Abstract
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.
Highlights
In previously unexposed individuals, blood-stage Plasmodium falciparum parasites rapidly replicate and almost invariably induce fever and other symptoms of malaria [1] through the production of pro-inflammatory cytokines and chemokines [2,3,4]
P. falciparum-inducible inflammation is downregulated and anti-parasitic effectors are upregulated after febrile malaria relative to responses induced at the healthy baseline
To obtain a global view of transcriptional changes that persist in children’s peripheral blood mononuclear cells (PBMCs) after the clinical resolution of febrile malaria, compared to each child’s own healthy baseline, we profiled RNA expression of PBMCs collected from 34 healthy Malian children before the six-month malaria season, when blood smears were negative for P. falciparum parasites, and 7 days after treatment of their first febrile malaria episode of the ensuing malaria season, when malaria symptoms had resolved
Summary
Blood-stage Plasmodium falciparum parasites rapidly replicate and almost invariably induce fever and other symptoms of malaria [1] through the production of pro-inflammatory cytokines and chemokines [2,3,4]. In malaria endemic areas where individuals are repeatedly exposed, P. falciparum infections more commonly cause a mild febrile illness or no symptoms at all, and parasite numbers in the blood are generally kept in check, even in young children [10,11,12] who have yet to acquire a fully protective antibody repertoire [13]. The notion of malaria ‘tolerance’ has long been invoked to explain the common finding of low-level, asymptomatic bloodstage infection in endemic areas [15], among children, as antibodies that reliably protect against febrile malaria are only acquired after many years of exposure to genetically diverse and clonally variant P. falciparum antigens [13]. Several mechanisms have been proposed to explain malaria tolerance or ‘anti-disease’ immunity [14,16] including antibody-mediated neutralization of P. falciparum pathogen-associated molecular pattern (PAMP) molecules such as GPI anchors [14,17,18]; desensitization of pattern-recognition receptor (PRR)-mediated signaling as a result
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