Drug-induced death of the asexual blood stages of Plasmodium falciparum occurs without typical signs of apoptosis.

There is clear evidence that most antimalarial drugs, while acting through different mechanisms, are associated with parasite growth/development inhibition and eventual parasite death. However, the exact mode of parasite death remains unclear. In the present study, we investigated the ability of various drugs, including two antimalarial drugs (chloroquine and atovaquone), a topoisemerase II inhibitor (etoposide) and a nitric oxide donor (S-nitro-N-acetyl-D, L-penicillamine), to induce apoptosis in a laboratory strain of Plasmodium falciparum. Results obtained from flow cytometric analysis showed a significant reduction in the percent of parasitemia and parasite growth in all drug-treated parasite cultures, including those treated with etoposide and S-nitro-N-acetyl-D, L-penicillamine. For further investigation, we used various biochemical approaches including the terminal dUTP nick-end labeling assay, determination of mitochondrial membrane integrity and DNA degradation/fragmentation, to analyze the changes occurring during parasite-drug interactions and eventual death. We observed that loss of membrane potential was induced in parasite cultures treated with atovaquone, while S-nitro-N-acetyl-D, L-penicillamine induced abnormal parasite forms, "crisis forms", and minor DNA degradation. However, these features were not observed in the parasite cultures treated with chloroquine nor were other features of apoptosis-like death associated with any of the drugs used in this study. The death resulting from the various drug treatments is atypical of apotosis. More studies will be needed to define the precise mode of death exhibited by P. falciparum.

IL4-589C/T polymorphism and IgE levels in severe malaria.

Previous studies identified an allelic variant of the IL4 promoter region (IL4-589T) that appears to enhance the transcriptional activity of IL4, and is associated with increased IgE levels. Total serum IgE levels are elevated in malaria endemic regions, and higher in children with severe malaria. Here, we investigated the relationship of the IL4-589C/T polymorphism with severity of the disease in a case-control study of severe malaria in Burkina Faso, West Africa. No association between the IL4-589T and severe malaria was observed. No difference in Plasmodium falciparum-specific IgE was detected between severe and uncomplicated malaria patients. Among children with severe malaria, total IgE levels were significantly elevated in those carrying the IL4-589T allele (P = 0.018). In children with uncomplicated malaria, no significant difference was found. These results raise the possibility that there is a relationship between susceptibility to severe malaria, IgE production and genetic variation in the IL4 region, which merits further investigation in other epidemiological settings.

IgE antibodies to Plasmodium falciparum and severity of malaria in children of one ethnic group living in Burkina Faso.

Plasmodium falciparum malaria infection induces elevated blood levels of both total immunoglobulin and anti-plasmodial antibodies belonging to different isotypes. We have previously shown that donors living in areas of malaria transmission develop malaria-specific IgE antibodies that are present at highest concentrations in patients with severe disease, suggesting a role for this isotype in malaria pathogenesis. To establish the possible importance of IgE in the course and severity of this disease, we have analyzed a large and homogenous group of African children (age range = 6 months to 15 years) belonging to one ethnic group (Mossi) living in identical epidemiologic conditions in the same urban area (Ougadougo) of Burkina Faso. While IgG antibodies to P. falciparum increased to high concentrations in very young children and then remained at these levels in older patients, IgE antibodies increased with age, becoming most significantly elevated in children more than four years of age. In older children, those with severe malaria had significantly higher IgE antibody levels than those with non-severe disease. No significant differences between the patient groups were seen for IgG antibodies to P. falciparum. However, when the patients with severe malaria were divided into two groups distinguished by the presence of absence of coma, both IgG and IgE antibodies against malaria were lower in the comatous patients than in the non-comatous patients. The results support the conclusion that IgE antibodies against malaria, regardless of their possible protectivity, also contribute to disease severity in this large and homogenous group of African children.

Malaria research: host-parasite interactions and new developments in chemotherapy, immunology and vaccinology.

Malaria remains the major parasitic disease, with 300-500 million new infections each year. This survey covers recent advances in the field of parasite-host interactions, focusing on Plasmodium falciparum, the most virulent of the human parasites. Rapid progress in genomic research is creating a basis for the development of new drugs and vaccines. Identification of drug-resistance mutations facilitates evaluation of improved drug policies, and attempts are being made to develop new compounds that inhibit metabolic pathways that are specific to the parasite. Cytoadherence of parasitized erythrocytes to microvascular endothelium is responsible for the sequestration of parasites, causing pathology and severe disease. Newly identified molecular fine structures that mediate cytoadherence may provide new targets for specific therapies. Humoral and cell-mediated immunity induced by the parasite may be protective, but may also be harmful by generating imbalance in cytokine responses. Efforts are made to determine the pathways that give rise to protection, with vaccination being the principal goal for achieving malaria control. Different vaccine constructs are being evaluated in preclinical and clinical trials, including modified viral vectors, synthetic peptides, DNA and new adjuvants.