Signatures of divergent anti-malarial treatment responses in peripheral blood from adults and young children in Malawi

Paul L Maurizio,Gerald Tegha,Kristina De Paris,Mina Hosseinipour,Hubaida Fuseini

doi:10.1186/s12936-019-2842-7

Abstract

BackgroundHeterogeneity in the immune response to parasite infection is mediated in part by differences in host genetics, gender, and age group. In infants and young children, ongoing immunological maturation often results in increased susceptibility to infection and variable responses to drug treatment, increasing the risk of complications. Even though significant age-associated effects on host cytokine responses to Plasmodium falciparum infection have been identified, age-associated effects on uncomplicated malaria infection and anti-malarial treatment remain poorly understood.MethodsIn samples of whole blood from a cohort of naturally infected malaria-positive individuals with non-severe falciparum malaria in Malawi (n = 63 total; 34 infants and young children < 2 years old, 29 adults > 18 years old), blood cytokine levels and monocyte and dendritic cell frequencies were assessed at two timepoints: acute infection, and 4 weeks post anti-malarial treatment. The effects of age group, gender, and timepoint were modeled, and the role of these factors on infection and treatment outcomes was evaluated.ResultsRegardless of treatment timepoint, in this population age was significantly associated with overall blood haemoglobin, which was higher in adults, and plasma nitric oxide metabolites, IL-10, and TNF levels, which were higher in young children. There was a significant effect of age on the haemoglobin treatment response, whereby after treatment, levels increased in young children and decreased in adults. Furthermore, there were significant age-associated effects on treatment response for overall parasite load, IFN-γ, and IL-12(p40), and these effects were gender-dependent. Significant age effects on the overall levels and treatment response of myeloid dendritic cell frequencies were observed. In addition, within each age group, results showed continuous age effects on gametocyte levels (Pfs16), TNF, and nitric oxide metabolites.ConclusionsIn a clinical study of young children and adults experiencing natural falciparum malaria infection and receiving anti-malarial treatment, age-associated signatures of infection and treatment responses in peripheral blood were identified. This study describes host markers that may indicate, and potentially contribute to, differential post-treatment outcomes for malaria in young children versus adults.

Highlights

Heterogeneity in the immune response to parasite infection is mediated in part by differences in host genetics, gender, and age group
Ageassociated effects on B cell response magnitude [14] and post-treatment parasite clearance [15] have been described. Whereas these studies focused on identifying age-associated differences in adaptive and antibodyrelated responses to parasite infection, this study focuses on age-associated differences in plasma cytokine and monocyte levels, since these may be critical for determining treatment efficacy in infant and young child populations
severe malarial anaemia (SMA) and cerebral malaria (CM) have been a major focus of research in young children, the main interest of this study is to identify age-associated markers of treatment response in uncomplicated malaria (UM)—an area that is arguably less well studied and yet remains critical to understanding phenotypic variation in the majority of malaria-infected and treated young children

Summary

Introduction

Heterogeneity in the immune response to parasite infection is mediated in part by differences in host genetics, gender, and age group. Even though significant age-associated effects on host cytokine responses to Plasmodium falciparum infection have been identified, age-associated effects on uncomplicated malaria infection and anti-malarial treatment remain poorly understood. A general lack of knowledge about age-associated differences in immune responses to Plasmodium falciparum infection and treatment constrains the development of protective anti-malarial vaccines and therapeutics for young children who, initially at decreased risk for severe malaria during a primary infection, compared with adults, may be at increased risk for severe complications due to exposure history and/or immune dynamics [3,4,5]. Recent studies have explored age-associated effects in order to understand the relative contribution of parasitological and host immunological effects on heterogeneity in the response to malaria infection

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