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

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.

Factors influencing innate immunity and vaccine responses in infancy

“…Similar data were reported from Papua New Guinea and across a number of countries using comparable methodology [10][11][12].…”

Malaria Modifies Neonatal and Early-Life Toll-Like Receptor Cytokine Responses

“…At all times, the balance between production of proand anti-inflammatory mediators is tightly regulated to allow efficient, protective immune responses to develop while preventing the pathological consequences of excessive inflammation (26). In the particular context of control of inflammatory activity in early life, a pivotal role for neonatal B cells producing IL-10 as a result of TLR9 activation has been reported (27), a role that is consistent with reports of robust TLR ligand-mediated IL-10 responses present at birth both in non-African and in African populations (28)(29)(30).…”

Listeria monocytogenes

“…104 Finally, although the developmental patterns of the various inflammasome pathways in humans in response to Lm have not been unravelled, it is known that activation of the inflammasome is one way through which aluminum hydroxide (alum, the most common vaccine adjuvant) exerts its function. 109 Given that innate immune responses induced by alum decrease over the first 2 y of life, 110 age-dependent differences in at least some inflammasome activities are likely to exist. 104 This has, however, not been investigated in relation to Lm.…”