Immune Signatures and Systems Biology of Vaccines

  • F. M. Buonaguro
  • M. L. Tornesello
  • L. Buonaguro


Vaccines represent a strategic successful tool to prevent or contain diseases with high morbidity or mortality. However, despite the extensive and wide use, we still have a limited knowledge on mechanisms underlying the effective elicitation of protective immune responses by vaccines, which represents the final outcome of a effective cooperation between the innate and adaptive arms of the immunity.

Immunity is made of a multifaceted set of integrated responses involving a dynamic interaction of thousands of molecules, whose list is constantly updated to fill the several empty spaces of this puzzle. The recent development of new technologies and computational tools allows to perform a comprehensive and quantitative analysis of the interactions between all of the components of immunity over time.

Here we review the role of the innate immunity in the host response to vaccine antigens and the potential of systems biology in providing relevant and novel insights in the mechanisms of action of vaccines in order to improve their design and effectiveness.


Innate immunity PRRs PAMPs TLRs APCs Adaptive immunity Vaccine Adjuvants Immune memory Systems biology Immunogenomics Proteomics 


  1. Abbas AR, Baldwin D, Ma Y et al. (2005) Immune response in silico (IRIS): immune-specific genes identified from a compendium of microarray expression data. Genes Immun 6:319–331.PubMedCrossRefGoogle Scholar
  2. Agrawal S, Agrawal A, Doughty B et al. (2003) Cutting edge: different Toll-like receptor agonists instruct dendritic cells to induce distinct Th responses via differential modulation of extracellular signal-regulated kinase-mitogen-activated protein kinase and c-Fos. J Immunol 171:4984–4989.PubMedGoogle Scholar
  3. Ahmad-Nejad P, Hacker H, Rutz M et al. (2002) Bacterial CpG-DNA and lipopolysaccharides activate Toll-like receptors at distinct cellular compartments. Eur J Immunol 32:1958–1968.PubMedCrossRefGoogle Scholar
  4. Akira S, Uematsu S, Takeuchi O (2006) Pathogen recognition and innate immunity. Cell 124:783–801.PubMedCrossRefGoogle Scholar
  5. Alderson MR, Smith CA, Tough TW et al. (1994) Molecular and biological characterization of human 4-1BB and its ligand. Eur J Immunol 24:2219–2227.PubMedCrossRefGoogle Scholar
  6. Alexopoulou L, Holt AC, Medzhitov R et al. (2001) Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature 413:732–738.PubMedCrossRefGoogle Scholar
  7. Alexopoulou L, Thomas V, Schnare M et al. (2002) Hyporesponsiveness to vaccination with Borrelia burgdorferi OspA in humans and in TLR1- and TLR2-deficient mice. Nat Med 8:878–884.PubMedGoogle Scholar
  8. Alizadeh AA and Staudt LM (2000) Genomic-scale gene expression profiling of normal and malignant immune cells. Curr Opin Immunol 12:219–225.PubMedCrossRefGoogle Scholar
  9. Allen A, Obaro S, Bojang K et al. (2003) Variation in Toll-like receptor 4 and susceptibility to group A meningococcal meningitis in Gambian children. Pediatr Infect Dis J 22:1018–1019.PubMedCrossRefGoogle Scholar
  10. Alvarez D, Vollmann EH, von Andrian UH (2008) Mechanisms and consequences of dendritic cell migration. Immunity 29:325–342.PubMedCrossRefGoogle Scholar
  11. Andres PG, Howland KC, Nirula A et al. (2004) Distinct regions in the CD28 cytoplasmic domain are required for T helper type 2 differentiation. Nat Immunol 5:435–442.PubMedCrossRefGoogle Scholar
  12. Aricò E, Wang E, Tornesello ML et al. (2005) Immature monocyte derived dendritic cells gene expression profile in response to Virus-Like Particles stimulation. J Transl Med 3:45PubMedCrossRefGoogle Scholar
  13. Asahi-Ozaki Y, Itamura S, Ichinohe T et al. (2006) Intranasal administration of adjuvant-combined recombinant influenza virus HA vaccine protects mice from the lethal H5N1 virus infection. Microbes Infect 8:2706–2714.PubMedCrossRefGoogle Scholar
  14. Assudani D, Cho HI, DeVito N et al. (2008) In vivo expansion, persistence, and function of peptide vaccine-induced CD8 T cells occur independently of CD4 T cells. Cancer Res 68:9892–9899.PubMedCrossRefGoogle Scholar
  15. Bachmann MF, Zinkernagel RM, Oxenius A (1998) Immune responses in the absence of costimulation: viruses know the trick. J Immunol 161:5791–5794.PubMedGoogle Scholar
  16. Bakal C, Linding R, Llense F et al. (2008) Phosphorylation networks regulating JNK activity in diverse genetic backgrounds. Science 322:453–456.PubMedCrossRefGoogle Scholar
  17. Baldridge JR and Crane RT (1999) Monophosphoryl lipid A (MPL) formulations for the next generation of vaccines. Methods 19:103–107.PubMedCrossRefGoogle Scholar
  18. Banchereau J and Steinman RM (1998) Dendritic cells and the control of immunity. Nature 392:245–252.PubMedCrossRefGoogle Scholar
  19. Banchereau J, Klechevsky E, Schmitt N et al. (2009) Harnessing human dendritic cell subsets to design novel vaccines. Ann N Y Acad Sci 1174:24–32.PubMedCrossRefGoogle Scholar
  20. Banus S, Bottema RW, Siezen CL et al. (2007) Toll-like receptor 4 polymorphism associated with the response to whole-cell pertussis vaccination in children from the KOALA study. Clin Vaccine Immunol 14:1377–1380.PubMedCrossRefGoogle Scholar
  21. Belshe RB, Edwards KM, Vesikari T et al. (2007) Live attenuated versus inactivated influenza vaccine in infants and young children. N Engl J Med 356:685–696.PubMedCrossRefGoogle Scholar
  22. Beltinger CP, White PS, Maris JM et al. (1996) Physical mapping and genomic structure of the human TNFR2 gene. Genomics 35:94–100.PubMedCrossRefGoogle Scholar
  23. Beutler B (2004) Inferences, questions and possibilities in Toll-like receptor signalling. Nature 430:257–263.PubMedCrossRefGoogle Scholar
  24. Bhat NK, Thompson CB, Lindsten T et al. (1990) Reciprocal expression of human ETS1 and ETS2 genes during T-cell activation: regulatory role for the protooncogene ETS1. Proc Natl Acad Sci U S A 87:3723–3727.PubMedCrossRefGoogle Scholar
  25. Blumenthal SG, Aichele G, Wirth T et al. (1999) Regulation of the human interleukin-5 promoter by Ets transcription factors. Ets1 and Ets2, but not Elf-1, cooperate with GATA3 and HTLV-I Tax1. J Biol Chem 274:12910–12916.PubMedCrossRefGoogle Scholar
  26. Bochud PY, Bochud M, Telenti A et al. (2007a) Innate immunogenetics: a tool for exploring new frontiers of host defence. Lancet Infect Dis 7:531–542.PubMedCrossRefGoogle Scholar
  27. Bochud PY, Hersberger M, Taffe P et al. (2007b) Polymorphisms in Toll-like receptor 9 influence the clinical course of HIV-1 infection. AIDS 21:441–446.PubMedCrossRefGoogle Scholar
  28. Bowie A and O’Neill LA (2000) The interleukin-1 receptor/Toll-like receptor superfamily: signal generators for pro-inflammatory interleukins and microbial products. J Leukoc Biol 67:508–514.PubMedGoogle Scholar
  29. Bowie AG and Unterholzner L (2008) Viral evasion and subversion of pattern-recognition receptor signalling. Nat Rev Immunol 8:911–922.PubMedCrossRefGoogle Scholar
  30. Brass AL, Dykxhoorn DM, Benita Y et al. (2008) Identification of host proteins required for HIV infection through a functional genomic screen. Science 319:921–926.PubMedCrossRefGoogle Scholar
  31. Brightbill HD, Libraty DH, Krutzik SR et al. (1999) Host defense mechanisms triggered by microbial lipoproteins through toll-like receptors. Science 285:732–736.PubMedCrossRefGoogle Scholar
  32. Bulut Y, Faure E, Thomas L et al. (2001) Cooperation of Toll-like receptor 2 and 6 for cellular activation by soluble tuberculosis factor and Borrelia burgdorferi outer surface protein A lipoprotein: role of Toll-interacting protein and IL-1 receptor signaling molecules in Toll-like receptor 2 signaling. J Immunol 167:987–994.PubMedGoogle Scholar
  33. Buonaguro L, Racioppi L, Tornesello ML et al. (2002) Induction of neutralizing antibodies and CTLs in Balb/c mice immunized with Virus-like Particles presenting a gp120 molecule from a HIV-1 isolate of clade A (HIV-VLPAs). Antiviral Res 54:189–201.PubMedCrossRefGoogle Scholar
  34. Buonaguro L, Visciano ML, Tornesello ML et al. (2005) Induction of systemic and mucosal cross-clade neutralizing antibodies in BALB/c mice immunized with human immunodeficiency virus type 1 clade A virus-like particles administered by different routes of inoculation. J Virol 79:7059–7067.PubMedCrossRefGoogle Scholar
  35. Buonaguro L, Tornesello ML, Tagliamonte M et al. (2006) Baculovirus-derived human immunodeficiency virus type 1 virus-like particles activate dendritic cells and induce ex vivo T-cell responses. J Virol 80:9134–9143.PubMedCrossRefGoogle Scholar
  36. Buonaguro L, Devito C, Tornesello ML et al. (2007) DNA-VLP prime-boost intra-nasal immunization induces cellular and humoral anti-HIV-1 systemic and mucosal immunity with cross-clade neutralizing activity. Vaccine 25:5968–5977.PubMedCrossRefGoogle Scholar
  37. Buonaguro L, Monaco A, Arico E et al. (2008) Gene expression profile of peripheral blood mononuclear cells in response to HIV-VLPs stimulation. BMC Bioinformatics 9(Suppl 2):S5PubMedCrossRefGoogle Scholar
  38. Buonaguro L, Tornesello ML, Gallo RC et al. (2009a) Th2 polarization in peripheral blood mononuclear cells from human immunodeficiency virus (HIV)-infected subjects, as activated by HIV virus-like particles. J Virol 83:304–313.PubMedCrossRefGoogle Scholar
  39. Buonaguro L, Tornesello ML, Jewis GK et al. (2009b) Short communication: limited induction of IL-10 in PBMCs from HIV-infected subjects treated with HIV-VLPs. AIDS Res Hum Retroviruses 25:819–822.PubMedCrossRefGoogle Scholar
  40. Ceol A, Chatr AA, Licata L et al. (2010) MINT, the molecular interaction database: 2009 update. Nucleic Acids Res 38:D532–D539.PubMedCrossRefGoogle Scholar
  41. Chatr-aryamontri A, Ceol A, Peluso D et al. (2009) VirusMINT: a viral protein interaction database. Nucleic Acids Res 37:D669–D673.PubMedCrossRefGoogle Scholar
  42. Chaussabel D, Quinn C, Shen J et al. (2008) A modular analysis framework for blood genomics studies: application to systemic lupus erythematosus. Immunity 29:150–164.PubMedCrossRefGoogle Scholar
  43. de Chassey B, Navratil V, Tafforeau L et al. (2008) Hepatitis C virus infection protein network. Mol Syst Biol 4:230PubMedGoogle Scholar
  44. de la Torre MS, Torres C, Nieto G et al. (2008) Vitamin D receptor gene haplotypes and susceptibility to HIV-1 infection in injection drug users. J Infect Dis 197:405–410.PubMedCrossRefGoogle Scholar
  45. den Dunnen J, Gringhuis SI, Geijtenbeek TB (2009) Innate signaling by the C-type lectin DC-SIGN dictates immune responses. Cancer Immunol Immunother 58:1149–1157.CrossRefGoogle Scholar
  46. Dhiman N, Ovsyannikova IG, Vierkant RA et al. (2008) Associations between SNPs in toll-like receptors and related intracellular signaling molecules and immune responses to measles vaccine: preliminary results. Vaccine 26:1731–1736.PubMedCrossRefGoogle Scholar
  47. Dickinson AM and Holler E (2008) Polymorphisms of cytokine and innate immunity genes and GVHD. Best Pract Res Clin Haematol 21:149–164.PubMedCrossRefGoogle Scholar
  48. Didierlaurent A, Brissoni B, Velin D et al. (2006) Tollip regulates proinflammatory responses to interleukin-1 and lipopolysaccharide. Mol Cell Biol 26:735–742.PubMedCrossRefGoogle Scholar
  49. Diebold SS (2008) Recognition of viral single-stranded RNA by Toll-like receptors. Adv Drug Deliv Rev 60:813–823.PubMedCrossRefGoogle Scholar
  50. Diebold SS, Kaisho T, Hemmi H et al. (2004) Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science 303:1529–1531.PubMedCrossRefGoogle Scholar
  51. Dillon S, Agrawal A, van DT et al. (2004) A Toll-like receptor 2 ligand stimulates Th2 responses in vivo, via induction of extracellular signal-regulated kinase mitogen-activated protein kinase and c-Fos in dendritic cells. J Immunol 172:4733–4743.Google Scholar
  52. Dillon S, Agrawal S, Banerjee K et al. (2006) Yeast zymosan, a stimulus for TLR2 and dectin-1, induces regulatory antigen-presenting cells and immunological tolerance. J Clin Invest 116:916–928.PubMedCrossRefGoogle Scholar
  53. Draper SJ and Heeney JL (2010) Viruses as vaccine vectors for infectious diseases and cancer. Nat Rev Microbiol 8:62–73.PubMedCrossRefGoogle Scholar
  54. Driscoll T, Dyer MD, Murali TM et al. (2009) PIG--the pathogen interaction gateway. Nucleic Acids Res 37:D647–D650.PubMedCrossRefGoogle Scholar
  55. Elkon R, Linhart C, Halperin Y et al. (2007) Functional genomic delineation of TLR-induced transcriptional networks. BMC Genomics 8:394PubMedCrossRefGoogle Scholar
  56. Ferwerda B, McCall MB, Alonso S et al. (2007) TLR4 polymorphisms, infectious diseases, and evolutionary pressure during migration of modern humans. Proc Natl Acad Sci U S A 104:16645–16650.PubMedCrossRefGoogle Scholar
  57. Ferwerda B, McCall MB, Verheijen K et al. (2008) Functional consequences of toll-like receptor 4 polymorphisms. Mol Med 14:346–352.PubMedCrossRefGoogle Scholar
  58. Fraser CK, Diener KR, Brown MP et al. (2007) Improving vaccines by incorporating immunological coadjuvants. Expert Rev Vaccines 6:559–578.PubMedCrossRefGoogle Scholar
  59. Gallant S and Gilkeson G (2006) ETS transcription factors and regulation of immunity. Arch Immunol Ther Exp (Warsz ) 54:149–163.CrossRefGoogle Scholar
  60. Gardy JL, Lynn DJ, Brinkman FS et al. (2009) Enabling a systems biology approach to immunology: focus on innate immunity. Trends Immunol 30:249–262.PubMedCrossRefGoogle Scholar
  61. Gaucher D, Therrien R, Kettaf N et al. (2008) Yellow fever vaccine induces integrated multilineage and polyfunctional immune responses. J Exp Med 205:3119–3131.PubMedCrossRefGoogle Scholar
  62. Geijtenbeek TB, van Vliet SJ, Engering A et al. (2004) Self- and nonself-recognition by C-type lectins on dendritic cells. Annu Rev Immunol 22:33–54.PubMedCrossRefGoogle Scholar
  63. Gelman AE, Zhang J, Choi Y et al. (2004) Toll-like receptor ligands directly promote activated CD4+ T cell survival. J Immunol 172:6065–6073.PubMedGoogle Scholar
  64. Georgel P, Macquin C, Bahram S (2009) The heterogeneous allelic repertoire of human toll-like receptor (TLR) genes. PLoS One 4:e7803PubMedCrossRefGoogle Scholar
  65. Germain RN (2004) An innately interesting decade of research in immunology. Nat Med 10:1307–1320.PubMedCrossRefGoogle Scholar
  66. Gilliet M, Cao W, Liu YJ (2008) Plasmacytoid dendritic cells: sensing nucleic acids in viral infection and autoimmune diseases. Nat Rev Immunol 8:594–606.PubMedCrossRefGoogle Scholar
  67. Gluck R, Moser C, Metcalfe IC (2004) Influenza virosomes as an efficient system for adjuvanted vaccine delivery. Expert Opin Biol Ther 4:1139–1145.PubMedCrossRefGoogle Scholar
  68. Groux H, O’Garra A, Bigler M et al. (1997) A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 389:737–742.PubMedCrossRefGoogle Scholar
  69. Hayashi F, Smith KD, Ozinsky A et al. (2001) The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5. Nature 410:1099–1103.PubMedCrossRefGoogle Scholar
  70. Heil F, Hemmi H, Hochrein H et al. (2004) Species-specific recognition of single-stranded RNA via toll- like receptor 7 and 8. Science 303:1526–1529.PubMedCrossRefGoogle Scholar
  71. Hemmi H, Takeuchi O, Kawai T et al. (2000) A Toll-like receptor recognizes bacterial DNA. Nature 408:740–745.PubMedCrossRefGoogle Scholar
  72. Hemmi H, Kaisho T, Takeuchi O et al. (2002) Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nat Immunol 3:196–200.PubMedCrossRefGoogle Scholar
  73. Hemmi H, Kaisho T, Takeda K et al. (2003) The roles of Toll-like receptor 9, MyD88, and DNA-dependent protein kinase catalytic subunit in the effects of two distinct CpG DNAs on dendritic cell subsets. J Immunol 170:3059–3064.PubMedGoogle Scholar
  74. Heng TS and Painter MW (2008) The Immunological Genome Project: networks of gene expression in immune cells. Nat Immunol 9:1091–1094.PubMedCrossRefGoogle Scholar
  75. Hervas-Stubbs S, Olivier A, Boisgerault F et al. (2007) TLR3 ligand stimulates fully functional memory CD8+ T cells in the absence of CD4+ T-cell help. Blood 109:5318–5326.PubMedCrossRefGoogle Scholar
  76. Hijikata A, Kitamura H, Kimura Y et al. (2007) Construction of an open-access database that integrates cross-reference information from the transcriptome and proteome of immune cells. Bioinformatics 23:2934–2941.PubMedCrossRefGoogle Scholar
  77. Hoek KL, Carlesso G, Clark ES et al. (2009) Absence of mature peripheral B cell populations in mice with concomitant defects in B cell receptor and BAFF-R signaling. J Immunol 183:5630–5643.PubMedCrossRefGoogle Scholar
  78. Holzer BR, Hatz C, Schmidt-Sissolak D et al. (1996) Immunogenicity and adverse effects of inactivated virosome versus alum-adsorbed hepatitis A vaccine: a randomized controlled trial. Vaccine 14:982–986.PubMedCrossRefGoogle Scholar
  79. Houghton M and Abrignani S (2005) Prospects for a vaccine against the hepatitis C virus. Nature 436:961–966.PubMedCrossRefGoogle Scholar
  80. Hu J, Sealfon SC, Hayot F et al. (2007) Chromosome-specific and noisy IFNB1 transcription in individual virus-infected human primary dendritic cells. Nucleic Acids Res 35:5232–5241.PubMedCrossRefGoogle Scholar
  81. Huleatt JW, Nakaar V, Desai P et al. (2008) Potent immunogenicity and efficacy of a universal influenza vaccine candidate comprising a recombinant fusion protein linking influenza M2e to the TLR5 ligand flagellin. Vaccine 26:201–214.PubMedCrossRefGoogle Scholar
  82. Inohara, Chamaillard, McDonald C et al. (2005) NOD-LRR proteins: role in host-microbial interactions and inflammatory disease. Annu Rev Biochem 74:355–383.PubMedCrossRefGoogle Scholar
  83. Ishii KJ and Akira S (2007) Toll or toll-free adjuvant path toward the optimal vaccine development. J Clin Immunol 27:363–371.PubMedCrossRefGoogle Scholar
  84. Janeway CA, Jr. and Medzhitov R (2002) Innate immune recognition. Annu Rev Immunol 20:197–216.PubMedCrossRefGoogle Scholar
  85. Jenner RG and Young RA (2005) Insights into host responses against pathogens from transcriptional profiling. Nat Rev Microbiol 3:281–294.PubMedCrossRefGoogle Scholar
  86. Johnston D, Zaidi B, Bystryn JC (2007) TLR7 imidazoquinoline ligand 3M-019 is a potent adjuvant for pure protein prototype vaccines. Cancer Immunol Immunother 56:1133–1141.PubMedCrossRefGoogle Scholar
  87. Kaech SM, Wherry EJ, Ahmed R (2002) Effector and memory T-cell differentiation: implications for vaccine development. Nat Rev Immunol 2:251–262.PubMedCrossRefGoogle Scholar
  88. Kang SM and Compans RW (2009) Host responses from innate to adaptive immunity after vaccination: molecular and cellular events. Mol Cells 27:5–14.PubMedCrossRefGoogle Scholar
  89. Kawabe T, Naka T, Yoshida K et al. (1994) The immune responses in CD40-deficient mice: impaired immunoglobulin class switching and germinal center formation. Immunity 1:167–178.PubMedCrossRefGoogle Scholar
  90. Keam SJ and Harper DM (2008) Human papillomavirus types 16 and 18 vaccine (recombinant, AS04 adjuvanted, adsorbed) [Cervarix]. Drugs 68:359–372.PubMedCrossRefGoogle Scholar
  91. Khan WN (2009) B cell receptor and BAFF receptor signaling regulation of B cell homeostasis. J Immunol 183:3561–3567.PubMedCrossRefGoogle Scholar
  92. Kimberlin DW and Whitley RJ (2007) Varicella-zoster vaccine for the prevention of herpes zoster. N Engl J Med 356:1338–1343.PubMedCrossRefGoogle Scholar
  93. Kimman TG, Banus S, Reijmerink N et al. (2008) Association of interacting genes in the toll-like receptor signaling pathway and the antibody response to pertussis vaccination. PLoS One 3:e3665PubMedCrossRefGoogle Scholar
  94. Korb M, Rust AG, Thorsson V et al. (2008) The Innate Immune Database (IIDB). BMC Immunol 9:7PubMedCrossRefGoogle Scholar
  95. Korber BT, Letvin NL, Haynes BF (2009) T-cell vaccine strategies for human immunodeficiency virus, the virus with a thousand faces. J Virol 83:8300–8314.PubMedCrossRefGoogle Scholar
  96. Kozlow EJ, Wilson GL, Fox CH et al. (1993) Subtractive cDNA cloning of a novel member of the Ig gene superfamily expressed at high levels in activated B lymphocytes. Blood 81:454–461.PubMedGoogle Scholar
  97. Krieg AM (2006) Therapeutic potential of Toll-like receptor 9 activation. Nat Rev Drug Discov 5:471–484.PubMedCrossRefGoogle Scholar
  98. Krieg AM (2008) Toll-like receptor 9 (TLR9) agonists in the treatment of cancer. Oncogene 27:161–167.PubMedCrossRefGoogle Scholar
  99. Krishnan MN, Ng A, Sukumaran B et al. (2008) RNA interference screen for human genes associated with West Nile virus infection. Nature 455:242–245.PubMedCrossRefGoogle Scholar
  100. Kwissa M, Amara RR, Robinson HL et al. (2007a) Adjuvanting a DNA vaccine with a TLR9 ligand plus Flt3 ligand results in enhanced cellular immunity against the simian immunodeficiency virus. J Exp Med 204:2733–2746.PubMedCrossRefGoogle Scholar
  101. Kwissa M, Kasturi SP, Pulendran B (2007b) The science of adjuvants. Expert Rev Vaccines 6:673–684.PubMedCrossRefGoogle Scholar
  102. Lafaille JJ (1998) The role of helper T cell subsets in autoimmune diseases. Cytokine Growth Factor Rev 9:139–151.PubMedCrossRefGoogle Scholar
  103. Lahiri A, Das P, Chakravortty D (2008) Engagement of TLR signaling as adjuvant: towards smarter vaccine and beyond. Vaccine 26:6777–6783.PubMedCrossRefGoogle Scholar
  104. Latz E, Franko J, Golenbock DT et al. (2004a) Haemophilus influenzae type b-outer membrane protein complex glycoconjugate vaccine induces cytokine production by engaging human toll-like receptor 2 (TLR2) and requires the presence of TLR2 for optimal immunogenicity. J Immunol 172:2431–2438.PubMedGoogle Scholar
  105. Latz E, Schoenemeyer A, Visintin A et al. (2004b) TLR9 signals after translocating from the ER to CpG DNA in the lysosome. Nat Immunol 5:190–198.PubMedCrossRefGoogle Scholar
  106. Leber JH, Crimmins GT, Raghavan S et al. (2008) Distinct TLR- and NLR-mediated transcriptional responses to an intracellular pathogen. PLoS Pathog 4:e6PubMedCrossRefGoogle Scholar
  107. Liu YJ (2005) IPC: professional type 1 interferon-producing cells and plasmacytoid dendritic cell precursors. Annu Rev Immunol 23:275–306.PubMedCrossRefGoogle Scholar
  108. Longhi MP, Trumpfheller C, Idoyaga J et al. (2009) Dendritic cells require a systemic type I interferon response to mature and induce CD4+ Th1 immunity with poly IC as adjuvant. J Exp Med 206:1589–1602.PubMedCrossRefGoogle Scholar
  109. Lorenz E, Mira JP, Frees KL et al. (2002) Relevance of mutations in the TLR4 receptor in patients with gram-negative septic shock. Arch Intern Med 162:1028–1032.PubMedCrossRefGoogle Scholar
  110. Lund JM, Alexopoulou L, Sato A et al. (2004) Recognition of single-stranded RNA viruses by Toll-like receptor 7. Proc Natl Acad Sci U S A 101:5598–5603.PubMedCrossRefGoogle Scholar
  111. Lynn DJ, Winsor GL, Chan C et al. (2008) InnateDB: facilitating systems-level analyses of the mammalian innate immune response. Mol Syst Biol 4:218PubMedCrossRefGoogle Scholar
  112. Ma R, Du JL, Huang J et al. (2007) Additive effects of CpG ODN and R-848 as adjuvants on augmenting immune responses to HBsAg vaccination. Biochem Biophys Res Commun 361:537–542.PubMedCrossRefGoogle Scholar
  113. Magistrelli G, Jeannin P, Elson G et al. (1999) Identification of three alternatively spliced variants of human CD28 mRNA. Biochem Biophys Res Commun 259:34–37.PubMedCrossRefGoogle Scholar
  114. McCaffrey RL, Fawcett P, O’Riordan M et al. (2004) A specific gene expression program triggered by Gram-positive bacteria in the cytosol. Proc Natl Acad Sci U S A 101:11386–11391.PubMedCrossRefGoogle Scholar
  115. McGuirk P and Mills KH (2002) Pathogen-specific regulatory T cells provoke a shift in the Th1/Th2 paradigm in immunity to infectious diseases. Trends Immunol 23:450–455.PubMedCrossRefGoogle Scholar
  116. Mikszta JA, Dekker JP, III, Harvey NG et al. (2006) Microneedle-based intradermal delivery of the anthrax recombinant protective antigen vaccine. Infect Immun 74:6806–6810.PubMedCrossRefGoogle Scholar
  117. Misch EA and Hawn TR (2008) Toll-like receptor polymorphisms and susceptibility to human disease. Clin Sci (Lond) 114:347–360.CrossRefGoogle Scholar
  118. Miyairi I and DeVincenzo JP (2008) Human genetic factors and respiratory syncytial virus disease severity. Clin Microbiol Rev 21:686–703.PubMedCrossRefGoogle Scholar
  119. Monaco A, Marincola FM, Sabatino M et al. (2009) Molecular immune signatures of HIV-1 vaccines in human PBMCs. FEBS Lett 583:3004–3008.PubMedCrossRefGoogle Scholar
  120. Monath TP (2005) Yellow fever vaccine. Expert Rev Vaccines 4:553–574.PubMedCrossRefGoogle Scholar
  121. Monie TP, Bryant CE, Gay NJ (2009) Activating immunity: lessons from the TLRs and NLRs. Trends Biochem Sci 34:553–561.PubMedCrossRefGoogle Scholar
  122. Moser M and Murphy KM (2000) Dendritic cell regulation of TH1-TH2 development. Nat Immunol 1:199–205.PubMedCrossRefGoogle Scholar
  123. Mowen KA and Glimcher LH (2004) Signaling pathways in Th2 development. Immunol Rev 202:203–222.PubMedCrossRefGoogle Scholar
  124. Navabi H, Jasani B, Reece A et al. (2009) A clinical grade poly I:C-analogue (Ampligen) promotes optimal DC maturation and Th1-type T cell responses of healthy donors and cancer patients in vitro. Vaccine 27:107–115.PubMedCrossRefGoogle Scholar
  125. Navratil V, de CB, Meyniel L et al. (2009) VirHostNet: a knowledge base for the management and the analysis of proteome-wide virus-host interaction networks. Nucleic Acids Res 37:D661–D668.Google Scholar
  126. Nguyen TH, Mai NL, Le TP et al. (2009) Toll-like receptor 4 (TLR4) and typhoid fever in Vietnam. PLoS One 4:e4800.PubMedCrossRefGoogle Scholar
  127. O’Garra A and Robinson D (2004) Development and function of T helper 1 cells. Adv Immunol 83:133–162.PubMedCrossRefGoogle Scholar
  128. O’Garra A and Vieira P (2004) Regulatory T cells and mechanisms of immune system control. Nat Med 10:801–805.PubMedCrossRefGoogle Scholar
  129. Oda K and Kitano H (2006) A comprehensive map of the toll-like receptor signaling network. Mol Syst Biol 2:2006.CrossRefGoogle Scholar
  130. Ogus AC, Yoldas B, Ozdemir T et al. (2004) The Arg753GLn polymorphism of the human toll-like receptor 2 gene in tuberculosis disease. Eur Respir J 23:219–223.PubMedCrossRefGoogle Scholar
  131. Ott G, Barchfeld GL, Chernoff D et al. (1995) MF59. Design and evaluation of a safe and potent adjuvant for human vaccines. Pharm Biotechnol 6:277–296.PubMedCrossRefGoogle Scholar
  132. Ovsyannikova IG, Dhiman N, Haralambieva IH et al. (2010) Rubella vaccine-induced cellular immunity: evidence of associations with polymorphisms in the Toll-like, vitamin A and D receptors, and innate immune response genes. Hum Genet 127:207–221.PubMedCrossRefGoogle Scholar
  133. Ozinsky A, Underhill DM, Fontenot JD et al. (2000) The repertoire for pattern recognition of pathogens by the innate immune system is defined by cooperation between toll-like receptors. Proc Natl Acad Sci U S A 97:13766–13771.PubMedCrossRefGoogle Scholar
  134. Pancharoen C, Mekmullica J, Thisyakorn U et al. (2005) Reduced-dose intradermal vaccination against hepatitis A with an aluminum-free vaccine is immunogenic and can lower costs. Clin Infect Dis 41:1537–1540.PubMedCrossRefGoogle Scholar
  135. Pasare C and Medzhitov R (2005) Toll-like receptors: linking innate and adaptive immunity. Adv Exp Med Biol 560:11–18.PubMedCrossRefGoogle Scholar
  136. Pashine A, Valiante NM, Ulmer JB (2005) Targeting the innate immune response with improved vaccine adjuvants. Nat Med 11:S63–S68.PubMedCrossRefGoogle Scholar
  137. Pine SO, McElrath MJ, Bochud PY (2009) Polymorphisms in toll-like receptor 4 and toll-like receptor 9 influence viral load in a seroincident cohort of HIV-1-infected individuals. AIDS 23:2387–2395.PubMedCrossRefGoogle Scholar
  138. Pitti RM, Marsters SA, Lawrence DA et al. (1998) Genomic amplification of a decoy receptor for Fas ligand in lung and colon cancer. Nature 396:699–703.PubMedCrossRefGoogle Scholar
  139. Plotkin SA (2005) Vaccines: past, present and future. Nat Med 11:S5–S11.PubMedCrossRefGoogle Scholar
  140. Poltorak A, He X, Smirnova I et al. (1998) Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282:2085–2088.PubMedCrossRefGoogle Scholar
  141. Potti A, Dressman HK, Bild A et al. (2006) Genomic signatures to guide the use of chemotherapeutics. Nat Med 12:1294–1300.PubMedCrossRefGoogle Scholar
  142. Pulendran B and Ahmed R (2006) Translating innate immunity into immunological memory: implications for vaccine development. Cell 124:849–863.PubMedCrossRefGoogle Scholar
  143. Querec T, Bennouna S, Alkan S et al. (2006) Yellow fever vaccine YF-17D activates multiple dendritic cell subsets via TLR2, 7, 8, and 9 to stimulate polyvalent immunity. J Exp Med 203:413–424.PubMedCrossRefGoogle Scholar
  144. Querec TD, Akondy RS, Lee EK et al. (2009) Systems biology approach predicts immunogenicity of the yellow fever vaccine in humans. Nat Immunol 10:116–125.PubMedCrossRefGoogle Scholar
  145. Ramilo O, Allman W, Chung W et al. (2007) Gene expression patterns in blood leukocytes discriminate patients with acute infections. Blood 109:2066–2077.PubMedCrossRefGoogle Scholar
  146. Rappuoli R (2004) From Pasteur to genomics: progress and challenges in infectious diseases. Nat Med 10:1177–1185.PubMedCrossRefGoogle Scholar
  147. Rappuoli R (2007) Bridging the knowledge gaps in vaccine design. Nat Biotechnol 25:1361–1366.PubMedCrossRefGoogle Scholar
  148. Read RC, Pullin J, Gregory S et al. (2001) A functional polymorphism of toll-like receptor 4 is not associated with likelihood or severity of meningococcal disease. J Infect Dis 184:640–642.PubMedCrossRefGoogle Scholar
  149. Redecke V, Hacker H, Datta SK et al. (2004) Cutting edge: activation of Toll-like receptor 2 induces a Th2 immune response and promotes experimental asthma. J Immunol 172:2739–2743.PubMedGoogle Scholar
  150. Reed SG, Bertholet S, Coler RN et al. (2009) New horizons in adjuvants for vaccine development. Trends Immunol 30:23–32.PubMedCrossRefGoogle Scholar
  151. Rerks-Ngarm S, Pitisuttithum P, Nitayaphan S et al. (2009) Vaccination with ALVAC and AIDSVAX to Prevent HIV-1 Infection in Thailand. N Engl J Med 361:2209–2220.Google Scholar
  152. Rezazadeh M, Hajilooi M, Rafiei A et al. (2006) TLR4 polymorphism in Iranian patients with brucellosis. J Infect 53:206–210.PubMedCrossRefGoogle Scholar
  153. Ricciardi-Castagnoli P and Granucci F (2002) Opinion: Interpretation of the complexity of innate immune responses by functional genomics. Nat Rev Immunol 2:881–889.PubMedCrossRefGoogle Scholar
  154. Richter JD and Sonenberg N (2005) Regulation of cap-dependent translation by eIF4E inhibitory proteins. Nature 433:477–480.PubMedCrossRefGoogle Scholar
  155. Robbins JB, Schneerson R, Szu SC (1995) Perspective: hypothesis: serum IgG antibody is sufficient to confer protection against infectious diseases by inactivating the inoculum. J Infect Dis 171:1387–1398.PubMedCrossRefGoogle Scholar
  156. Robbins JB, Schneerson R, Szu SC (1996) Hypothesis: how licensed vaccines confer protective immunity. Adv Exp Med Biol 397:169–182.PubMedGoogle Scholar
  157. Ron D and Walter P (2007) Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol 8:519–529.PubMedCrossRefGoogle Scholar
  158. Ryan ET and Calderwood SB (2000) Cholera vaccines. Clin Infect Dis 31:561–565.PubMedCrossRefGoogle Scholar
  159. Sallberg M, Frelin L, Weiland O (2009) DNA vaccine therapy for chronic hepatitis C virus (HCV) infection: immune control of a moving target. Expert Opin Biol Ther 9:805–815.PubMedCrossRefGoogle Scholar
  160. Santos AP, Matos DC, Bertho AL et al. (2008) Detection of Th1/Th2 cytokine signatures in yellow fever 17DD first-time vaccinees through ELISpot assay. Cytokine 42:152–155.PubMedCrossRefGoogle Scholar
  161. Sato Y, Goto Y, Narita N et al. (2009) Cancer Cells Expressing Toll-like Receptors and the Tumor Microenvironment. Cancer Microenviron 2(Suppl 1):205–214.PubMedCrossRefGoogle Scholar
  162. Schmidt WM, Spiel AO, Jilma B et al. (2009) In vivo profile of the human leukocyte microRNA response to endotoxemia. Biochem Biophys Res Commun 380:437–441.PubMedCrossRefGoogle Scholar
  163. Schonbeck U and Libby P (2001) The CD40/CD154 receptor/ligand dyad. Cell Mol Life Sci 58:4–43.PubMedCrossRefGoogle Scholar
  164. Schroder NW and Schumann RR (2005) Single nucleotide polymorphisms of Toll-like receptors and susceptibility to infectious disease. Lancet Infect Dis 5:156–164.PubMedCrossRefGoogle Scholar
  165. Shimazu R, Akashi S, Ogata H et al. (1999) MD-2, a molecule that confers lipopolysaccharide responsiveness on Toll-like receptor 4. J Exp Med 189:1777–1782.PubMedCrossRefGoogle Scholar
  166. Sioud M (2009) Does our current understanding of immune tolerance, autoimmunity, and immunosuppressive mechanisms facilitate the design of efficient cancer vaccines? Scand J Immunol 70:516–525.PubMedCrossRefGoogle Scholar
  167. Smirnova I, Mann N, Dols A et al. (2003) Assay of locus-specific genetic load implicates rare Toll-like receptor 4 mutations in meningococcal susceptibility. Proc Natl Acad Sci U S A 100:6075–6080.PubMedCrossRefGoogle Scholar
  168. Sorlie T, Perou CM, Tibshirani R et al. (2001) Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A 98:10869–10874.PubMedCrossRefGoogle Scholar
  169. Speiser DE, Lienard D, Rufer N et al. (2005) Rapid and strong human CD8+ T cell responses to vaccination with peptide, IFA, and CpG oligodeoxynucleotide 7909. J Clin Invest 115:739–746.PubMedGoogle Scholar
  170. Stahl S, Fung E, Adams C et al. (2009) Proteomics and pathway analysis identifies JNK signaling as critical for high linear energy transfer radiation-induced apoptosis in non-small lung cancer cells. Mol Cell Proteomics 8:1117–1129.PubMedCrossRefGoogle Scholar
  171. Stephan MT, Ponomarev V, Brentjens RJ et al. (2007) T cell-encoded CD80 and 4-1BBL induce auto- and transcostimulation, resulting in potent tumor rejection. Nat Med 13:1440–1449.PubMedCrossRefGoogle Scholar
  172. Sun HJ, Xu X, Wang XL et al. (2006) Transcription factors Ets2 and Sp1 act synergistically with histone acetyltransferase p300 in activating human interleukin-12 p40 promoter. Acta Biochim Biophys Sin (Shanghai) 38:194–200.CrossRefGoogle Scholar
  173. Takeda K and Akira S (2007) Toll-like receptors. Curr Protoc Immunol  Chapter 14:Unit PMID: 18432983 DOI: 10.1002/0471142735.im1412s77.
  174. Takeda K, Kaisho T, Akira S (2003) Toll-like receptors. Annu Rev Immunol 21:335–376.PubMedCrossRefGoogle Scholar
  175. Takeuchi O, Kawai T, Muhlradt PF et al. (2001) Discrimination of bacterial lipoproteins by Toll-like receptor 6. Int Immunol 13:933–940.PubMedCrossRefGoogle Scholar
  176. Takeuchi O, Sato S, Horiuchi T et al. (2002) Cutting edge: role of Toll-like receptor 1 in mediating immune response to microbial lipoproteins. J Immunol 169:10–14.PubMedGoogle Scholar
  177. Tanabe M, Kurita-Taniguchi M, Takeuchi K et al. (2003) Mechanism of up-regulation of human Toll-like receptor 3 secondary to infection of measles virus-attenuated strains. Biochem Biophys Res Commun 311:39–48.PubMedCrossRefGoogle Scholar
  178. Thomas V and Fikrig E (2002) The Lyme disease vaccine takes its toll. Vector Borne Zoonotic Dis 2:217–222.PubMedCrossRefGoogle Scholar
  179. Tong NK, Beran J, Kee SA et al. (2005) Immunogenicity and safety of an adjuvanted hepatitis B vaccine in pre-hemodialysis and hemodialysis patients. Kidney Int 68:2298–2303.PubMedCrossRefGoogle Scholar
  180. Tsuji S, Matsumoto M, Takeuchi O et al. (2000) Maturation of human dendritic cells by cell wall skeleton of Mycobacterium bovis bacillus Calmette-Guerin: involvement of toll-like receptors. Infect Immun 68:6883–6890.PubMedCrossRefGoogle Scholar
  181. Uehori J, Matsumoto M, Tsuji S et al. (2003) Simultaneous blocking of human Toll-like receptors 2 and 4 suppresses myeloid dendritic cell activation induced by Mycobacterium bovis bacillus Calmette-Guerin peptidoglycan. Infect Immun 71:4238–4249.PubMedCrossRefGoogle Scholar
  182. van Manen D, Rits MA, Beugeling C et al. (2008) The effect of Trim5 polymorphisms on the clinical course of HIV-1 infection. PLoS Pathog 4:e18.PubMedCrossRefGoogle Scholar
  183. Van DP, Oosterhuis-Kafeja F, Van der WM et al. (2009) Safety and efficacy of a novel micro­needle device for dose sparing intradermal influenza vaccination in healthy adults. Vaccine 27:454–459.CrossRefGoogle Scholar
  184. Vasilescu C, Rossi S, Shimizu M et al. (2009) MicroRNA fingerprints identify miR-150 as a plasma prognostic marker in patients with sepsis. PLoS One 4:e7405PubMedCrossRefGoogle Scholar
  185. Velez DR, Wejse C, Stryjewski ME et al. (2010) Variants in toll-like receptors 2 and 9 influence susceptibility to pulmonary tuberculosis in Caucasians, African-Americans, and West Africans. Hum Genet 127:65–73.PubMedCrossRefGoogle Scholar
  186. Villadangos JA and Young L (2008) Antigen-presentation properties of plasmacytoid dendritic cells. Immunity 29:352–361.PubMedCrossRefGoogle Scholar
  187. von Andrian UH and Mempel TR (2003) Homing and cellular traffic in lymph nodes. Nat Rev Immunol 3:867–878.CrossRefGoogle Scholar
  188. Wang Z, Gerstein M, Snyder M (2009) RNA-Seq: a revolutionary tool for transcriptomics. Nat Rev Genet 10:57–63.PubMedCrossRefGoogle Scholar
  189. Wille-Reece U, Flynn BJ, Lore K et al. (2006) Toll-like receptor agonists influence the magnitude and quality of memory T cell responses after prime-boost immunization in nonhuman primates. J Exp Med 203:1249–1258.PubMedCrossRefGoogle Scholar
  190. Wurfel MM, Gordon AC, Holden TD et al. (2008) Toll-like receptor 1 polymorphisms affect innate immune responses and outcomes in sepsis. Am J Respir Crit Care Med 178:710–720.PubMedCrossRefGoogle Scholar
  191. Yim JJ, Lee HW, Lee HS et al. (2006) The association between microsatellite polymorphisms in intron II of the human Toll-like receptor 2 gene and tuberculosis among Koreans. Genes Immun 7:150–155.PubMedCrossRefGoogle Scholar
  192. Yin JQ, Zhao RC, Morris KV (2008) Profiling microRNA expression with microarrays. Trends Biotechnol 26:70–76.PubMedCrossRefGoogle Scholar
  193. Yoneyama M and Fujita T (2009) RNA recognition and signal transduction by RIG-I-like receptors. Immunol Rev 227:54–65.PubMedCrossRefGoogle Scholar
  194. Yoneyama M, Kikuchi M, Natsukawa T et al. (2004) The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. Nat Immunol 5:730-737.PubMedCrossRefGoogle Scholar
  195. Yoneyama M, Kikuchi M, Matsumoto K et al. (2005) Shared and unique functions of the DExD/H-box helicases RIG-I, MDA5, and LGP2 in antiviral innate immunity. J Immunol 175:2851–2858.PubMedGoogle Scholar
  196. Yoshida A, Inagawa H, Kohchi C et al. (2009) The role of toll-like receptor 2 in survival strategies of Mycobacterium tuberculosis in macrophage phagosomes. Anticancer Res 29:907–910.PubMedGoogle Scholar
  197. Zhou R, Hu G, Liu J et al. (2009) NF-kappaB p65-dependent transactivation of miRNA genes following Cryptosporidium parvum infection stimulates epithelial cell immune responses. PLoS Pathog 5:e1000681.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • F. M. Buonaguro
  • M. L. Tornesello
  • L. Buonaguro
    • 1
  1. 1.Lab. Mol Biology and Viral Oncogenesis and AIDS Reference CenterIstituto Nazionale Tumori “Fond. G. Pascale”NaplesItaly

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