Abstract
Molecular characterization of mechanisms by which human pattern recognition receptors (PRRs) detect danger signals has greatly expanded our understanding of the innate immune system. PRRs include Toll-like receptors, nucleotide oligomerization domain-like receptors, retinoic acid inducible gene-like receptors, and C-type lectin receptors. Characterization of the developmental expression of these systems in the fetus, newborn, and infant is incomplete but has yielded important insights into neonatal susceptibility to infection. Activation of PRRs on antigen-presenting cells enhances costimulatory function, and thus PRR agonists are potential vaccine adjuvants, some of which are already in clinical use. Thus, study of PRRs has also revealed how previously mysterious immunomodulators are able to mediate their actions, including the vaccine adjuvant aluminum hydroxide that activates a cytosolic protein complex known as the Nacht domain leucine-rich repeat and pyrin domain-containing protein 3 inflammasome leading to interleukin-1β production. Progress in characterizing PRRs is thus informing and expanding the design of improved adjuvants. This review summarizes recent developments in the field of innate immunity emphasizing developmental expression in the fetus, newborn, and infant and its implications for the design of more effective neonatal and infant vaccines.
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Abbreviations
- APC:
-
antigen-presenting cell
- BCG:
-
Bacille Calmette-Guerin
- MyD88:
-
myeloid differentiation factor 88
- NALP3:
-
Nacht domain leucine-rich repeat and PYD-containing protein 3
- RLRs:
-
retinoic acid inducible gene-like receptors
- TLR:
-
Toll-like receptor
- Treg:
-
T-regulatory cell
References
WHO 2005 The World Health Report. World Health Organization, Geneva
Siegrist CA 2003 Immunologic requirements for vaccines to be used in early life. In: Bloom B, Lambert PH (ed) The Vaccine Book. Academic Press, Boston, pp 73–83
Angelone DF, Wessels MR, Coughlin M, Suter EE, Valentini P, Kalish LA, Levy O 2006 Innate immunity of the human newborn is polarized toward a high ratio of IL-6/TNF-alpha production in vitro and in vivo. Pediatr Res 60: 205–209
Levy O 2007 Innate immunity of the newborn: basic mechansims and clinical correlates. Nat Rev Immunol 7: 379–390
Kallewaard NL, McKinney BA, Gu Y, Chen A, Prasad BV, Crowe JE Jr 2008 Functional maturation of the human antibody response to rotavirus. J Immunol 180: 3980–3989
Morein B, Blomqvist G, Hu K 2007 Immune responsiveness in the neonatal period. J Comp Pathol 137: S27–S31
Jones CA, Holloway JA, Warner JO 2002 Phenotype of fetal monocytes and B lymphocytes during the third trimester of pregnancy. J Reprod Immunol 56: 45–60
Saito S 2000 Cytokine network at the feto-maternal interface. J Reprod Immunol 47: 87–103
Levy O, Coughlin M, Cronstein B, Roy RM, Desai A, Wessels MR 2006 The adenosine system selectively inhibits TLR-mediated TNF-alpha production in the human newborn. J Immunol 177: 1956–1966
Langrish CL, Buddle JC, Thrasher AJ, Goldblatt D 2002 Neonatal dendritic cells are intrinsically biased against Th-1 immune responses. Clin Exp Immunol 128: 118–123
Muthukkumar S, Goldstein J, Stein KE 2000 The ability of B cells and dendritic cells to present antigen increases during ontogeny. J Immunol 165: 4803–4813
Zhao J, Kim KD, Yang X, Auh S, Fu YX, Tang H 2008 Hyper innate responses in neonates lead to increased morbidity and mortality after infection. Proc Natl Acad Sci USA 105: 7528–7533
Roach JC, Glusman G, Rowen L, Kaur A, Purcell MK, Smith KD, Hood LE, Aderem A 2005 The evolution of vertebrate Toll-like receptors. Proc Natl Acad Sci USA 102: 9577–9582
Philbin VJ, Iqbal M, Boyd Y, Goodchild MJ, Beal RK, Bumstead N, Young J, Smith AL 2005 Identification and characterization of a functional, alternatively spliced Toll-like receptor 7 (TLR7) and genomic disruption of TLR8 in chickens. Immunology 114: 507–521
Levy O, Zarember KA, Roy RM, Cywes C, Godowski PJ, Wessels MR 2004 Selective impairment of TLR-mediated innate immunity in human newborns: neonatal blood plasma reduces monocyte TNF-alpha induction by bacterial lipopeptides, lipopolysaccharide, and imiquimod, but preserves the response to R-848. J Immunol 173: 4627–4634
Michaelsson J, Mold JE, McCune JM, Nixon DF 2006 Regulation of T cell responses in the developing human fetus. J Immunol 176: 5741–5748
Godfrey WR, Spoden DJ, Ge YG, Baker SR, Liu B, Levine BL, June CH, Blazar BR, Porter SB 2005 Cord blood CD4(+)CD25(+)-derived T regulatory cell lines express FoxP3 protein and manifest potent suppressor function. Blood 105: 750–758
Wing K, Larsson P, Sandstrom K, Lundin SB, Suri-Payer E, Rudin A 2005 CD4+ CD25+FOXP3+ regulatory T cells from human thymus and cord blood suppress antigen-specific T cell responses. Immunology 115: 516–525
Deaglio S, Dwyer KM, Gao W, Friedman D, Usheva A, Erat A, Chen JF, Enjyoji K, Linden J, Oukka M, Kuchroo VK, Strom TB, Robson SC 2007 Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J Exp Med 204: 1257–1265
Bodor J, Fehervari Z, Diamond B, Sakaguchi S 2007 Regulatory T cell-mediated suppression: potential role of ICER. J Leukoc Biol 81: 161–167
Fernandez MA, Puttur FK, Wang YM, Howden W, Alexander SI, Jones CA 2008 T regulatory cells contribute to the attenuated primary CD8+ and CD4+ T cell responses to herpes simplex virus type 2 in neonatal mice. J Immunol 180: 1556–1564
Toka FN, Suvas S, Rouse BT 2004 CD4+CD25+ T cells regulate vaccine-generated primary and memory CD8+ T-cell responses against herpes simplex virus type 1. J Virol 78: 13082–13089
Stober CB, Lange UG, Roberts MT, Alcami A, Blackwell JM 2005 IL-10 from regulatory T cells determines vaccine efficacy in murine Leishmania major infection. J Immunol 175: 2517–2524
Iwasaki A, Medzhitov R 2004 Toll-like receptor control of the adaptive immune responses. Nat Immunol 5: 987–995
O'Neill LA 2008 When signaling pathways collide: positive and negative regulation of toll-like receptor signal transduction. Immunity 29: 12–20
Pasare C, Medzhitov R 2003 Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells. Science 299: 1033–1036
Matzinger P 2007 Friendly and dangerous signals: is the tissue in control?. Nat Immunol 8: 11–13
Soderberg KA, Payne GW, Sato A, Medzhitov R, Segal SS, Iwasaki A 2005 Innate control of adaptive immunity via remodeling of lymph node feed arteriole. Proc Natl Acad Sci USA 102: 16315–16320
Webster B, Ekland EH, Agle LM, Chyou S, Ruggieri R, Lu TT 2006 Regulation of lymph node vascular growth by dendritic cells. J Exp Med 203: 1903–1913
Diebold SS, Kaisho T, Hemmi H, Akira S, Reis e Sousa C 2004 Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science 303: 1529–1531
Heil F, Hemmi H, Hochrein H, Ampenberger F, Kirschning C, Akira S, Lipford G, Wagner H, Bauer S 2004 Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science 303: 1526–1529
O'Neill LA, Bowie AG 2007 The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling. Nat Rev Immunol 7: 353–364
Dumitru CD, Ceci JD, Tsatsanis C, Kontoyiannis D, Stamatakis K, Lin JH, Patriotis C, Jenkins NA, Copeland NG, Kollias G, Tsichlis PN 2000 TNF-alpha induction by LPS is regulated posttranscriptionally via a Tpl2/ERK-dependent pathway. Cell 103: 1071–1083
Huang Q, Yang J, Lin Y, Walker C, Cheng J, Liu ZG, Su B 2004 Differential regulation of interleukin 1 receptor and Toll-like receptor signaling by MEKK3. Nat Immunol 5: 98–103
von Bernuth H, Picard C, Jin Z, Pankla R, Xiao H, Ku CL, Chrabieh M, Mustapha IB, Ghandil P, Camcioglu Y, Vasconcelos J, Sirvent N, Guedes M, Vitor AB, Herrero-Mata MJ, Arostegui JI, Rodrigo C, Alsina L, Ruiz-Ortiz E, Juan M, Fortuny C, Yague J, Anton J, Pascal M, Chang HH, Janniere L, Rose Y, Garty BZ, Chapel H, Issekutz A, Marodi L, Rodriguez-Gallego C, Banchereau J, Abel L, Li X, Chaussabel D, Puel A, Casanova JL 2008 Pyogenic bacterial infections in humans with MyD88 deficiency. Science 321: 691–696
Ku CL, von Bernuth H, Picard C, Zhang SY, Chang HH, Yang K, Chrabieh M, Issekutz AC, Cunningham CK, Gallin J, Holland SM, Roifman C, Ehl S, Smart J, Tang M, Barrat FJ, Levy O, McDonald D, Day-Good NK, Miller R, Takada H, Hara T, Al-Hajjar S, Al-Ghonaium A, Speert D, Sanlaville D, Li X, Geissmann F, Vivier E, Marodi L, Garty BZ, Chapel H, Rodriguez-Gallego C, Bossuyt X, Abel L, Puel A, Casanova JL 2007 Selective predisposition to bacterial infections in IRAK-4-deficient children: IRAK-4-dependent TLRs are otherwise redundant in protective immunity. J Exp Med 204: 2407–2422
Medvedev AE, Lentschat A, Kuhns DB, Blanco JC, Salkowski C, Zhang S, Arditi M, Gallin JI, Vogel SN 2003 Distinct mutations in IRAK-4 confer hyporesponsiveness to lipopolysaccharide and interleukin-1 in a patient with recurrent bacterial infections. J Exp Med 198: 521–531
Yan SR, Qing G, Byers DM, Stadnyk AW, Al-Hertani W, Bortolussi R 2004 Role of MyD88 in diminished tumor necrosis factor alpha production by newborn mononuclear cells in response to lipopolysaccharide. Infect Immun 72: 1223–1229
Goriely S, Van Lint C, Dadkhah R, Libin M, De Wit D, Demonte D, Willems F, Goldman M 2004 A defect in nucleosome remodeling prevents IL-12(p35) gene transcription in neonatal dendritic cells. J Exp Med 199: 1011–1016
De Wit D, Olislagers V, Goriely S, Vermeulen F, Wagner H, Goldman M, Willems F 2004 Blood plasmacytoid dendritic cell responses to CpG oligodeoxynucleotides are impaired in human newborns. Blood 103: 1030–1032
Aksoy E, Albarani V, Nguyen M, Laes JF, Ruelle JL, De Wit D, Willems F, Goldman M, Goriely S 2007 Interferon regulatory factor 3-dependent responses to lipopolysaccharide are selectively blunted in cord blood cells. Blood 109: 2887–2893
Levy O, Suter EE, Miller RL, Wessels MR 2006 Unique efficacy of Toll-like receptor 8 agonists in activating human neonatal antigen-presenting cells. Blood 108: 1284–1290
Yoneyama M, Kikuchi M, Natsukawa T, Shinobu N, Imaizumi T, Miyagishi M, Taira K, Akira S, Fujita T 2004 The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. Nat Immunol 5: 730–737
Andrejeva J, Childs KS, Young DF, Carlos TS, Stock N, Goodbourn S, Randall RE 2004 The V proteins of paramyxoviruses bind the IFN-inducible RNA helicase, mda-5, and inhibit its activation of the IFN-beta promoter. Proc Natl Acad Sci USA 101: 17264–17269
Gotsch F, Romero R, Chaiworapongsa T, Erez O, Vaisbuch E, Espinoza J, Kusanovic JP, Mittal P, Mazaki-Tovi S, Kim CJ, Kim JS, Edwin S, Nhan-Chang CL, Hamill N, Friel L, Than NG, Mazor M, Yoon BH, Hassan SS 2008 Evidence of the involvement of caspase-1 under physiologic and pathologic cellular stress during human pregnancy: a link between the inflammasome and parturition. J Matern Fetal Neonatal Med 21: 605–616
Forster-Waldl E, Sadeghi K, Tamandl D, Gerhold B, Hallwirth U, Rohrmeister K, Hayde M, Prusa AR, Herkner K, Boltz-Nitulescu G, Pollak A, Spittler A 2005 Monocyte toll-like receptor 4 expression and LPS-induced cytokine production increase during gestational aging. Pediatr Res 58: 121–124
Sadeghi K, Berger A, Langgartner M, Prusa AR, Hayde M, Herkner K, Pollak A, Spittler A, Forster-Waldl E 2007 Immaturity of infection control in preterm and term newborns is associated with impaired toll-like receptor signaling. J infect Dis 195: 296–302
Gadjeva M, Takahashi K, Thiel S 2004 Mannan-binding lectin—a soluble pattern recognition molecule. Mol Immunol 41: 113–121
Jack DL, Read RC, Tenner AJ, Frosch M, Turner MW, Klein NJ 2001 Mannose-binding lectin regulates the inflammatory response of human professional phagocytes to Neisseria meningitidis serogroup B. J Infect Dis 184: 1152–1162
Oudshoorn AM, van den Dungen FA, Bach KP, Koomen I, Fetter WP, Catsburg A, Savelkoul PH, van Elburg RM 2008 Mannose-binding lectin in term newborns and their mothers: genotypic and phenotypic relationship. Hum Immunol 69: 344–348
Dzwonek AB, Neth OW, Thiebaut R, Gulczynska E, Chilton M, Hellwig T, Bajaj-Elliott M, Hawdon J, Klein NJ 2008 The role of mannose-binding lectin in susceptibility to infection in preterm neonates. Pediatr Res 63: 680–685
Guttormsen HK, Stuart LM, Shi L, Carroll MC, Chen J, Kasper DL, Ezekowitz RA, Takahashi K 2008 Deficiency of mannose-binding lectin greatly increases antibody response in a mouse model of vaccination. Clin Immunol 130: 264–271
Schultz H, Hume J, Zhang de S, Gioannini TL, Weiss JP 2007 A novel role for the bactericidal/permeability increasing protein in interactions of gram-negative bacterial outer membrane blebs with dendritic cells. J Immunol 179: 2477–2484
Oppenheim JJ, Biragyn A, Kwak LW, Yang D 2003 Roles of antimicrobial peptides such as defensins in innate and adaptive immunity. Ann Rheum Dis 62: ii17–ii21
Kornbluth RS, Stone GW 2006 Immunostimulatory combinations: designing the next generation of vaccine adjuvants. J Leukoc Biol 80: 1084–1102
Vekemans J, Amedei A, Ota MO, D'Elios MM, Goetghebuer T, Ismaili J, Newport MJ, Del Prete G, Goldman M, McAdam KP, Marchant A 2001 Neonatal bacillus Calmette-Guerin vaccination induces adult-like IFN-gamma production by CD4+ T lymphocytes. Eur J Immunol 31: 1531–1535
Marchant A, Goetghebuer T, Ota MO, Wolfe I, Ceesay SJ, De Groote D, Corrah T, Bennett S, Wheeler J, Huygen K, Aaby P, McAdam KP, Newport MJ 1999 Newborns develop a Th1-type immune response to Mycobacterium bovis bacillus Calmette-Guerin vaccination. J Immunol 163: 2249–2255
Pasare C, Medzhitov R 2004 Toll-like receptors: linking innate and adaptive immunity. Microbes Infect 6: 1382–1387
Ridge JP, Fuchs EJ, Matzinger P 1996 Neonatal tolerance revisited: turning on newborn T cells with dendritic cells. Science 271: 1723–1726
Means TK, Wang S, Lien E, Yoshimura A, Golenbock DT, Fenton MJ 1999 Human toll-like receptors mediate cellular activation by Mycobacterium tuberculosis. J Immunol 163: 3920–3927
Uehori J, Matsumoto M, Tsuji S, Akazawa T, Takeuchi O, Akira S, Kawata T, Azuma I, Toyoshima K, Seya T 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
Tsuji S, Matsumoto M, Takeuchi O, Akira S, Azuma I, Hayashi A, Toyoshima K, Seya T 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
Bafica A, Scanga CA, Feng CG, Leifer C, Cheever A, Sher A 2005 TLR9 regulates Th1 responses and cooperates with TLR2 in mediating optimal resistance to Mycobacterium tuberculosis. J Exp Med 202: 1715–1724
Davila S, Hibberd ML, Hari Dass R, Wong HE, Sahiratmadja E, Bonnard C, Alisjahbana B, Szeszko JS, Balabanova Y, Drobniewski F, van Crevel R, van de Vosse E, Nejentsev S, Ottenhoff TH, Seielstad M 2008 Genetic association and expression studies indicate a role of toll-like receptor 8 in pulmonary tuberculosis. PLoS Genet 4: e1000218
Williams R 2006 Global challenges in liver disease. Hepatology 44: 521–526
Mogensen TH, Paludan SR, Kilian M, Ostergaard L 2006 Live Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis activate the inflammatory response through Toll-like receptors 2, 4, and 9 in species-specific patterns. J Leukoc Biol 80: 267–277
Latz E, Franko J, Golenbock DT, Schreiber JR 2004 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
Bieback K, Lien E, Klagge IM, Avota E, Schneider-Schaulies J, Duprex WP, Wagner H, Kirschning CJ, Ter Meulen V, Schneider-Schaulies S 2002 Hemagglutinin protein of wild-type measles virus activates toll-like receptor 2 signaling. J Virol 76: 8729–8736
Berghall H, Siren J, Sarkar D, Julkunen I, Fisher PB, Vainionpaa R, Matikainen S 2006 The interferon-inducible RNA helicase, mda-5, is involved in measles virus-induced expression of antiviral cytokines. Microbes Infect 8: 2138–2144
Eisenbarth SC, Colegio OR, O'Connor W, Sutterwala FS, Flavell RA 2008 Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants. Nature 453: 1122–1127
Kool M, Petrilli V, De Smedt T, Rolaz A, Hammad H, van Nimwegen M, Bergen IM, Castillo R, Lambrecht BN, Tschopp J 2008 Cutting edge: alum adjuvant stimulates inflammatory dendritic cells through activation of the NALP3 inflammasome. J Immunol 181: 3755–3759
Ott G, Barchfeld GL, Chernoff D, Radhakrishnan R, van Hoogevest P, Van Nest G 1995 MF59. Design and evaluation of a safe and potent adjuvant for human vaccines. Pharm Biotechnol 6: 277–296
Mosca F, Tritto E, Muzzi A, Monaci E, Bagnoli F, Iavarone C, O'Hagan D, Rappuoli R, De Gregorio E 2008 Molecular and cellular signatures of human vaccine adjuvants. Proc Natl Acad Sci USA 105: 10501–10506
Schultze V, D'Agosto V, Wack A, Novicki D, Zorn J, Hennig R 2008 Safety of MF59 adjuvant. Vaccine 26: 3209–3222
Dupuis M, Denis-Mize K, LaBarbara A, Peters W, Charo IF, McDonald DM, Ott G 2001 Immunization with the adjuvant MF59 induces macrophage trafficking and apoptosis. Eur J Immunol 31: 2910–2918
Moreira LO, Smith AM, Defreitas AA, Qualls JE, El Kasmi KC, Murray PJ 2008 Modulation of adaptive immunity by different adjuvant-antigen combinations in mice lacking Nod2. Vaccine 26: 5808–5813
Lambert PH 1997 Vaccines for the world: major challenges for the future. Southeast Asian J Trop Med Public Health 28: 122–126
Kollmann TR, Reikie B, Blimkie D, Way SS, Hajjar AM, Arispe K, Shaulov A, Wilson CB 2007 Induction of protective immunity to Listeria monocytogenes in neonates. J Immunol 178: 3695–3701
Warren SE, Mao DP, Rodriguez AE, Miao EA, Aderem A 2008 Multiple nod-like receptors activate caspase 1 during Listeria monocytogenes infection. J Immunol 180: 7558–7564
Imaizumi T, Sashinami H, Mori F, Matsumiya T, Yoshida H, Nakane A, Wakabayashi K, Oyama C, Satoh K 2006 Listeria monocytogenes induces the expression of retinoic acid-inducible gene-I. Microbiol Immunol 50: 811–815
Starks H, Bruhn KW, Shen H, Barry RA, Dubensky TW, Brockstedt D, Hinrichs DJ, Higgins DE, Miller JF, Giedlin M, Bouwer HG 2004 Listeria monocytogenes as a vaccine vector: virulence attenuation or existing antivector immunity does not diminish therapeutic efficacy. J Immunol 173: 420–427
Philbin VJ, Levy O 2007 Immunostimulatory activity of Toll-like receptor 8 agonists towards human leucocytes: basic mechanisms and translational opportunities. Biochem Soc Trans 35: 1485–1491
Peng G, Guo Z, Kiniwa Y, Voo KS, Peng W, Fu T, Wang DY, Li Y, Wang HY, Wang RF 2005 Toll-like receptor 8-mediated reversal of CD4+ regulatory T cell function. Science 309: 1380–1384
Hemmi H, Kaisho T, Takeuchi O, Sato S, Sanjo H, Hoshino K, Horiuchi T, Tomizawa H, Takeda K, Akira S 2002 Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway [comment]. Nat Immunol 3: 196–200
Bayerl C, Feller G, Goerdt S 2003 Experience in treating molluscum contagiosum in children with imiquimod 5% cream. Br J Dermatol 149: 25–29
Hengge UR, Cusini M 2003 Topical immunomodulators for the treatment of external genital warts, cutaneous warts and molluscum contagiosum. Br J Dermatol 149: 15–19
Miller RL, Meng TC, Tomai MA 2008 The antiviral activity of Toll-like receptor 7 and 7/8 agonists. Drug News Perspect 21: 69–87
Jurk M, Heil F, Vollmer J, Schetter C, Krieg AM, Wagner H, Lipford G, Bauer S 2002 Human TLR7 or TLR8 independently confer responsiveness to the antiviral compound R-848 [comment]. Nat Immunol 3: 499
Ma R, Du JL, Huang J, Wu CY 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
Zhang WW, Matlashewski G 2008 Immunization with a Toll-like receptor 7 and/or 8 agonist vaccine adjuvant increases protective immunity against Leishmania major in BALB/c mice. Infect Immun 76: 3777–3783
Wille-Reece U, Flynn BJ, Lore K, Koup RA, Kedl RM, Mattapallil JJ, Weiss WR, Roederer M, Seder RA 2005 HIV Gag protein conjugated to a toll-like receptor 7/8 agonist improves the magnitude and quality of Th1 and CD8+ T cell responses in nonhuman primates. Proc Natl Acad Sci USA 102: 15190–15194
Gibson SJ, Lindh JM, Riter TR, Gleason RM, Rogers LM, Fuller AE, Oesterich JL, Gorden KB, Qiu X, McKane SW, Noelle RJ, Miller RL, Kedl RM, Fitzgerald-Bocarsly P, Tomai MA, Vasilakos JP 2002 Plasmacytoid dendritic cells produce cytokines and mature in response to the TLR7 agonists, imiquimod and resiquimod. Cell Immunol 218: 74–86
Bracci L, La Sorsa V, Belardelli F, Proietti E 2008 Type I interferons as vaccine adjuvants against infectious diseases and cancer. Expert Rev Vaccines 7: 373–381
Lan T, Kandimalla ER, Yu D, Bhagat L, Li Y, Wang D, Zhu F, Tang JX, Putta MR, Cong Y, Trombino AF, Sullivan T, Agrawal S 2007 Stabilized immune modulatory RNA compounds as agonists of Toll-like receptors 7 and 8. Proc Natl Acad Sci USA 104: 13750–13755
Sung JJ, Lik-Yuen H 2006 HBV-ISS (Dynavax). Curr Opin Mol Ther 8: 150–155
Koyama S, Ishii KJ, Kumar H, Tanimoto T, Coban C, Uematsu S, Kawai T, Akira S 2007 Differential role of TLR- and RLR-signaling in the immune responses to influenza A virus infection and vaccination. J Immunol 179: 4711–4720
Demirjian A, Levy O 2008 Safety and efficacy of neonatal vaccination. Eur J Immunol 39: 36–46
Offit PA 2004 Multiple vaccines and the immune system. In: Plotkin SA, Orenstein WA (eds) Vaccines. Saunders, Philadelphia, pp 1583–1589
Goriely S, Goldman M 2007 From tolerance to autoimmunity: is there a risk in early life vaccination?. J Comp Pathol 137: S57–S61
Gruber C, Nilsson L, Bjorksten B 2001 Do early childhood immunizations influence the development of atopy and do they cause allergic reactions?. Pediatr Allergy Immunol 12: 296–311
Jo EK 2008 Mycobacterial interaction with innate receptors: TLRs, C-type lectins, and NLRs. Curr Opin Infect Dis 21: 279–286
Le Goffic R, Pothlichet J, Vitour D, Fujita T, Meurs E, Chignard M, Si-Tahar M 2007 Cutting edge: influenza A virus activates TLR3-dependent inflammatory and RIG-I-dependent antiviral responses in human lung epithelial cells. J Immunol 178: 3368–3372
Geeraedts F, Goutagny N, Hornung V, Severa M, de Haan A, Pool J, Wilschut J, Fitzgerald KA, Huckriede A 2008 Superior immunogenicity of inactivated whole virus H5N1 influenza vaccine is primarily controlled by toll-like receptor signalling. PLoS Pathog 4: e1000138
Matikainen S, Siren J, Tissari J, Veckman V, Pirhonen J, Severa M, Sun Q, Lin R, Meri S, Uze G, Hiscott J, Julkunen I 2006 Tumor necrosis factor alpha enhances influenza A virus-induced expression of antiviral cytokines by activating RIG-I gene expression. J Virol 80: 3515–3522
Wang JP, Kurt-Jones EA, Shin OS, Manchak MD, Levin MJ, Finberg RW 2005 Varicella-zoster virus activates inflammatory cytokines in human monocytes and macrophages via toll-like receptor 2. J Virol 79: 12658–12666
American Academy of Pediatrics Committee on Infectious Diseases 2009 Recommended childhood and adolescent immunization schedules–United States, 2009. Pediatrics 123: 189–190
Acknowledgements
We thank Drs. Michael Wessels, Eva Guinan, Jerrold Weiss, Peter Elsbach, Raif Geha, and Richard Malley for their mentorship.
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Supported in part by AHA postdoctoral fellowship (V.J.P.) and NIH R01 grant AI067353, the Patterson Trust, reagent support from 3M Pharmaceuticals, and a sponsorship by Idera Pharmaceuticals.
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Philbin, V., Levy, O. Developmental Biology of the Innate Immune Response: Implications for Neonatal and Infant Vaccine Development. Pediatr Res 65, 98–105 (2009). https://doi.org/10.1203/PDR.0b013e31819f195d
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DOI: https://doi.org/10.1203/PDR.0b013e31819f195d
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