pentostatin and Malaria

Malaria still affects around 200 million people and is responsible for more than 400,000 deaths per year, mostly children in subequatorial areas. This disease is caused by parasites of the

Topics: Antimalarials; Biological Transport; Drug Design; Erythrocytes; Humans; Inhibitory Concentration 50; Malaria; Nucleosides; Nucleotides; Plasmodium falciparum; Purines; Pyrimidines

Resistance to infection with the nonlethal rodent malaria parasite Plasmodium yoelii 17XNL (Py 17XNL) is mediated by humoral, T-cell and accessory cell activity. The purpose this study was to profile host resistance to infection with this organism in mice exposed to 2'-deoxycoformycin (2dCF), a potent adenosine deaminase (ADA) inhibitor. Inhibition of ADA activity by 2dFC results in defective T-cell function and either suppression or augmentation of the humoral response, depending on whether 2dCF exposure precedes (suppression) or follows (augmentation) immunization. In this study, mice injected with 2dCF during the first five days of infection cleared the infection at the same time as controls, but had lower peak parasitemia than controls. Mice infected with the lethal variant of P. yoelii were more susceptible to infection when injected with 2dCF after infection, suggesting that 2dCF injection did not directly affect the parasite. Rather, suppression of parasitemia in 2dCF-treated mice may have been mediated by augmented humoral immunity, since 2dCF injection increases antibody responses when 2dCF injection follows antigen (in this case, parasite) injection. Conversely, in mice given 2dCF prior to infection, parasitemia peaked 2 days later and was eliminated more gradually than in control mice. Exposure to 2dCF did not deplete reticulocytes and thus temporarily limit parasitemia. Similarly, enrichment of NK cells or augmentation of macrophage phagocytic activity prior to infection were not sufficient to alter the pattern of infection. In contrast, the pattern of infection in mice treated with tilorone (a macrophage activator which also causes suppressed T-cell function) prior to infection was similar to that observed in 2dCF-exposed animals. These results indicate that 2dCF, given before or after infection, alters the host response to infection with Py17XNL. It appears that a combination of increased macrophage activity and altered T-cell activity contributed to the delay in peak parasitemia and clearance of infection in mice exposed to 2dCF before infection with Py17XNL.

Topics: Adenosine Deaminase Inhibitors; Animals; Chlorides; Female; Macrophages; Malaria; Manganese; Manganese Compounds; Mice; Mice, Inbred C57BL; Pentostatin; Plasmodium yoelii; T-Lymphocytes; Tilorone; Time Factors

The role of enzymatic deamination of adenosine monophosphate (AMP) and adenosine in the in vitro growth of the malaria parasite Plasmodium falciparum was investigated by means of human red cells deficient in AMP deaminase to which the adenosine deaminase inhibitor 2'-deoxycoformycin was added. Malaria parasites grew normally in red cells lacking one or both of these enzyme activities. As a further probe of adenosine triphosphate (ATP) catabolism, both infected and uninfected RBCs were incubated with NaF (with and without 2'-deoxycoformycin) and the purine nucleotide/nucleoside content was analyzed by high-performance liquid chromatography (HPLC). Uninfected RBCs lacking either AMP or adenosine deaminase were able to bypass the enzyme block and degrade ATP to hypoxanthine. Uninfected RBCs with both deaminases blocked were unable to produce significant quantities of hypoxanthine. On the other hand, infected RBCs were able to bypass blockade of both deaminases and produce hypoxanthine and adenosine. These findings establish that deamination of adenosine and/or AMP are not essential for plasmodial growth. However, further work will be required to elucidate the pathways that permit the parasites to bypass these catabolic steps.

Topics: Adenosine; Adenosine Monophosphate; Adult; AMP Deaminase; Animals; Coformycin; Deamination; Erythrocytes; Female; Humans; Malaria; Nucleotide Deaminases; Pentostatin; Plasmodium falciparum; Ribonucleosides

Topics: Adenosine; Adenosine Deaminase; Animals; Coformycin; Erythrocytes; Humans; Macaca mulatta; Malaria; Male; Nucleoside Deaminases; Pentostatin; Plasmodium

Topics: Adenosine Deaminase; Adenosine Deaminase Inhibitors; Animals; Coformycin; Erythrocytes; Macaca mulatta; Malaria; Male; Nucleoside Deaminases; Pentostatin; Plasmodium; Ribonucleosides