Differential regulation of beta-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-1alpha, MIP-1beta, and RANTES) and their respective transcriptional profiles in ex vivo peripheral blood mononuclear cells (PBMCs) were investigated. Peripheral blood MIP-1alpha and MIP-1beta levels were significantly elevated in mild and severe malaria, while RANTES levels decreased with increasing disease severity. Beta-chemokine gene expression profiles in blood mononuclear cells closely matched those of circulating beta-chemokines, illustrating that PBMCs are a primary source for the observed pattern of beta-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-1alpha and MIP-1beta 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 (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-1alpha and MIP-1beta and decreased RANTES. Altered patterns of circulating beta-chemokines result, at least in part, from Hz-induced changes in beta-chemokine gene expression in blood mononuclear cells.
Department of Infectious Diseases & Microbiology, University of Pittsburgh, 130 DeSoto Street, 603 Parran Hall, Pittsburgh, Pennsylvania 15261, USA.
Daniel O
DO
Ochiel
Gordon A
GA
Awandare
Christopher C
CC
Keller
James B
JB
Hittner
Peter G
PG
Kremsner
J Brice
JB
Weinberg
Douglas J
DJ
Perkins
D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5 / Q000097:blood / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005260:Female; D020869:Gene Expression Profiling; D006420:Hemeproteins / Q000494:pharmacology; D006454:Hemoglobins / Q000032:analysis; D006801:Humans; D019402:Macrophage Inflammatory Proteins / Q000097:blood / Q000235:genetics*; D016778:Malaria, Falciparum / Q000097:blood / Q000276:immunology* / Q000469:parasitology; D008297:Male
D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5; D006420:Hemeproteins; D006454:Hemoglobins; D019402:Macrophage Inflammatory Proteins; C020753:hemozoin