novel member of an expanding toll-like receptor family. Gene. 1999;231:59–65. doi: 10.1016/s0378-1119(99)00098-0. [DOI] [PubMed] [Google Scholar]
  99. Texereau J., Chiche J.D., Taylor W., Choukroun G., Comba B., Mira J.P. The importance of Toll-like receptor 2 polymorphisms in severe infections. Clin Infect Dis. 2005;41(Suppl7):S408–415. doi: 10.1086/431990. [DOI] [PubMed] [Google Scholar]
  100. Thorley-Lawson D.A., Duca K.A., Shapiro M. Epstein-Barr virus: a paradigm for persistent infection — for real and in virtual reality. Trends Immunol. 2008;29:195–201. doi: 10.1016/j.it.2008.01.006. [DOI] [PubMed] [Google Scholar]
  101. Torigo S., Ihara T., Kamiya H. IL-12, IFN-gamma, and TNF-alpha released from mononuclear cells inhibit the spread of varicella-zoster virus at an early stage of varicella. Microbiol Immunol. 2000;44:1027–1031. doi: 10.1111/j.1348-0421.2000.tb02599.x. [DOI] [PubMed] [Google Scholar]
  102. Town T., Jeng D., Alexopoulou L., Tan J., Flavell R.A. Microglia recognize double-stranded RNA via TLR3. J Immunol. 2006;176:3804–3812. doi: 10.4049/jimmunol.176.6.3804. [DOI] [PubMed] [Google Scholar]
  103. Triantafilou M., Triantafilou K. Lipopolysaccharide recognition: CD14, TLRs and the LPS-activation cluster. Trends Immunol. 2002;23:301–304. doi: 10.1016/s1471-4906(02)02233-0. [DOI] [PubMed] [Google Scholar]
  104. Tsuchida T., Kawai T., Akira S. Inhibition of IRF3-dependent antiviral responses by cellular and viral proteins. Cell Res. 2009;19:3–4. doi: 10.1038/cr.2009.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  105. Underhill D.M., Ozinsky A., Hajjar A.M., Stevens A., Wilson C.B., Bassetti M., Aderem A. The Toll-like receptor 2 is recruited to macrophage phagosomes and discriminates between pathogens. Nature. 1999;401:811–815. doi: 10.1038/44605. [DOI] [PubMed] [Google Scholar]
  106. Unterholzner L., Bowie A.G. The interplay between viruses and innate immune signaling: recent insights and therapeutic opportunities. Biochem Pharmacol. 2008;75:589–602. doi: 10.1016/j.bcp.2007.07.043. [DOI] [PubMed] [Google Scholar]
  107. van Lint A.L., Murawski M.R., Goodbody R.E., Severa M., Fitzgerald K.A., Finberg R.W., Knipe D.M., Kurt-Jones E.A. Herpes simplex virus immediate-early ICP0 protein inhibits Toll-like receptor 2-dependent inflammatory responses and NF-kappaB signaling. J Virol. 2010;84:10802–10811. doi: 10.1128/JVI.00063-10. [DOI] [PMC free article] [PubMed] [Google Scholar]
  108. Vollstedt S., Franchini M., Alber G., Ackermann M., Suter M. Interleukin-12- and gamma interferon-dependent innate immunity are essential and sufficient for long-term survival of passively immunized mice infected with herpes simplex virus type 1. J Virol. 2001;75:9596–9600. doi: 10.1128/JVI.75.20.9596-9600.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  109. von Aulock S., Schroder N.W., Traub S., Gueinzius K., Lorenz E., Hartung T., Schumann R.R., Hermann C. Heterozygous toll-like receptor 2 polymorphism does not affect lipoteichoic acid-induced chemokine and inflammatory responses. Infect Immun. 2004;72:1828–1831. doi: 10.1128/IAI.72.3.1828-1831.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  110. Waldman W.J., Williams M.V., Jr., Lemeshow S., Binkley P., Guttridge D., Kiecolt-Glaser J.K., Knight D.A., Ladner K.J., Glaser R. Epstein-Barr virus-encoded dUTPase enhances proinflammatory cytokine production by macrophages in contact with endothelial cells: evidence for depression-induced atherosclerotic risk. Brain Behav Immun. 2008;22:215–223. doi: 10.1016/j.bbi.2007.07.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  111. Wang J.P., Kurt-Jones E.A., Shin O.S., Manchak M.D., Levin M.J., Finberg R.W. Varicella-zoster virus activates inflammatory cytokines in human monocytes and macrophages via Toll-like receptor 2. J Virol. 2005;79:12658–12666. doi: 10.1128/JVI.79.20.12658-12666.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  112. Wang X., Huang D.Y., Huong S.M., Huang E.S. Integrin alphavbeta3 is a coreceptor for human cytomegalovirus. Nat Med. 2005;11:515–521. doi: 10.1038/nm1236. [DOI] [PMC free article] [PubMed] [Google Scholar]
  113. Weber F., Haller O. Viral suppression of the interferon system. Biochimie. 2007;89:836–842. doi: 10.1016/j.biochi.2007.01.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  114. Weber O. Novel mouse models for the investigation of experimental drugs with activity against human varicella-zoster virus. Antivir Chem Chemother. 2000;11:283–290. doi: 10.1177/095632020001100404. [DOI] [PubMed] [Google Scholar]
  115. Weidemann B., Schletter J., Dziarski R., Kusumoto S., Stelter F., Rietschel E.T., Flad H.D., Ulmer A.J. Specific binding of soluble peptidoglycan and muramyldipeptide to CD14 on human monocytes. Infect Immun. 1997;65:858–864. doi: 10.1128/iai.65.3.858-864.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  116. Whitley R.J., Whitley H. J. Cercopithecine herpesvirus (B virus) In: Knipe H.P., editor. Fields Virology. Philadelphia: Lippincott Williams and Wilkins; 2001. pp. 2835–2848. [Google Scholar]
  117. Wright S.D., Ramos R.A., Tobias P.S., Ulevitch R.J., Mathison J.C. CD14, a receptor for complexes of lipopolysaccharide (LPS) and LPS binding protein. Science. 1990;249:1431–1433. doi: 10.1126/science.1698311. [DOI] [PubMed] [Google Scholar]
  118. Yang R.B., Mark M.R., Gray A., Huang A., Xie M.H., Zhang M., Goddard A., Wood W.I., Gurney A.L., Godowski P.J. Toll-like receptor-2 mediates lipopolysaccharide-induced cellular signalling. Nature. 1998;395:284–288. doi: 10.1038/26239. [DOI] [PubMed] [Google Scholar]
  119. Zarember K.A., Godowski P.J. Tissue expression of human Toll-like receptors and differential regulation of Toll-like receptor mRNAs in leukocytes in response to microbes, their products, and cytokines. J Immunol. 2002;168:554–561. doi: 10.4049/jimmunol.168.2.554. [DOI] [PubMed] [Google Scholar]
  120. Zhang D., Zhang G., Hayden M.S., Greenblatt M.B., Bussey C., Flavell R.A., Ghosh S. A toll-like receptor that prevents infection by uropathogenic bacteria. Science. 2004;303:1522–1526. doi: 10.1126/science.1094351. [DOI] [PubMed] [Google Scholar]
  121. Zhang G., Ghosh S. Toll-like receptor-mediated NF-kappaB activation: a phylogenetically conserved paradigm in innate immunity. J Clin Invest. 2001;107:13–19. doi: 10.1172/JCI11837. [DOI] [PMC free article] [PubMed] [Google Scholar]
  122. Zhou S., Kurt-Jones E.A., Mandell L., Cerny A., Chan M., Golenbock D.T., Finberg R.W. MyD88 is critical for the development of innate and adaptive immunity during acute lymphocytic choriomeningitis virus infection. Eur J Immunol. 2005;35:822–830. doi: 10.1002/eji.200425730. [DOI] [PubMed] [Google Scholar]
  123. Zhu J., Martinez J., Huang X., Yang Y. Innate immunity against vaccinia virus is mediated by TLR2 and requires TLR-independent production of IFN-beta. Blood. 2007;109:619–625. doi: 10.1182/blood-2006-06-027136. [DOI] [PMC free article] [PubMed] [Google Scholar]

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