title: Maturation of innate responses to mycobacteria over the first nine months of life.
abstract: Newborns and young infants are particularly susceptible to infections, including Mycobacterium tuberculosis. Further, immunogenicity of vaccines against tuberculosis and other infectious diseases appears suboptimal early in life compared with later in life. We hypothesized that developmental changes in innate immunity would underlie these observations. To determine the evolution of innate responses to mycobacteria early in life, whole blood or PBMC from newborns, as well as 10- and 36-wk-old infants, was incubated with viable Mycobacterium bovis bacillus Calmette-Guérin or TLR ligands. Innate cell expression of cytokines and maturation markers was assessed, as well as activation of the proinflammatory NF-κB- and MAPK-signaling pathways. Bacillus Calmette-Guérin-induced production of the proinflammatory cytokines TNF-α, IL-6, and IL-12p40 increased from the newborn period to 9 mo of age in monocytes but not in myeloid dendritic cells. No changes in production of anti-inflammatory IL-10 were observed. CD40 expression increased with age in both cell populations. Older infants displayed substantial activation of all three signal transduction molecules: degradation of NF-κB inhibitor IκBα and phosphorylation of MAPK Erk and p38 upon TLR1/2 triggering, compared with predominant activation of only one of any of these molecules in newborns. Maturation of innate proinflammatory responses during the first 9 mo of life may underlie more effective control of mycobacteria and other pathogens observed later in infancy and age-related differential induction of Th1 responses by vaccination.
authors.affiliation: South African Tuberculosis Vaccine Initiative and School of Child and Adolescent Health, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town 7925, South Africa;
authors.forename: Muki S
authors.initials: MS
authors.lastname: Shey
authors.forename: Elisa
authors.initials: E
authors.lastname: Nemes
authors.forename: Wendy
authors.initials: W
authors.lastname: Whatney
authors.forename: Marwou
authors.initials: M
authors.lastname: de Kock
authors.forename: Hadn
authors.initials: H
authors.lastname: Africa
authors.forename: Charlene
authors.initials: C
authors.lastname: Barnard
authors.forename: Michele
authors.initials: M
authors.lastname: van Rooyen
authors.forename: Lynnett
authors.initials: L
authors.lastname: Stone
authors.forename: Catherine
authors.initials: C
authors.lastname: Riou
authors.forename: Tobias
authors.initials: T
authors.lastname: Kollmann
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Hawn
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Scriba
authors.forename: Willem A
authors.initials: WA
authors.lastname: Hanekom
mesh_terms: D000328:Adult; D000367:Age Factors; D000375:Aging / Q000502:physiology*; D019013:CD40 Antigens / Q000378:metabolism; D016207:Cytokines / Q000276:immunology; D005260:Female; D006801:Humans; D007113:Immunity, Innate / Q000502:physiology*; D007223:Infant; D007231:Infant, Newborn; D020935:MAP Kinase Signaling System / Q000276:immunology*; D008297:Male; D009000:Monocytes / Q000276:immunology*; D009163:Mycobacterium bovis / Q000276:immunology*; D016328:NF-kappa B / Q000276:immunology; D051194:Toll-Like Receptor 1 / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000276:immunology
chemical_list: D019013:CD40 Antigens; D016207:Cytokines; D016328:NF-kappa B; C495342:TLR2 protein, human; D051194:Toll-Like Receptor 1; D051195:Toll-Like Receptor 2
references.citation: Cell Microbiol. 2003 Mar;5(3):133-42
references.pmid: 12614457
references.citation: Infect Immun. 2002 Sep;70(9):4961-7
references.pmid: 12183542
references.citation: J Allergy Clin Immunol. 2009 Sep;124(3):544-50, 550.e1-2
references.pmid: 19500827
references.citation: J Immunol. 1996 Apr 15;156(8):2700-9
references.pmid: 8609386
references.citation: Eur Respir J. 2006 Oct;28(4):721-9
references.pmid: 16870663
references.citation: Proc Natl Acad Sci U S A. 2012 Oct 23;109(43):17537-42
references.pmid: 22988082
references.citation: World J Pediatr. 2010 May;6(2):132-40
references.pmid: 20127220
references.citation: J Matern Fetal Neonatal Med. 2011 Jan;24(1):25-31
references.pmid: 20569168
references.citation: Acta Paediatr. 2006 May;95(5):535-9
references.pmid: 16825132
references.citation: Clin Dev Immunol. 2011;2011:405310
references.pmid: 21603213
references.citation: JAMA. 1994 Mar 2;271(9):698-702
references.pmid: 8309034
references.citation: Pediatr Pulmonol. 2008 May;43(5):505-10
references.pmid: 18383116
references.citation: Clin Immunol. 2009 Nov;133(2):228-37
references.pmid: 19648060
references.citation: Front Cell Infect Microbiol. 2012 Nov 23;2:145
references.pmid: 23189273
references.citation: J Immunol. 2009 Dec 1;183(11):7150-60
references.pmid: 19917677
references.citation: Nature. 2013 Dec 5;504(7478):158-62
references.pmid: 24196717
references.citation: Trends Mol Med. 2007 Nov;13(11):460-9
references.pmid: 18029230
references.citation: Nat Rev Immunol. 2007 May;7(5):379-90
references.pmid: 17457344
references.citation: J Clin Immunol. 2003 May;23(3):194-201
references.pmid: 12797541
references.citation: Int J Tuberc Lung Dis. 2010 Feb;14(2):149-54
references.pmid: 20074404
references.citation: Am J Med. 1950 Nov;9(5):623-32
references.pmid: 14783132
references.citation: Epigenetics. 2011 Sep 1;6(9):1085-94
references.pmid: 21814035
references.citation: PLoS One. 2011 Apr 13;6(4):e18185
references.pmid: 21533209
references.citation: Immunity. 2012 Nov 16;37(5):771-83
references.pmid: 23159225
references.citation: J Immunol. 2001 Feb 1;166(3):2141-6
references.pmid: 11160266
references.citation: FEMS Immunol Med Microbiol. 2007 Aug;50(3):309-18
references.pmid: 17521393
references.citation: J Immunol Methods. 2012 Feb 28;376(1-2):79-88
references.pmid: 22155193
references.citation: PLoS One. 2010 Apr 28;5(4):e10407
references.pmid: 20442853
references.citation: J Infect Dis. 2011 Oct 1;204(7):1075-85
references.pmid: 21881123
references.citation: Blood. 2008 Aug 15;112(4):1290-8
references.pmid: 18541719
references.citation: J Immunol. 2007 Mar 1;178(5):2844-52
references.pmid: 17312128
references.citation: Pediatr Res. 2008 Feb;63(2):115
references.pmid: 18209663
references.citation: J Exp Med. 2003 Jan 6;197(1):7-17
references.pmid: 12515809
references.citation: Nat Rev Immunol. 2008 Apr;8(4):247-58
references.pmid: 18323851
references.citation: Int J Tuberc Lung Dis. 2004 Apr;8(4):392-402
references.pmid: 15141729
references.citation: Eur J Immunol. 2001 Mar;31(3):959-65
references.pmid: 11241301
references.citation: Nat Immunol. 2010 May;11(5):373-84
references.pmid: 20404851
references.citation: Clin Immunol. 2006 Dec;121(3):251-9
references.pmid: 17010668
references.citation: Int Immunopharmacol. 2007 Feb;7(2):230-40
references.pmid: 17178391
references.citation: Mucosal Immunol. 2011 May;4(3):261-70
references.pmid: 21451501
references.citation: Blood. 2006 Aug 15;108(4):1284-90
references.pmid: 16638933
references.citation: Vaccine. 2009 Sep 4;27(40):5488-95
references.pmid: 19616494
references.citation: J Infect Dis. 2008 Sep 15;198(6):928-36
references.pmid: 18684097
references.citation: J Immunol. 2000 Jul 1;165(1):419-25
references.pmid: 10861080
references.citation: Clin Exp Immunol. 2010 Dec;162(3):494-9
references.pmid: 20964643
references.citation: Nat Med. 2007 Jul;13(7):843-50
references.pmid: 17558415
references.citation: PLoS One. 2012;7(9):e44763
references.pmid: 23028609
references.citation: J Immunol. 2006 Aug 1;177(3):1956-66
references.pmid: 16849509
references.citation: Immunology. 2008 Jul;124(3):401-11
references.pmid: 18217953
references.citation: Semin Immunol. 2004 Feb;16(1):35-41
references.pmid: 14751762
references.citation: Eur J Clin Invest. 2013 Aug;43(8):881-4
references.pmid: 23869409
references.citation: J Immunol Methods. 2004 Aug;291(1-2):185-95
references.pmid: 15345316
references.citation: J Immunol. 2004 Apr 15;172(8):4826-33
references.pmid: 15067060
references.citation: Clin Dev Immunol. 2013;2013:781320
references.pmid: 23762096
references.citation: Immunology. 2004 Sep;113(1):26-34
references.pmid: 15312133
references.citation: PLoS One. 2010 Nov 30;5(11):e15041
references.pmid: 21152080