title: The basis of the immunomodulatory activity of malaria pigment (hemozoin).
abstract: The most common and deadly form of the malaria parasite, Plasmodium falciparum, is responsible for 1.5-2.7 million deaths and 300-500 million acute illnesses annually [Bremen in J. Trop. Med. Hyg. 64:1-11 (2001); World Health Organization (2002)]. Hemozoin, the biomineral formed to detoxify the free heme produced during parasitic hemoglobin catabolism, has long been suspected of contributing to the pathological immunodeficiencies that occur during malarial infection. While there is a growing consensus in the literature that native hemozoin maintains immunosuppressive activity, there is considerable controversy over the reactivity of the synthetic form, beta-hematin (BH). Given the emerging importance of hemozoin in modulating a host immune response to malarial infection, a careful examination of the effects of the constitutive components of the malaria pigment on macrophage response has been made in order to clarify the understanding of this process. Herein, we present evidence that BH alone is unable to inhibit stimulation of NADPH oxidase and inducible nitric oxide synthase, the key enzymes involved in oxidative burst, and is sensitive to the microbicidal agents of these enzymes both in vitro and in vivo. Further, by systematically examining each of the malaria pigment's components, we were able to dissect their impact on the immune reactivity of a macrophage model cell line. Reactions between BH and red blood cell (RBC) ghosts effectively reconstituted the observed immunomodulatory reactivity of native hemozoin. Together, these results suggest that the interaction between hemozoin and the RBC lipids results in the generation of toxic products and that these products are responsible for disrupting macrophage function in vivo.
authors.affiliation: Department of Chemistry, Vanderbilt University, Station B. 351822, Nashville, TN 37235, USA.
authors.forename: Clare K
authors.initials: CK
authors.lastname: Carney
authors.forename: Alexandra C
authors.initials: AC
authors.lastname: Schrimpe
authors.forename: Kristin
authors.initials: K
authors.lastname: Halfpenny
authors.forename: Reese S
authors.initials: RS
authors.lastname: Harry
authors.forename: Crystal M
authors.initials: CM
authors.lastname: Miller
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Broncel
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Sewell
authors.forename: Jacob E
authors.initials: JE
authors.lastname: Schaff
authors.forename: Ravinder
authors.initials: R
authors.lastname: Deol
authors.forename: Melissa D
authors.initials: MD
authors.lastname: Carter
authors.forename: David W
authors.initials: DW
authors.lastname: Wright
mesh_terms: D000447:Aldehydes / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D004910:Erythrocyte Membrane / Q000737:chemistry / Q000378:metabolism; D006420:Hemeproteins / Q000737:chemistry / Q000276:immunology* / Q000494:pharmacology*; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D008288:Malaria / Q000276:immunology*; D051379:Mice; D018613:Microscopy, Confocal; D015394:Molecular Structure; D019255:NADPH Oxidases / Q000187:drug effects / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D026361:Reactive Nitrogen Species / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000447:Aldehydes; D006420:Hemeproteins; D006893:Hydroxyeicosatetraenoic Acids; D007166:Immunosuppressive Agents; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; C020753:hemozoin; C025984:15-hydroxy-5,8,11,13-eicosatetraenoic acid; D052247:Nitric Oxide Synthase Type II; D019255:NADPH Oxidases; C027576:4-hydroxy-2-nonenal