Human malaria is caused by an intracellular protozoan of the genus Plasmodium, of which Plasmodium falciparum is by far the most prevalent and lethal species, accounting for 1-2 million deaths per year, mostly children under the age of five. Complications due to severe anemia and cerebral malaria are the major causes of morbidity and mortality, but the molecular mechanisms involved in the development of these life-threatening conditions remain to be fully defined. It is known that the intraerythrocytic stages comprising hemoglobin catabolism (pigmented trophozoites) and erythrocyte lysis (schizogony) are responsible for the pathologic sequelae of malaria. Our work seeks to identify and characterize the role of the host response to parasite products in malaria pathogenesis. Several investigations have shown that hemozoin, infected erythrocytes, and other macromolecules of parasite origin induce macrophage TNF secretion on phagocytosis. Our past research has identified other potential pathogenic products released by macrophages upon ingestion of the parasite-specific product hemozoin or malaria pigment. We have preliminary data demonstrating the release of large amounts of macrophage migration inhibitory factor (MIF) by macrophages after ingestion of hemozoin or parasitized erythrocytes. We also have preliminary data that strongly suggest that MIF may contribute to the development of malaria anemia. This proposal, in response to PA-96-07 (Molecular correlates of pathogenesis in parasitic disease) focuses on two related areas: a] the role of hemozoin and MIF on malaria anemia, and b] potential pathogenic effects of hemozoin on neutrophil function. The PI proposes to examine in detail the induction of MIF by hemozoin ingestion, and its relationship to malaria anemia. In addition, they will determine if ingestion of hemozoin by neutrophils has pathogenic consequences for the host, such as the loss of anti-microbial functions. The long-term objectives are to define the manner in which products modulate cellular and systemic responses of the host to infection. An understanding of the role of host leukocytes in malaria infection is important not only in clarifying the mechanisms by which infectious organisms subvert the host immune response, but also for how the host response counteracts the invading organism. This information will help identify novel approaches to potential therapeutic intervention, develop better diagnostic tools and determine basic pathogenesis and immunology data useful for vaccine development.
