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Differential Regulation of ß-Chemokines in Children with Plasmodium falciparum Malaria

Department of Infectious Diseases and Microbiology, University of Pittsburgh, Pittsburgh, Pennsylvania,¹ Department of Psychology, College of Charleston, Charleston, South Carolina,² Department of Parasitology, Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany,³ Research Unit, Albert Schweitzer Hospital, Lambaréné, Gabon,⁴ Department of Medicine, VA and Duke University Medical Centers, Durham, North Carolina⁵

Received 4 November 2004/ Returned for modification 7 January 2005/ Accepted 16 February 2005

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 ß-chemokines (MIP-1, MIP-1ß, and RANTES) and their respective transcriptional profiles in ex vivo peripheral blood mononuclear cells (PBMCs) were investigated. Peripheral blood MIP-1 and MIP-1ß levels were significantly elevated in mild and severe malaria, while RANTES levels decreased with increasing disease severity. ß-Chemokine gene expression profiles in blood mononuclear cells closely matched those of circulating ß-chemokines, illustrating that PBMCs are a primary source for the observed pattern of ß-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-1 and MIP-1ß 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 (ß-hematin) promote a similar pattern of ß-chemokine gene expression. Taken together, the results presented here demonstrate that children with severe malaria have a distinct profile of ß-chemokines characterized by increased circulating levels of MIP-1 and MIP-1ß and decreased RANTES. Altered patterns of circulating ß-chemokines result, at least in part, from Hz-induced changes in ß-chemokine gene expression in blood mononuclear cells.

Editor: W. A. Petri, Jr.

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