Abstract
BACKGROUND: Heterogeneity 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. METHODS: In 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. RESULTS: Regardless 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. CONCLUSIONS: In 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.