The neonatal immune system: Immunomodulation of infections in early life

Expert Review of Anti-Infective Therapy

Volumn 10, Issue 3, 2012, Pages 289-298

  Futata, Eliana Akemi ^a   Fusaro, Ana Elisa ^a   De Brito, Cyro Alves ^a   Sato, Maria Notomi ^a  

^a UNIVERSITY OF SÃO PAULO   (Brazil)

Author keywords

adaptive immunity; adjuvants; antimicrobial; bacterial; chemokines; cytokine; fungal; immunomodulators; innate immunity; neonate; sepsis; Toll like receptors; viral infections

Indexed keywords

ANTIBIOTIC AGENT; CATHELICIDIN ANTIMICROBIAL PEPTIDE LL 37; FLUCONAZOLE; GAMMA INTERFERON; INTERLEUKIN 10; INTERLEUKIN 12P70; INTERLEUKIN 17; INTERLEUKIN 1BETA; INTERLEUKIN 23; INTERLEUKIN 6; INTERLEUKIN 7; INTERLEUKIN 8; LACTOFERRIN; PROBIOTIC AGENT; TOLL LIKE RECEPTOR; TUMOR NECROSIS FACTOR ALPHA;

ADAPTIVE IMMUNITY; BACTERIAL INFECTION; CD4+ T LYMPHOCYTE; CD8+ T LYMPHOCYTE; CYTOKINE PRODUCTION; CYTOKINE RELEASE; CYTOMEGALOVIRUS INFECTION; DOSE RESPONSE; DRUG EFFICACY; DRUG MEGADOSE; FUNGEMIA; GROUP B STREPTOCOCCAL INFECTION; HOST RESISTANCE; HUMAN; IMMUNOCOMPETENT CELL; IMMUNOMODULATION; IMMUNOPATHOGENESIS; INNATE IMMUNITY; LOW DRUG DOSE; NECROTIZING ENTEROCOLITIS; NEWBORN INFECTION; NEWBORN MORTALITY; NEWBORN SEPSIS; NONHUMAN; REVIEW; UNSPECIFIED SIDE EFFECT;

ADAPTIVE IMMUNITY; ADJUVANTS, IMMUNOLOGIC; BACTERIAL INFECTIONS; HUMANS; IMMUNE SYSTEM; IMMUNITY, INNATE; IMMUNOMODULATION; IMMUNOTHERAPY; INFANT, NEWBORN; VIRUS DISEASES;

EID: 84858261454     PISSN: 14787210     EISSN: 17448336     Source Type: Journal    
DOI: 10.1586/eri.12.9     Document Type: Review

References (117)

1. WHO. Part 1, Ten Highlights In Health Statistics. World Health Statistics. WHO (2008).
2. Lawn JE, Wilczynska-Ketende K, Cousens SN. Estimating the causes of 4 million neonatal deaths in the year 2000. Int. J. Epidemiol. 35(3), 706-718 (2006). (Pubitemid 43985565)
3. Urlichs F, Speer CP. Neutrophil function in preterm and term infants. Neoreviews 5(10), e417-e430 (2004).
4. Manroe BL, Weinberg AG, Rosenfeld CR, Browne R. The neonatal blood count in health and disease. I. Reference values for neutrophilic cells. J. Pediatr. 95(1), 89-98 (1979). (Pubitemid 9183688)
5. Levy O, Martin S, Eichenwald E et al. Impaired innate immunity in the newborn: newborn neutrophils are deficient in bactericidal/permeability- increasing protein. Pediatrics 104(6), 1327-1333 (1999).
6. Hogasen AK, Overlie I, Hansen TW, Abrahamsen TG, Finne PH, Hogasen K. The analysis of the complement activation product SC5 b-9 is applicable in neonates in spite of their profound C9 deficiency. J. Perinat. Med. 28(1), 39-48 (2000). (Pubitemid 30114116)
7. Miyano A, Miyamichi T, Nakayama M, Kitajima H, Shimizu A. Differences among acute, subacute, and chronic chorioamnionitis based on levels of inflammation-associated proteins in cord blood. Pediatr. Dev. Pathol. 1(6), 513-521 (1998). (Pubitemid 128542169)
8. Frakking FN, Brouwer N, Van Eijkelenburg Nk et al. Low mannose-binding lectin (MBL) levels in neonates with pneumonia and sepsis. Clin. Exp. Immunol. 150(2), 255-262 (2007). (Pubitemid 47609559)
9. Dzwonek AB, Neth OW, Thiebaut R et al. The role of mannose-binding lectin in susceptibility to infection in preterm neonates. Pediatr. Res. 63(6), 680-685 (2008).
10. Manzoni P, Rinaldi M, Cattani S et al. Bovine lactoferrin supplementation for prevention of late-onset sepsis in very low-birth-weight neonates: a randomized trial. JAMA 302(13), 1421-1428 (2009).
11. Marodi L. Neonatal innate immunity to infectious agents. Infect. Immun. 74(4), 1999-2006 (2006).
12. Kovarik J, Siegrist CA. Optimization of vaccine responses in early life: the role of delivery systems and immunomodulators. Immunol. Cell Biol. 76(3), 222-236 (1998). (Pubitemid 28281150)
13. Takeda K, Cretney E, Hayakawa Y et al. TRAIL identifies immature natural killer cells in newborn mice and adult mouse liver. Blood 105(5), 2082-2089 (2005). (Pubitemid 40731795)
14. Adkins B, Leclerc C, Marshall-Clarke S. Neonatal adaptive immunity comes of age. Nat. Rev. Immunol. 4(7), 553-564 (2004). (Pubitemid 38931770)
15. Wynn JL, Neu J, Moldawer LL, Levy O. Potential of immunomodulatory agents for prevention and treatment of neonatal sepsis. J. Perinatol. 29(2), 79-88 (2009).
16. Levy O. Innate immunity of the newborn: basic mechanisms and clinical correlates. Nat. Rev. Immunol. 7(5), 379-390 (2007). (Pubitemid 46674489)
17. Reis E, Sousa C. Toll-like receptors and dendritic cells: for whom the bug tolls. Semin. Immunol. 16(1), 27-34 (2004). (Pubitemid 38147431)
18. Pasare C, Medzhitov R. Toll-like receptors and acquired immunity. Semin. Immunol. 16(1), 23-26 (2004). (Pubitemid 38147430)
19. Dakic A, Shao QX, D'amico A et al. Development of the dendritic cell system during mouse ontogeny. J. Immunol. 172(2), 1018-1027 (2004). (Pubitemid 38113761)
20. Goriely S, Van Lint C, Dadkhah R et al. A defect in nucleosome remodeling prevents IL-12(p35) gene transcription in neonatal dendritic cells. J. Exp. Med. 199(7), 1011-1016 (2004). (Pubitemid 38481092)
21. Vanden Eijnden S, Goriely S, De Wit D, Goldman M, Willems F. Preferential production of the IL-12(p40)/IL-23(p19) heterodimer by dendritic cells from human newborns. Eur. J. Immunol. 36(1), 21-26 (2006). (Pubitemid 43116388)
22. Hallwirth U, Pomberger G, Zaknun D et al. Monocyte phagocytosis as a reliable parameter for predicting early-onset sepsis in very low birthweight infants. Early. Hum. Dev. 67(1-2), 1-9 (2002). (Pubitemid 34226667)
23. Klein RB, Fischer TJ, Gard SE, Biberstein M, Rich KC, Stiehm ER. Decreased mononuclear and polymorphonuclear chemotaxis in human newborns, infants, and young children. Pediatrics 60(4), 467-472 (1977). (Pubitemid 8208126)
24. Chelvarajan L, Popa D, Liu Y, Getchell TV, Stromberg AJ, Bondada S. Molecular mechanisms underlying anti-inflammatory phenotype of neonatal splenic macrophages. J. Leukoc. Biol. 82(2), 403-416 (2007). (Pubitemid 47230652)
25. Marodi L. Innate cellular immune responses in newborns. Clin. Immunol. 118(2-3), 137-144 (2006). (Pubitemid 43199650)
26. Aikio O, Vuopala K, Pokela ML, Hallman M. Diminished inducible nitric oxide synthase expression in fulminant early-onset neonatal pneumonia. Pediatrics 105(5), 1013-1019 (2000). (Pubitemid 30243777)
27. Nguyen M, Leuridan E, Zhang T et al. Acquisition of adult-like TLR4 and TLR9 responses during the first year of life. PLoS One 5(4), e10407 (2010).
28. De Wit D, Tonon S, Olislagers V et al. Impaired responses to toll-like receptor 4 and toll-like receptor 3 ligands in human cord blood. J. Autoimmun. 21(3), 277-281 (2003). (Pubitemid 37410116)
29. Belderbos ME, Van Bleek GM, Levy O et al. Skewed pattern of Toll-like receptor 4-mediated cytokine production in human neonatal blood: low LPS-induced IL-12p70 and high IL-10 persist throughout the first month of life. Clin. Immunol. 133(2), 228-237 (2009).
30. Sorg RV, Kogler G, Wernet P. Identification of cord blood dendritic cells as an immature CD11c-population. Blood 93(7), 2302-2307 (1999). (Pubitemid 29153633)
31. Goriely S, Vincart B, Stordeur P et al. Deficient IL-12(p35) gene expression by dendritic cells derived from neonatal monocytes. J. Immunol. 166(3), 2141-2146 (2001). (Pubitemid 32114705)
32. Koga Y, Matsuzaki A, Suminoe A, Hattori H, Hara T. Expression of cytokine-associated genes in dendritic cells (DCs): comparison between adult peripheral blood-and umbilical cord blood-derived DCs by cDNA microarray. Immunol. Lett. 116(1), 55-63 (2008).
33. Upham JW, Rate A, Rowe J, Kusel M, Sly PD, Holt PG. Dendritic cell immaturity during infancy restricts the capacity to express vaccine-specific T-cell memory. Infect. Immun. 74(2), 1106-1112 (2006). (Pubitemid 43185548)
34. Kollmann TR, Crabtree J, Rein-Weston A et al. Neonatal innate TLRmediated responses are distinct from those of adults. J. Immunol. 183(11), 7150-7160 (2009).
35. Angelone DF, Wessels MR, Coughlin M et al. 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(2), 205-209 (2006). (Pubitemid 44297594)
36. Caron JE, La Pine TR, Augustine NH, Martins TB, Hill HR. Multiplex analysis of toll-like receptor-stimulated neonatal cytokine response. Neonatology 97(3), 266-273 (2010).
37. Levy O, Zarember KA, Roy RM, Cywes C, Godowski PJ, Wessels MR. Selective impairment of TLRmediated 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(7), 4627-4634 (2004). (Pubitemid 39280696)
38. Levy O, Coughlin M, Cronstein BN, Roy RM, Desai A, Wessels MR. The adenosine system selectively inhibits TLRmediated TNF-alpha production in the human newborn. J. Immunol. 177(3), 1956-1966 (2006). (Pubitemid 44092536)
39. Schaub B, Liu J, Schleich I, Hoppler S, Sattler C, Von Mutius E. Impairment of T helper and T regulatory cell responses at birth. Allergy 63(11), 1438-1447 (2008).
40. Bogaert D, Weinberger D, Thompson C, Lipsitch M, Malley R. Impaired innate and adaptive immunity to Streptococcus pneumoniae and its effect on colonization in an infant mouse model. Infect. Immun. 77(4), 1613-1622 (2009).
41. Mold JE, Venkatasubrahmanyam S, Burt TD et al. Fetal and adult hematopoietic stem cells give rise to distinct T cell lineages in humans. Science 330(6011), 1695-1699 (2010).
42. Takahata Y, Nomura A, Takada H et al. CD25+CD4+ T cells in human cord blood: an immunoregulatory subset with naive phenotype and specific expression of forkhead box p3 (Foxp3) gene. Exp. Hematol. 32(7), 622-629 (2004). (Pubitemid 38891531)
43. Miyara M, Yoshioka Y, Kitoh A et al. Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. Immunity 30(6), 899-911 (2009).
44. You D, Ripple M, Balakrishna S et al. Inchoate CD8+ T cell responses in neonatal mice permit influenza-induced persistent pulmonary dysfunction. J. Immunol. 181(5), 3486-3494 (2008).
45. Fernandez MA, Evans IA, Hassan EH, Carbone FR, Jones CA. Neonatal CD8+ T cells are slow to develop into lytic effectors after HSV infection in vivo. Eur. J. Immunol. 38(1), 102-113 (2008).
46. Welliver TP, Garofalo RP, Hosakote Y et al. Severe human lower respiratory tract illness caused by respiratory syncytial virus and influenza virus is characterized by the absence of pulmonary cytotoxic lymphocyte responses. J. Infect. Dis. 195(8), 1126-1136 (2007). (Pubitemid 46543443)
47. Lenschow DJ, Walunas TL, Bluestone JA. CD28/B7 system of T cell costimulation. Annu. Rev. Immunol. 14, 233-258 (1996). (Pubitemid 26130184)
48. Mccarron MJ, Reen DJ. Neonatal CD8+ T-cell differentiation is dependent on interleukin-12. Hum. Immunol. 71(12), 1172-1179 (2010).
49. Streilein JW. Neonatal tolerance: towards an immunogenetic definition of self. Immunol. Rev. 46, 123-146 (1979).
50. Kovarik J, Gaillard M, Martinez X et al. Induction of adult-like antibody, Th1, and CTL responses to measles hemagglutinin by early life murine immunization with an attenuated vaccinia-derived NYVAC(K1L) viral vector. Virology 285(1), 12-20 (2001). (Pubitemid 32589003)
51. Schallert N, Pihlgren M, Kovarik J et al. Generation of adult-like antibody avidity profiles after early-life immunization with protein vaccines. Eur. J. Immunol. 32(3), 752-760 (2002). (Pubitemid 34257553)
52. Marshall-Clarke S, Tasker L, Parkhouse RM. Immature B lymphocytes from adult bone marrow exhibit a selective defect in induced hyperexpression of major histocompatibility complex class II and fail to show B7.2 induction. Immunology 100(2), 141-151 (2000). (Pubitemid 30348859)
53. Bot A, Bona C. Genetic immunization of neonates. Microbes Infect. 4(4), 511-520 (2002). (Pubitemid 34270688)
54. Wardemann H, Yurasov S, Schaefer A, Young JW, Meffre E, Nussenzweig MC. Predominant autoantibody production by early human B cell precursors. Science 301(5638), 1374-1377 (2003). (Pubitemid 37075812)
55. Carsetti R, Rosado MM, Wardmann H. Peripheral development of B cells in mouse and man. Immunol. Rev. 197, 179-191 (2004). (Pubitemid 38142176)
56. Pihlgren M, Schallert N, Tougne C et al. Delayed and deficient establishment of the long-term bone marrow plasma cell pool during early life. Eur. J. Immunol. 31(3), 939-946 (2001). (Pubitemid 32237130)
57. Pihlgren M, Friedli M, Tougne C, Rochat AF, Lambert PH, Siegrist CA. Reduced ability of neonatal and early-life bone marrow stromal cells to support plasmablast survival. J. Immunol. 176(1), 165-172 (2006). (Pubitemid 43023260)
58. Belnoue E, Pihlgren M, Mcgaha Tl et al. APRIL is critical for plasmablast survival in the bone marrow and poorly expressed by early-life bone marrow stromal cells. Blood 111(5), 2755-2764 (2008).
59. Zinkernagel RM. Maternal antibodies, childhood infections, and autoimmune diseases. N. Engl. J. Med. 345(18), 1331-1335 (2001).
60. Gray JW. Surveillance of infection in neonatal intensive care units. Early Hum. Dev. 83(3), 157-163 (2007). (Pubitemid 46335941)
61. Kaufman D, Fairchild KD. Clinical microbiology of bacterial and fungal sepsis in very-low-birth-weight infants. Clin. Microbiol. Rev. 17(3), 638-680 (2004). (Pubitemid 38970686)
62. Klinger G, Levy I, Sirota L, Boyko V, Reichman B, Lerner-Geva L. Epidemiology and risk factors for early onset sepsis among very-low-birthweight infants. Am. J. Obstet. Gynecol. 201(1), 38; e31-e36 (2009).
63. Van Den Hoogen A, Gerards LJ, Verboon-Maciolek MA, Fleer A, Krediet TG. Long-term trends in the epidemiology of neonatal sepsis and antibiotic susceptibility of causative agents. Neonatology 97(1), 22-28 (2010).
64. Chelvarajan RL, Collins SM, Doubinskaia IE et al. Defective macrophage function in neonates and its impact on unresponsiveness of neonates to polysaccharide antigens. J. Leukoc. Biol. 75(6), 982-994 (2004). (Pubitemid 38720638)
65. Wing EJ, Gregory SH. Listeria monocytogenes: clinical and experimental update. J. Infect. Dis. 185(Suppl. 1), S18-S24 (2002). (Pubitemid 34142825)
66. Siegman-Igra Y, Levin R, Weinberger M et al. Listeria monocytogenes infection in Israel and review of cases worldwide. Emerg. Infect. Dis. 8(3), 305-310 (2002). (Pubitemid 34266269)
67. Ito S, Ishii KJ, Gursel M, Shirotra H, Ihata A, Klinman DM. CpG oligodeoxynucleotides enhance neonatal resistance to Listeria infection. J. Immunol. 174(2), 777-782 (2005). (Pubitemid 40094272)
68. Barrier M, Lacroix-Lamande S, Mancassola R et al. Oral and intraperitoneal administration of phosphorothioate oligodeoxynucleotides leads to control of Cryptosporidium parvum infection in neonatal mice. J. Infect. Dis. 193(10), 1400-1407 (2006). (Pubitemid 43673388)
69. Levy O, Sisson RB, Kenyon J, Eichenwald E, Macone AB, Goldmann D. Enhancement of neonatal innate defense: effects of adding an N-terminal recombinant fragment of bactericidal/permeability-increasing protein on growth and tumor necrosis factor-inducing activity of gram-negative bacteria tested in neonatal cord blood ex vivo. Infect. Immun. 68(9), 5120-5125 (2000).
70. Doss M, White MR, Tecle T et al. Interactions of alpha-, beta-, and theta-defensins with influenza A virus and surfactant protein D. J. Immunol. 182(12), 7878-7887 (2009).
71. Kirikae T, Hirata M, Yamasu H et al. Protective effects of a human 18-kilodalton cationic antimicrobial protein (CAP18)-derived peptide against murine endotoxemia. Infect. Immun. 66(5), 1861-1868 (1998). (Pubitemid 28194075)
72. Fukumoto K, Nagaoka I, Yamataka A et al. Effect of antibacterial cathelicidin peptide CAP18/LL-37 on sepsis in neonatal rats. Pediatr. Surg. Int. 21(1), 20-24 (2005). (Pubitemid 40169453)
73. Kaguelidou F, Pandolfini C, Manzoni P, Choonara I, Bonati M, Jacqz-Aigrain E. European survey on the use of prophylactic fluconazole in neonatal intensive care units. Eur. J. Pediatr. doi:10.1007/s00431-011-1565-8 (2011) (Epub ahead of print).
74. Manzoni P, Rizzollo S, Vain N et al. Probiotics use in preterm neonates: what further evidence is needed? Early Hum. Dev. 87(Suppl 1.) S3-S4 (2011).
75. Manzoni P, Rizzollo S, Decembrino L et al. Recent advances in prevention of sepsis in the premature neonates in NICU. Early Hum. Dev. 87(Suppl 1.) S31-S33 (2011).
76. Manzoni P, Mostert M, Stronati M. Lactoferrin for prevention of neonatal infections. Curr. Opin. Infect. Dis. 24(3), 177-182 (2011).
77. Farnaud S, Evans RW. Lactoferrin -a multifunctional protein with antimicrobial properties. Mol. Immunol. 40(7), 395-405 (2003). (Pubitemid 37244032)
78. Gifford JL, Hunter HN, Vogel HJ. Lactoferricin: a lactoferrin-derived peptide with antimicrobial, antiviral, antitumor and immunological properties. Cell Mol. Life Sci. 62(22), 2588-2598 (2005). (Pubitemid 41721232)
79. Kuipers ME, De Vries HG, Eikelboom MC, Meijer DK, Swart PJ. Synergistic fungistatic effects of lactoferrin in combination with antifungal drugs against clinical Candida isolates. Antimicrob. Agents Chemother. 43(11), 2635-2641 (1999). (Pubitemid 29519541)
80. Venkatesh MP, Pham D, Kong L, Weisman LE. Prophylaxis with lactoferrin, a novel antimicrobial agent, in a neonatal rat model of coinfection. Adv. Ther. 24(5), 941-954 (2007). (Pubitemid 350274771)
81. Pammi M, Abrams SA. Oral lactoferrin for the treatment of sepsis and necrotizing enterocolitis in neonates. Cochrane Database Syst. Rev. 10, CD007138 (2011).
82. Wynn JL, Scumpia PO, Winfield Rd et al. Defective innate immunity predisposes murine neonates to poor sepsis outcome but is reversed by TLR agonists. Blood 112(5), 1750-1758 (2008).
83. Roth A, Jensen H, Garly Ml et al. Low birth weight infants and Calmette-Guerin bacillus vaccination at birth: community study from Guinea-Bissau. Pediatr. Infect. Dis. J. 23(6), 544-550 (2004). (Pubitemid 38802300)
84. Echeverry A, Saijo S, Schesser K, Adkins B. Yersinia enterocolitica promotes robust mucosal inflammatory T-cell immunity in murine neonates. Infect. Immun. 78(8), 3595-3608 (2010).
85. Vancott JL, Prada AE, Mcneal MM et al. Mice develop effective but delayed protective immune responses when immunized as neonates either intranasally with nonliving VP6/LT(R192G) or orally with live rhesus rotavirus vaccine candidates. J. Virol. 80(10), 4949-4961 (2006).
86. Bjarnarson SP, Jakobsen H, Del Giudice G, Trannoy E, Siegrist CA, Jonsdottir I. The advantage of mucosal immunization for polysaccharide-specific memory responses in early life. Eur. J. Immunol. 35(4), 1037-1045 (2005). (Pubitemid 40542210)
87. Bowman LM, Holt PG. Selective enhancement of systemic Th1 immunity in immunologically immature rats with an orally administered bacterial extract. Infect. Immun. 69(6), 3719-3727 (2001). (Pubitemid 32493290)
88. Empey KM, Hollifield M, Garvy BA. Exogenous heat-killed Escherichia coli improves alveolar macrophage activity and reduces Pneumocystis carinii lung burden in infant mice. Infect. Immun. 75(7), 3382-3393 (2007). (Pubitemid 47040939)
89. Gareau MG, Wine E, Reardon C, Sherman PM. Probiotics prevent death caused by Citrobacter rodentium infection in neonatal mice. J. Infect. Dis. 201(1), 81-91 (2010).
90. Arnold IC, Lee JY, Amieva MR et al. Tolerance rather than immunity protects from Helicobacter pylori-induced gastric preneoplasia. Gastroenterology 140(1), 199-209 (2011).
91. Singh AM, Busse WW. Asthma exacerbations. 2: aetiology. Thorax 61(9), 809-816 (2006).
92. Tregoning JS, Yamaguchi Y, Harker J, Wang B, Openshaw PJ. The role of T cells in the enhancement of respiratory syncytial virus infection severity during adult reinfection of neonatally sensitized mice. J. Virol. 82(8), 4115-4124 (2008). (Pubitemid 351521246)
93. Dakhama A, Park JW, Taube C et al. The enhancement or prevention of airway hyperresponsiveness during reinfection with respiratory syncytial virus is critically dependent on the age at first infection and IL-13 production. J. Immunol. 175(3), 1876-1883 (2005). (Pubitemid 41023094)
94. Sigurs N, Aljassim F, Kjellman B et al. Asthma and allergy patterns over 18 years after severe RSV bronchiolitis in the first year of life. Thorax 65(12), 1045-1052 (2010).
95. Brown ZA, Selke S, Zeh J et al. The acquisition of herpes simplex virus during pregnancy. N. Engl. J. Med. 337(8), 509-515 (1997). (Pubitemid 27352016)
96. Cheeran MC, Lokensgard JR, Schleiss MR. Neuropathogenesis of congenital cytomegalovirus infection: disease mechanisms and prospects for intervention. Clin. Microbiol. Rev. 22(1), 99-126 (2009).
97. Gandhi MK, Khanna R. Human cytomegalovirus: clinical aspects, immune regulation, and emerging treatments. Lancet Infect. Dis. 4(12), 725-738 (2004). (Pubitemid 39574344)
98. Kenneson A, Cannon MJ. Review and meta-analysis of the epidemiology of congenital cytomegalovirus (CMV) infection. Rev. Med. Virol. 17(4), 253-276 (2007). (Pubitemid 47066638)
99. Miles DJ, Sande M, Kaye S et al. CD4(+) T cell responses to cytomegalovirus in early life: a prospective birth cohort study. J. Infect. Dis. 197(5), 658-662 (2008). (Pubitemid 351364463)
100. Tu W, Chen S, Sharp M et al. Persistent and selective deficiency of CD4+ T cell immunity to cytomegalovirus in immunocompetent young children. J. Immunol. 172(5), 3260-3267 (2004). (Pubitemid 38263718)
101. Renneson J, Dutta B, Goriely S et al. IL-12 and type I IFN response of neonatal myeloid DC to human CMV infection. Eur. J. Immunol. 39(10), 2789-2799 (2009).
102. Iversen AC, Steinkjer B, Nilsen N et al. A proviral role for CpG in cytomegalovirus infection. J. Immunol. 182(9), 5672-5681 (2009).
103. Bukowski JF, Warner JF, Dennert G, Welsh RM. Adoptive transfer studies demonstrating the antiviral effect of natural killer cells in vivo. J. Exp. Med. 161(1), 40-52 (1985). (Pubitemid 15169719)
104. Sun JC, Beilke JN, Lanier LL. Adaptive immune features of natural killer cells. Nature 457(7229), 557-561 (2009).
105. Siegle JS, Hansbro N, Dong C, Angkasekwinai P, Foster PS, Kumar RK. Blocking induction of T helper type 2 responses prevents development of disease in a model of childhood asthma. Clin. Exp. Immunol. 165(1), 19-28 (2011).
106. Ripple MJ, You D, Honnegowda S et al. Immunomodulation with IL-4R alpha antisense oligonucleotide prevents respiratory syncytial virus-mediated pulmonary disease. J. Immunol. 185(8), 4804-4811 (2010).
107. Gill MA, Bajwa G, George TA et al. Counterregulation between the FcepsilonRI pathway and antiviral responses in human plasmacytoid dendritic cells. J. Immunol. 184(11), 5999-6006 (2010).
108. Janssen R, Bont L, Siezen Cl et al. Genetic susceptibility to respiratory syncytial virus bronchiolitis is predominantly associated with innate immune genes. J. Infect. Dis. 196(6), 826-834 (2007). (Pubitemid 47378931)
109. Siezen CL, Bont L, Hodemaekers HM et al. Genetic susceptibility to respiratory syncytial virus bronchiolitis in preterm children is associated with airway remodeling genes and innate immune genes. Pediatr. Infect. Dis. J. 28(4), 333-335 (2009).
110. De Brito CA, Goldoni AL, Sato MN. Immune adjuvants in early life: targeting the innate immune system to overcome impaired adaptive response. Immunotherapy 1(5), 883-895 (2009).
111. Pedras-Vasconcelos JA, Goucher D, Puig M et al. CpG oligodeoxynucleotides protect newborn mice from a lethal challenge with the neurotropic Tacaribe arenavirus. J. Immunol. 176(8), 4940-4949 (2006).
112. Nichani AK, Dar MA, Mirakhur KK et al. Subcutaneous, but not intratracheal administration of the TLR9 agonist, CpG DNA transiently reduces parainfluenza-3 virus shedding in newborn lambs. Comp. Immunol. Microbiol. Infect. Dis. 33(6), e111-e117 (2010).
113. Pulendran B, Ahmed R. Immunological mechanisms of vaccination. Nat. Immunol. 12(6), 509-517 (2011).
114. Mbow ML, De Gregorio E, Valiante NM, Rappuoli R. New adjuvants for human vaccines. Curr. Opin. Immunol. 22(3), 411-416 (2010).
115. Coffman RL, Sher A, Seder RA. Vaccine adjuvants: putting innate immunity to work. Immunity 33(4), 492-503 (2010).
116. Pedras-Vasconcelos JA, Puig M, Sauder C et al. Immunotherapy with CpG oligonucleotides and antibodies to TNF-alpha rescues neonatal mice from lethal arenavirus-induced meningoencephalitis. J. Immunol. 180(12), 8231-8240 (2008).
117. Zhao J, Kim KD, Yang X, Auh S, Fu YX, Tang H. Hyper innate responses in neonates lead to increased morbidity and mortality after infection. Proc. Natl. Acad. Sci. USA 105(21), 7528-7533 (2008). (Pubitemid 351830052)