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 beta-chemokines (MIP-1 alpha, MIP-1 beta, and RANTES) and their respective transcriptional profiles in ex vivo peripheral blood mononuclear cells (PBMCs) were investigated. Peripheral blood MIP-1 alpha and MIP-1 beta levels were significantly elevated in mild and severe malaria, while RANTES levels decreased with increasing disease severity. P-Chemokine gene expression profiles in blood mononuclear cells closely matched those of circulating P-chemokines, illustrating that PBMCs are a primary source for the observed pattern of P-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-1a and MIP-1 beta did not significantly differ between children with prior severe malaria and those with mild malaria. Additional in vitro experiments in PBMCs from healthy, malaria-naive donors revealed that P. falciparum-derived hemozoin (Hz; malarial pigment) and synthetic Hz (beta-hematin) promote a similar pattern of beta-chemokine gene expression. Taken together, the results presented here demonstrate that children with severe malaria have a distinct profile of beta-chemokines characterized by increased circulating levels of MIP-1 alpha and MIP-1 beta and decreased RANTES. Altered patterns of circulating P-chemokines result, at least in part, from Hz-induced changes in beta-chemokine gene expression in blood mononuclear cells.