by Keller, Christopher Charles

Abstract (Summary)
Childhood malarial anemia (MA) remains a global health burden with the vast morbidity and mortality occurring mostly in sub-Saharan Africa. Although design and testing of malaria vaccines is currently underway, the pattern of inflammatory mediator production that predicts a protective immune response against severe malaria, which would dramatically enhance vaccine testing, is largely unknown. Protective malarial immunity is regulated in part by cytokines, such as interleukin (IL)-12, IL-10, and tumor necrosis factor (TNF)-?, and effector molecules, such as prostaglandin E2 (PGE2) and nitric oxide (NO). Previous studies have illustrated that children with severe MA have lower levels of circulating IL-12p70 and PGE2, and increased plasma levels of IL-10, TNF-?, and NO relative to children with mild malaria, however, the mechanism(s) responsible for this pattern of immune production is unknown. Phagocytosis of parasitic products, such as hemozoin, by cultured peripheral blood mononuclear cell (PBMC) elicits dysregulation of inflammatory mediator production, therefore, the regulation and interactions of cytokines and effector molecules was investigated during acute childhood malaria and in cultured PBMC stimulated with Plasmodium falciparum-derived hemozoin. Children with high-density parasitemia had decreased IL-12p70 and increased levels of IL-10 and TNF-?. Experiments in cultured PBMC from malaria-naïve donors revealed that hemozoin suppressed IL-12p70 through induction of IL-10, but not over-expression of TNF-? transcripts and protein, which was independent of suppressor of cytokine signaling (SOCS)-3 induction. Hemozoin suppressed cyclooxygenase (COX)-2-dependent PGE2 production through reductions in COX-2 transcript and protein formation, and inhibition of COX-2 enzymatic activity. Suppression of PGE2, which was independent of hemozoin-induced IL-10, resulted in over-production of TNF-?. The ratio of plasma PGE2/TNF-? was decreased in children with severe disease. Cultured PBMC from children with severe malaria had elevated nitric oxide synthase (NOS)2 enzyme activity, which occurred at least in part through PBMC ingestion of hemozoin. Thus, ingestion of hemozoin by PBMC elicits a similar pattern of inflammatory mediator production to that observed in children with severe MA. Results presented here are of significant public health relevance in that understanding the regulation of cytokine and effector molecule production during severe malaria will vastly improve vaccine design and testing.
Bibliographical Information:

Advisor:Todd Reinhart; Charles R. Rinaldo; Douglas J. Perkins; Robert E. Ferrell

School:University of Pittsburgh

School Location:USA - Pennsylvania

Source Type:Master's Thesis

Keywords:infectious diseases and microbiology


Date of Publication:09/12/2005

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