Both inflammatory and regulatory cytokine responses to malaria are blunted with increasing age in highly exposed children

Lila Farrington,Prasanna Jagannathan,Hilary Vance,Grant Dorsey,Moses R Kamya,John Rek,Mary Prahl,Emmanuel Arinaitwe,Margaret E Feeney,Agaba Katureebe

doi:10.1186/s12936-017-2148-6

Abstract

BackgroundYoung children are at greatest risk for malaria-associated morbidity and mortality. The immune response of young children differs in fundamental ways from that of adults, and these differences likely contribute to the increased susceptibility of children to severe malaria and to their delayed development of immunity. Elevated levels of pro-inflammatory cytokines and chemokines in the peripheral blood during acute infection contribute to the control of parasitaemia, but are also responsible for much of the immunopathology seen during symptomatic disease. Clinical immunity to malaria may depend upon the ability to regulate these pro-inflammatory responses, possibly through mechanisms of immunologic tolerance. In order to explore the effect of age on the immune response to malaria and the development of clinical immunity, cytokines and chemokines were measured in the plasma of children at day 0 of an acute malaria episode and during convalescence.ResultsYounger children presenting with acute malaria exhibited much higher levels of TNF, IL2, and IL6, as well as increased Th1 associated chemokines IP10, MIG, and MCP1, compared to older children with acute malaria. Additionally, the regulatory cytokines IL10 and TNFRI were dramatically elevated in younger children compared to older children during acute infection, indicating that regulatory as well as pro-inflammatory cytokine responses are dampened in later childhood.ConclusionsTogether these data suggest that there is a profound blunting of the cytokine and chemokine response to malaria among older children residing in endemic settings, which may be due to repeated malaria exposure, intrinsic age-based differences in the immune response, or both.

Highlights

Young children are at greatest risk for malaria-associated morbidity and mortality
Study design and clinical characteristics Children who presented at the time of an acute malaria episode were enrolled to undergo an initial blood draw and a follow up draw 3 weeks after treatment
To minimize heterogeneity in plasma cytokine levels resulting from incident malaria, children were excluded if they arrived to the clinic more than 48 h after the onset of fever, had a parasite density less than 5000 parasites/μl, had received anti-malarial treatment any time in the prior month, or if there was any clinical suspicion of non-malarial intercurrent illness

Summary

Introduction

The immune response of young children differs in fundamental ways from that of adults, and these differences likely contribute to the increased susceptibility of children to severe malaria and to their delayed development of immunity. It is not surprising that the acquisition of anti-malarial immunity follows a different trajectory in young children than in adults, as has been described in several longitudinal studies of Javanese transmigrants [3, 4]. These studies suggest that adults are initially more susceptible to severe malaria than young children, but develop immunity to repeated infection much more rapidly

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