Journal article
Type 1 IFN Induction by Cytosolic Nucleic Acid Is Intact in Neonatal Mononuclear Cells, Contrasting Starkly with Neonatal Hyporesponsiveness to TLR Ligation Due to Independence from Endosome-Mediated IRF3 Activation
The Journal of immunology (1950), Vol.201(4), pp.1131-1143
08/15/2018
DOI: 10.4049/jimmunol.1700956
PMID: 29980613
Abstract
Two million infants die each year from infectious diseases before they reach 12 mo; many of these diseases are vaccine preventable in older populations. Pattern recognition receptors represent the critical front-line defense against pathogens. Evidence suggests that the innate immune system does not fully develop until puberty, contributing to impaired response to infection and impaired vaccine responses in neonates, infants, and children. The activity of the pattern recognition receptor family of cytosolic nucleic acid (CNA) sensors in this pediatric population has not been reported. We show that in direct contrast to weak TLR-induced type I IFN in human cord blood mononuclear cells, cord blood mononuclear cells are capable of initiating a potent response to CNA, inducing both antiviral type I IFN and, unexpectedly, proinflammatory TNF-α. A deficiency in Rab11-GTPase endosome formation and consequent lack of IRF3 activation in neonatal monocytes is at least in part responsible for the marked disparity in TLR-induced IFN production between neonatal and adult monocytes. CNA receptors do not rely on endosome formation, and therefore, these responses remain intact in neonates. Heightened neonatal responses to CNA challenge are maintained in children up to 2 y of age and, in marked contrast to TLR4/9 agonists, result in IL-12p70 and IFN-γ generation. CNA sensors induce robust antiviral and proinflammatory pathways in neonates and children and possess great potential for use as immunostimulants or vaccine adjuvants for targeted neonatal and pediatric populations to promote cell-mediated immunity against invasive infectious disease.
Details
- Title: Subtitle
- Type 1 IFN Induction by Cytosolic Nucleic Acid Is Intact in Neonatal Mononuclear Cells, Contrasting Starkly with Neonatal Hyporesponsiveness to TLR Ligation Due to Independence from Endosome-Mediated IRF3 Activation
- Creators
- Kiva Brennan - Trinity College DublinBobby D O'Leary - National Maternity HospitalDanielle Mc Laughlin - Children's Health Ireland at CrumlinEamon P Breen - Trinity College DublinEmma Connolly - Trinity College DublinNusrat Ali - National Maternity HospitalDavid N O'Driscoll - National Maternity HospitalEma Ozaki - Trinity College DublinRebecca Mahony - National Children’s Research CentreKelly Mulfaul - National Children’s Research CentreAoife M Ryan - National Children’s Research CentreAine Ni Chianain - National Maternity HospitalAlison McHugh - National Maternity HospitalEleanor J Molloy - National Children’s Research CentreAndrew E Hogan - National Children’s Research CentreSri Paran - Our Lady's HospitalFionnuala M McAuliffe - University College DublinSarah L Doyle - National Children’s Research Centre
- Resource Type
- Journal article
- Publication Details
- The Journal of immunology (1950), Vol.201(4), pp.1131-1143
- DOI
- 10.4049/jimmunol.1700956
- PMID
- 29980613
- NLM abbreviation
- J Immunol
- ISSN
- 0022-1767
- eISSN
- 1550-6606
- Language
- English
- Date published
- 08/15/2018
- Academic Unit
- Iowa Neuroscience Institute; Neuroscience and Pharmacology
- Record Identifier
- 9984771651102771
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