The newborn and infant periods of early life are associated with heightened vulnerability to infection. Limited antigen exposure and distinct adaptive immune function compared to the adult places a greater burden on innate immunity for host defense to microbial challenge during this time. Trained immunity describes the phenomenon of augmented innate immune function following a stimulus that is not specific to the original stimulus. We review the concept of trained immunity in the context of the newborn's unique innate immune system function, the preclinical and clinical evidence that supports the tenet of innate immune memory in early life, and potential consequences of altered innate immune host responses.

Keywords:
Newborn, Infant, Trained immunity, Innate immunity
1.
Mackaness GB: The immunological basis of acquired cellular resistance. J Exp Med 1964;120:105-120.
2.
Netea MG, Quintin J, van der Meer JW: Trained immunity: a memory for innate host defense. Cell Host Microbe 2011;9:355-361.
3.
Rodrigues J, Brayner FA, Alves LC, Dixit R, Barillas-Mury C: Hemocyte differentiation mediates innate immune memory in Anopheles gambiae mosquitoes. Science 2010;329:1353-1355.
4.
Durrant WE, Dong X: Systemic acquired resistance. Annu Rev Phytopathol 2004;42:185-209.
5.
Slaughter A, Daniel X, Flors V, Luna E, Hohn B, Mauch-Mani B: Descendants of primed arabidopsis plants exhibit resistance to biotic stress. Plant Physiol 2012;158:835-843.
6.
Kurtz J: Specific memory within innate immune systems. Trends Immunol 2005;26:186-192.
7.
Moret Y, Siva-Jothy MT: Adaptive innate immunity? Responsive-mode prophylaxis in the mealworm beetle, Tenebrio molitor. Proc Biol Sci 2003;270:2475-2480.
8.
Perry VH, Nicoll JA, Holmes C: Microglia in neurodegenerative disease. Nat Rev Neurol 2010;6:193-201.
9.
Benn CS, Netea MG, Selin LK, Aaby P: A small jab - a big effect. Nonspecific immunomodulation by vaccines. Trends Immunol 2013;34:431-439.
10.
Strunk T, Currie A, Richmond P, Simmer K, Burgner D: Innate immunity in human newborn infants: prematurity means more than immaturity. J Matern Fetal Neonatal Med 2011;24:25-31.
11.
Belderbos ME, van Bleek GM, Levy O, Blanken MO, Houben ML, Schuijff L, Kimpen JL, Bont L: 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 2009;133:228-237.
12.
Kollmann TR, Crabtree J, Rein-Weston A, Blimkie D, Thommai F, Wang XY, Lavoie PM, Furlong J, Fortuno ES 3rd, Hajjar AM, Hawkins NR, Self SG, Wilson CB: Neonatal innate TLR-mediated responses are distinct from those of adults. J Immunol 2009;183:7150-7160.
13.
Wynn JL, Levy O: Role of innate host defenses in susceptibility to early-onset neonatal sepsis. Clin Perinatol 2010;37:307-337.
14.
Kollmann TR, Levy O, Montgomery RR, Goriely S: Innate immune function by Toll-like receptors: distinct responses in newborns and the elderly. Immunity 2012;37:771-783.
15.
Kumagai Y, Takeuchi O, Akira S: Pathogen recognition by innate receptors. J Infect Chemother 2008;14:86-92.
16.
Trinchieri G, Sher A: Cooperation of Toll-like receptor signals in innate immune defense. Nat Rev Immunol 2007;7:179-190.
17.
Kawai T, Akira S: Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity 2011;34:637-650.
18.
Krumbiegel D, Zepp F, Meyer CU: Combined toll-like receptor agonists synergistically increase production of inflammatory cytokines in human neonatal dendritic cells. Hum Immunol 2007;68:813-822.
19.
Levy O, Zarember KA, Roy RM, Cywes C, Godowski PJ, Wessels MR: 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 2004;173:4627-4634.
20.
Sadeghi K, Berger A, Langgartner M, Prusa AR, Hayde M, Herkner K, Pollak A, Spittler A, Forster-Waldl E: Immaturity of infection control in preterm and term newborns is associated with impaired Toll-like receptor signaling. J Infect Dis 2007;195:296-302.
21.
Shen CM, Lin SC, Niu DM, Kou YR: Development of monocyte Toll-like receptor 2 and Toll-like receptor 4 in preterm newborns during the first few months of life. Pediatr Res 2013;73:685-691.
22.
Hotchkiss RS, Karl IE: The pathophysiology and treatment of sepsis. N Engl J Med 2003;348:138-150.
23.
Ng PC, Li K, Wong RP, Chui K, Wong E, Li G, Fok TF: Proinflammatory and anti-inflammatory cytokine responses in preterm infants with systemic infections. Arch Dis Child Fetal Neonatal Ed 2003;88:F209-F213.
24.
Elahi S, Ertelt JM, Kinder JM, Jiang TT, Zhang X, Xin L, Chaturvedi V, Strong BS, Qualls JE, Steinbrecher KA, Kalfa TA, Shaaban AF, Way SS: Immunosuppressive CD71+ erythroid cells compromise neonatal host defence against infection. Nature 2013, DOI: 10.1038/nature12675.
25.
Belderbos ME, Levy O, Meyaard L, Bont L: Plasma-mediated immune suppression: a neonatal perspective. Pediatr Allergy Immunol 2013;24:102-113.
26.
Belderbos ME, Levy O, Stalpers F, Kimpen JL, Meyaard L, Bont L: Neonatal plasma polarizes TLR4-mediated cytokine responses towards low IL-12p70 and high IL-10 production via distinct factors. PLoS One 2012;7:e33419.
27.
Levy O, Coughlin M, Cronstein BN, Roy RM, Desai A, Wessels MR: The adenosine system selectively inhibits TLR-mediated TNF-alpha production in the human newborn. J Immunol 2006;177:1956-1966.
28.
Pettengill M, Robson S, Tresenriter M, Millan JL, Usheva A, Bingham T, Belderbos M, Bergelson I, Burl S, Kampmann B, Gelinas L, Kollmann T, Bont L, Levy O: Soluble ecto-5′-nucleotidase (5′nt), alkaline phosphatase, and adenosine deaminase (ada1) activities in neonatal blood favor elevated extracellular adenosine. J Biol Chem 2013;288:27315-273126.
29.
Jones SA: Directing transition from innate to acquired immunity: defining a role for IL-6. Immunology 2005;175:3463-3468.
30.
Wynn JL, Neu J, Moldawer LL, Levy O: Potential of immunomodulatory agents for prevention and treatment of neonatal sepsis. J Perinatol 2009;29:79-88.
31.
Zentay Z, Sharaf M, Qadir M, Drafta D, Davidson D: Mechanism for dexamethasone inhibition of neutrophil migration upon exposure to lipopolysaccharide in vitro: role of neutrophil interleukin-8 release. Pediatr Res 1999;46:406-410.
32.
Molloy EJ, O'Neill AJ, Grantham JJ, Sheridan-Pereira M, Fitzpatrick JM, Webb DW, Watson RW: Labor promotes neonatal neutrophil survival and lipopolysaccharide responsiveness. Pediatr Res 2004;56:99-103.
33.
Shen CM, Lin SC, Niu DM, Kou YR: Labour increases the surface expression of two Toll-like receptors in the cord blood monocytes of healthy term newborns. Acta Paediatr 2009;98:959-962.
34.
Yektaei-Karin E, Moshfegh A, Lundahl J, Berggren V, Hansson LO, Marchini G: The stress of birth enhances in vitro spontaneous and IL-8-induced neutrophil chemotaxis in the human newborn. Pediatr Allergy Immunol 2007;18:643-651.
35.
Zhang JP, Yang Y, Levy O, Chen C: Human neonatal peripheral blood leukocytes demonstrate pathogen-specific coordinate expression of TLR2, TLR4/MD2, and MyD88 during bacterial infection in vivo. Pediatr Res 2010;68:479-483.
36.
Wynn JL, Scumpia PO, Winfield RD, Delano MJ, Kelly-Scumpia K, Barker T, Ungaro R, Levy O, Moldawer LL: Defective innate immunity predisposes murine neonates to poor sepsis outcome but is reversed by TLR agonists. Blood 2008;112:1750-1758.
37.
Ito S, Ishii KJ, Gursel M, Shirotra H, Ihata A, Klinman DM: Cpg oligodeoxynucleotides enhance neonatal resistance to Listeria infection. J Immunol 2005;174:777-782.
38.
Pedras-Vasconcelos JA, Goucher D, Puig M, Tonelli LH, Wang V, Ito S, Verthelyi D: CPG oligodeoxynucleotides protect newborn mice from a lethal challenge with the neurotropic Tacaribe arena virus. J Immunol 2006;176:4940-4949.
39.
Kramer BW, Ikegami M, Moss TJ, Nitsos I, Newnham JP, Jobe AH: Endotoxin-induced chorioamnionitis modulates innate immunity of monocytes in preterm sheep. Am J Resp Crit Care Mede 2005;171:73-77.
40.
Kramer BW, Joshi SN, Moss TJ, Newnham JP, Sindelar R, Jobe AH, Kallapur SG: Endotoxin-induced maturation of monocytes in preterm fetal sheep lung. Am J Physiol Lung Cell Mol Physiol 2007;293:L345-L353.
41.
Strunk T, Doherty D, Jacques A, Simmer K, Richmond P, Kohan R, Charles A, Burgner D: Histologic chorioamnionitis is associated with reduced risk of late-onset sepsis in preterm infants. Pediatrics 2012;129:e134-e141.
42.
Wynn JL, Lopez MC, Ungaro R, Baker HV, Moldawer LL: Histologic Chorioamnionitis Exposure in the Absence of Infection Activates Early Expression of Innate Immunity-Related Genes in Preterm Newborns. Washington, Pediatric Academic Societies, 2013.
43.
Lin CB, Hornik CP, Clark R, Cotten CM, Benjamin DK Jr, Cohen-Wolkoweiz M, Smith PB, Wynn JL: Very low birth weight neonates who survive early-onset sepsis do not have an increased risk of developing late-onset sepsis. Early Hum Dev 2012;88:905-909.
44.
Wynn JL, Hansen NI, Das A, Cotten CM, Goldberg RN, Sanchez PJ, Bell EF, Van Meurs KP, Carlo WA, Laptook AR, Higgins RD, Benjamin DK Jr, Stoll BJ: Early sepsis does not increase the risk of late sepsis in very low birth weight neonates. J Pediatr 2013;162:942-948.
45.
Flanagan KL, van Crevel R, Curtis N, Shann F, Levy O: Heterologous (‘nonspecific') and sex-differential effects of vaccines: epidemiology, clinical trials, and emerging immunologic mechanisms. Clin Infect 2013;57:283-289.
46.
Gbédandé K, Varani S, Ibitokou S, Houngbegnon P, Borgella S, Nouatin O, Ezinmegnon S, Adeothy AL, Cottrell G, Massougbodji A, Moutairou K, Troye-Blomberg M, Deloron P, Fievet N, Luty AJ: Malaria modifies neonatal and early-life toll-like receptor cytokine responses. Infect Immun 2013;81:2686-2696.
47.
Sanchez-Schmitz G, Levy O: Development of newborn and infant vaccines. Sci Transl Med 2011;3:90ps27.
48.
Aaby P, Roth A, Ravn H, Napirna BM, Rodrigues A, Lisse IM, Stensballe L, Diness BR, Lausch KR, Lund N, Biering-Sorensen S, Whittle H, Benn CS: Randomized trial of BCG vaccination at birth to low-birth-weight children: beneficial nonspecific effects in the neonatal period? J Infect Dis 2011;204:245-252.
49.
Roth A, Jensen H, Garly ML, Djana Q, Martins CL, Sodemann M, Rodrigues A, Aaby P: Low birth weight infants and Calmette-Guerin bacillus vaccination at birth. Community study from Guinea-Bissau. Pediatr Infect Dis J 2004;23:544-550.
50.
Grischkan J, Storfer-Isser A, Rosen CL, Larkin EK, Kirchner HL, South A, Wilson-Costello DC, Martin RJ, Redline S: Variation in childhood asthma among former preterm infants. J Pediatr 2004;144:321-326.
51.
Saarinen UM, Kajosaari M: Breastfeeding as prophylaxis against atopic disease. Prospective follow-up study until 17 years old. Lancet 1995;346:1065-1069.
52.
Stoll BJ, Hansen NI, Bell EF, Shankaran S, Laptook AR, Walsh MC, Hale EC, Newman NS, Schibler K, Carlo WA, Kennedy KA, Poindexter BB, Finer NN, Ehrenkranz RA, Duara S, Sanchez PJ, O'Shea TM, Goldberg RN, Van Meurs KP, Faix RG, Phelps DL, Frantz ID 3rd, Watterberg KL, Saha S, Das A, Higgins RD: Neonatal outcomes of extremely preterm infants from the NICHD neonatal research network. Pediatrics 2010;126:443-456.
53.
Thomas W, Speer CP: Chorioamnionitis: important risk factor or innocent bystander for neonatal outcome? Neonatology 2011;99:177-187.
54.
Khwaja O, Volpe JJ: Pathogenesis of cerebral white matter injury of prematurity. Arch Dis Child Fetal Neonatal Ed 2008;93:F153-F161.
55.
Malaeb S, Dammann O: Fetal inflammatory response and brain injury in the preterm newborn. J Child Neurol 2009;24:1119-1126.
56.
Ambalavanan N, Carlo WA, D'Angio CT, McDonald SA, Das A, Schendel D, Thorsen P, Higgins RD: Cytokines associated with bronchopulmonary dysplasia or death in extremely low birth weight infants. Pediatrics 2009;123:1132-1141.
57.
Abitbol CL, Rodriguez MM: The long-term renal and cardiovascular consequences of prematurity. Nat Rev Nephrol 2012;8:265-274.
58.
Rogers LK, Velten M: Maternal inflammation, growth retardation, and preterm birth: insights into adult cardiovascular disease. Life Sci 2011;89:417-421.
59.
Barker DJ, Osmond C: Infant mortality, childhood nutrition, and ischaemic heart disease in England and Wales. Lancet 1986;i:1077-1081.
60.
Brocklehurst P, Gordon A, Heatley E, Milan SJ: Antibiotics for treating bacterial vaginosis in pregnancy. Cochrane Database Syst Rev 2013;1:CD000262.
61.
Michalowicz BS, Hodges JS, DiAngelis AJ, Lupo VR, Novak MJ, Ferguson JE, Buchanan W, Bofill J, Papapanou PN, Mitchell DA, Matseoane S, Tschida PA: Treatment of periodontal disease and the risk of preterm birth. N Engl J Med 2006;355:1885-1894.
62.
Goldenberg RL, Culhane JF, Iams JD, Romero R: Epidemiology and causes of preterm birth. Lancet 2008;371:75-84.
63.
Blencowe H, Cousens S, Oestergaard MZ, Chou D, Moller AB, Narwal R, Adler A, Vera Garcia C, Rohde S, Say L, Lawn JE: National, regional, and worldwide estimates of preterm birth rates in the year 2010 with time trends since 1990 for selected countries: a systematic analysis and implications. Lancet 2012;379:2162-2172.
64.
Norman JE, Shennan AH: Prevention of preterm birth - why can't we do any better? Lancet 2013;381:184-185.
© 2013 S. Karger AG, Basel
2013
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