Effects of interruption of apicoplast function on malaria infection, development, and transmission

A chloroplast-like organelle is present in many species of the Apicomplexa phylum. We have previously demonstrated that the plastid organelle of Plasm odium falciparum is essential to the survival of the blood-stage malaria pa rasite in culture. One known function of the plastid organelle in another A picomplexan, Toxoplasma gondii, involves the formation of the parasitophoro us vacuole. The effects of interruption of plastid function on sporozoites and sexual-stage parasites have not been investigated. In our previous stud ies of the effects of thiostrepton, a polypeptide antibiotic from streptoco ccus spp., on erythrocytic schizongony of the human malaria P. falciparum w e found that this antibiotic appears to interact with the guanosine triphos phatase (GTPase) binding domain of the organellar large subunit ribosomal R NA, as it does in bacteria. We investigate here the effects of this drug on life-cycle stages of the malaria parasite in vivo. Preincubation of mature infective sporozoites with thiostrepton has no observable effect on their infectivity. Sporozoite infection both by mosquito bite and sporozoite inje ction was prevented by pretreatment of mice with thiostrepton. Thiostrepton eliminates infection with erythrocytic forms of Plasmodium berghei in mice . Clearance of infected red blood cells follows the delayed kinetics associ ated with drugs that interact with the apicoplast. Thiostrepton treatment o f. infected mice reduces transmission of parasites by more than ten-fold, i ndicating that the plastid has a role in sexual development of the parasite . These results indicate that the plastid function is accessible to drug ac tion in vivo and important to the development of both sexual and asexual fo rms of the parasite. (C) 2000 Elsevier Science B.V. All rights reserved.