Falciparum malaria: Gene expression in the parasite and host.
Moormann, Ann Marie
1999
Abstract
Malaria parasites infect 300 to 500 million people annually resulting in 1.5 to 2.7 million deaths. Expanding our knowledge concerning parasite biology and malaria pathophysiology will assist in identifying new antimalarial interventions. First we investigated the iron-chelating drug, deferoxamine's effect on transcript levels in <italic>Plasmodium falciparum</italic>. Using differential display analysis we identified a transcript homologous to large ribosomal subunit E encoded by the mitochondria that increased after deferoxamine treatment. However, northern results contradicted this finding suggesting that differential display may be unreliable when investigating A-T rich genomes. To further characterize deferoxamine's effect on mitochondrial and nuclear gene expression we used northerns to examine transcripts for proteins that both contain and lack iron or heme cofactors. Five nuclear encoded messages (ribosomal P2 phosphoprotein, beta-tubulin, hypoxanthine-guanine phosphoribosyltransferase, ribonucleotide reductase small subunit, and lactate dehydrogenase) showed small decreases after deferoxamine treatment. One other nuclear encoded message, glyceraldehyde 3-phosphate dehydrogenase, showed a 40% increase after deferoxamine treatment. In contrast, deferoxamine caused 40--60% reductions in the expression of mitochondrial genes encoding three heme-containing proteins (cytochrome c oxidase subunits I and III, cytochrome b) without affecting mitochondrial DNA levels. Decreased mitochondrial gene expression was associated with decreased mitochondrial function, as manifested by a 40% reduction in parasite dihydroorotate dehydrogenase activity. These results indicate that deferoxamine inhibits mitochondrial gene expression which may contribute to deferoxamine's antimalarial activity. Secondly, we examined malaria infections during pregnancy, which can lead to the delivery of low-birth weight infants. Using Ribonuclease Protection Assays, we measured placental cytokine expression from <italic>P. falciparum </italic>-infected and uninfected primigravids. Significantly increased expression of IL-1beta, IL-8 and TNF-alpha and decreased expression of IL-6 and TGF-beta1 were found in malaria-infected placenta compared to uninfected placenta. Elevated TNF-alpha expression was associated with hemozoin content in placental tissue. Immunohistochemistry revealed that both TNF-alpha and IL-8 were produced by maternally derived hemozoin-laden placental macrophages. Fetal vascular endothelial cells within the chorionic villi produced IL-8 in both the infected and uninfected placentas. Increases in either TNF-alpha or IL-8 expression in the placenta was associated with intrauterine growth retardation. Our results suggest that severe malaria infection induces potentially harmful proinflammatory cytokine expression in the placenta.Subjects
Deferoxiamine Expression Gene Host Malaria Parasite Plasmodium Falciparum
Types
Thesis
Metadata
Show full item recordCollections
Remediation of Harmful Language
The University of Michigan Library aims to describe library materials in a way that respects the people and communities who create, use, and are represented in our collections. Report harmful or offensive language in catalog records, finding aids, or elsewhere in our collections anonymously through our metadata feedback form. More information at Remediation of Harmful Language.
Accessibility
If you are unable to use this file in its current format, please select the Contact Us link and we can modify it to make it more accessible to you.