In
malaria-naïve individuals, Plasmodium falciparum
infection results in high levels of parasite-infected red blood cells (iRBCs) that trigger systemic
inflammation and
fever. Conversely, individuals in endemic areas who are repeatedly infected are often asymptomatic and have low levels of iRBCs, even young children. We hypothesized that febrile
malaria alters the immune system such that P. falciparum re-exposure results in reduced production of pro-inflammatory
cytokines/
chemokines and enhanced anti-parasite effector responses compared to responses induced before
malaria. To test this hypothesis we used a systems biology approach to analyze PBMCs sampled from healthy children before the six-month
malaria season and the same children seven days
after treatment of their first febrile
malaria episode of the ensuing season. PBMCs were stimulated with iRBC in vitro and various immune parameters were measured. Before the
malaria season, children's immune cells responded to iRBCs by producing pro-inflammatory mediators such as IL-1β,
IL-6 and
IL-8. Following
malaria there was a marked shift in the response to iRBCs with the same children's immune cells producing lower levels of pro-inflammatory
cytokines and higher levels of anti-inflammatory
cytokines (IL-10, TGF-β). In addition, molecules involved in phagocytosis and activation of adaptive immunity were upregulated after
malaria as compared to before. This shift was accompanied by an increase in P. falciparum-specific CD4+Foxp3- T cells that co-produce
IL-10, IFN-γ and TNF; however, after the subsequent six-month dry season, a period of markedly reduced
malaria transmission, P. falciparum-inducible
IL-10 production remained partially upregulated only in children with persistent
asymptomatic infections. These findings suggest that in the face of P. falciparum re-exposure, children acquire exposure-dependent P. falciparum-specific immunoregulatory responses that dampen pathogenic
inflammation while enhancing anti-parasite effector mechanisms. These data provide mechanistic insight into the observation that P. falciparum-infected children in endemic areas are often afebrile and tend to control parasite replication.