Differential regulation of β-chemokines in children with Plasmodium falciparum malaria

Chemokines regulate the host immune response to a variety of infectious pathogens. Since the role of chemokines in regulating host immunity in children with Plasmodium falciparum malaria has not previously been reported, circulating levels of β-chemokines (MIP-1α, MIP-1β, and RANTES) and their respective transcriptional profiles in ex vivo peripheral blood mononuclear cells (PBMCs) were investigated. Peripheral blood MIP-1α and MIP-1β levels were significantly elevated in mild and severe malaria, while RANTES levels decreased with increasing disease severity. β-Chemokine gene expression profiles in blood mononuclear cells closely matched those of circulating β-chemokines, illustrating that PBMCs are a primary source for the observed pattern of β-chemokine production during acute malaria. Statistical modeling revealed that none of the chemokines was significantly associated with either parasitemia or anemia. Additional investigations in healthy children with a known history of malaria showed that children with prior severe malaria had significantly lower baseline RANTES production than children with a history of mild malaria, suggesting inherent differences in the ability to produce RANTES in these two groups. Baseline MIP-1α and MIP-1β did not significantly differ between children with prior severe malaria and those with mild malaria. Additional in vitro experiments in PBMCs from healthy, malaria-naïve donors revealed that P. falciparum-derived hemozoin (Hz; malarial pigment) and synthetic Hz (β-hematin) promote a similar pattern of β-chemokine gene expression. Taken together, the results presented here demonstrate that children with severe malaria have a distinct profile of β-chemokines characterized by increased circulating levels of MIP-1α and MIP-1β and decreased RANTES. Altered patterns of circulating β-chemokines result, at least in part, from Hz-induced changes in β-chemokine gene expression in blood mononuclear cells.