Brennan, Kiva and O'Leary, Bobby D. and McLaughlin, Danielle and Breen, Eamon P. and Connolly, Emma and Ali, Nusrat and O'Driscoll, David N. and Ozaki, Ema and Mahony, Rebecca and Mulfaul, Kelly and Ryan, Aoife M. and Ni Chianain, Aine and McHugh, Alison and Molloy, Eleanor J. and Hogan, Andrew E. and Paran, Sri and McAuliffe, Fionnuala M. and Doyle, Sarah L. (2018) 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. Journal of Immunology, 201. pp. 1131-1143. ISSN 0022-1767

Preview

Download (3MB) | Preview

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-a. 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-g 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.

Item Type:	Article
Keywords:	Type 1; IFN; Induction; Cytosolic Nucleic Acid; Neonatal Mononuclear Cells; Contrasting; Neonatal Hyporesponsiveness; TLR Ligation; Endosome-Mediated; IRF3 Activation;
Academic Unit:	Faculty of Science and Engineering > Biology
Item ID:	12400
Identification Number:	https://doi.org/10.4049/jimmunol.1700956
Depositing User:	Andrew Hogan
Date Deposited:	10 Feb 2020 17:35
Journal or Publication Title:	Journal of Immunology
Publisher:	American Association of Immunologists
Refereed:	Yes
URI:	Publisher
Use Licence:	This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available here

Repository Staff Only(login required)

Item control page

Downloads

Origin of downloads