Ontogeny of Toll-Like and NOD-Like Receptor-Mediated Innate Immune Responses in Papua New Guinean Infants

Joanne G Lisciandro,Meri C Tulic,Peter M Siba,William Pomat,Patrick G Holt,Anita H J Van Den Biggelaar,Marie G Nadal-Sims,Deborah Strickland,Susan L Prescott,Catherine J Devitt,Ann M Moormann

doi:10.1371/journal.pone.0036793

Abstract

Studies addressing the ontogeny of the innate immune system in early life have reported mainly on Toll-like receptor (TLR) responses in infants living in high-income countries, with little or even no information on other pattern recognition receptors or on early life innate immune responses in children living under very different environmental conditions in less-developed parts of the world. In this study, we describe whole blood innate immune responses to both Toll-like and nucleotide-binding oligomerization domain (NOD)-like receptor agonists including the widely used vaccine adjuvant ‘alum’ in a group of Papua New Guinean infants aged 1–3 (n = 18), 4–6 (n = 18), 7–12 (n = 21) and 13–18 (n = 10) months old. Depending on the ligands and cytokines studied, different age-related patterns were found: alum-induced IL-1β and CXCL8 responses were found to significantly decline with increasing age; inflammatory (IL-6, IL-1β, IFN-γ) responses to TLR2 and TLR3 agonists increased; and IL-10 responses remained constant or increased during infancy, while TNF-α responses either declined or remained the same. We report for the first time that whole blood innate immune responses to the vaccine adjuvant alum decrease with age in infancy; a finding that may imply that the adjuvant effect of alum in pediatric vaccines could be age-related. Our findings further suggest that patterns of innate immune development may vary between geographically diverse populations, which in line with the ‘hygiene hypothesis’ particularly involves persistence of innate IL-10 responses in populations experiencing higher infectious pressure.

Highlights

The human immune system undergoes developmental changes in postnatal life with some responses reaching adult-like profiles at early age and others continuing to develop into late childhood
One recent study reporting on toll-like receptor (TLR)-mediated immune responses in the first 12 months of life in infants in the Gambia, Africa [10] found some patterns of immune maturation to be different from what has been described for infants in the western world [11,12,13]: instead of declining innate IL-10 and IL-6, and gradually increasing TNF-a and IFN-c responses over the first year of life, responses in Gambian infants remained stable between 1 and 12 month of age after TNF-a and IFN-c production had increased during the first month of life
Papua New Guinean (PNG) infants aged 1–3, 4–6, 7–12 and 13–18 months old were compared for immune responses to a range of innate stimuli including TLR and NLR agonists (Figure 1)

Summary

Introduction

The human immune system undergoes developmental changes in postnatal life with some responses reaching adult-like profiles at early age and others continuing to develop into late childhood. Several studies have characterized innate immune responses to toll-like receptor (TLR)-ligands in human neonates and adults; reporting that the production of pro-inflammatory cytokines including IFN-c, IL-12 and in some studies TNF-a, is generally impaired in neonates, while the production of IL-1b, IL-6, IL-10 and IL-23 is equal to or even higher than that produced by adults [1,2,3,4] This profile of innate cytokine response in newborns favours T helper (Th) 2 rather than protective Th1 responses [5,6,7], which likely accounts for the high susceptibility of newborns to infectious agents [1]. These studies lend support to the hypothesis that innate immune maturation is not uniform across populations of high-income versus low-income settings

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