title: Host resistance to murine malaria in mice exposed to the adenosine deaminase inhibitor, 2'-deoxycoformycin.
abstract: 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.
authors.affiliation: Health Effects Research Laboratory, U.S. EPA, Research Triangle Park, North Carolina.
authors.forename: R W
authors.initials: RW
authors.lastname: Luebke
authors.forename: D L
authors.initials: DL
authors.lastname: Andrews
authors.forename: C B
authors.initials: CB
authors.lastname: Copeland
authors.forename: M M
authors.initials: MM
authors.lastname: Riddle
authors.forename: R R
authors.initials: RR
authors.lastname: Rogers
authors.forename: R J
authors.initials: RJ
authors.lastname: Smialowicz
mesh_terms: D058892:Adenosine Deaminase Inhibitors; D000818:Animals; D002712:Chlorides; D005260:Female; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D008288:Malaria / Q000188:drug therapy* / Q000276:immunology / Q000469:parasitology; D008345:Manganese / Q000494:pharmacology; D017895:Manganese Compounds; D051379:Mice; D008810:Mice, Inbred C57BL; D015649:Pentostatin / Q000494:pharmacology*; D010967:Plasmodium yoelii; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D013994:Tilorone / Q000494:pharmacology; D013997:Time Factors
chemical_list: D058892:Adenosine Deaminase Inhibitors; D002712:Chlorides; D017895:Manganese Compounds; D015649:Pentostatin; D008345:Manganese; D013994:Tilorone; C025340:manganese chloride