RESUMEN
Malaria parasites are diheteroxenous, requiring two hosts-a vertebrate and a mosquito-to complete their life cycle. Mosquitoes are the definitive host where malaria parasite sex occurs, and vertebrates are the intermediate host, supporting asexual amplification and more significant geographic spread. In this review, we examine the roles of a single malaria parasite compartment, the relict plastid known as the apicoplast, at each life cycle stage. We focus mainly on two malaria parasite species-Plasmodium falciparum and P. berghei-comparing the changing, yet ever crucial, roles of their apicoplasts.
Asunto(s)
Apicoplastos , Malaria , Parásitos , Humanos , Animales , Roedores , Plasmodium falciparum/genética , Estadios del Ciclo de Vida , Proteínas ProtozoariasRESUMEN
Insecticide-impregnated bed nets have saved millions from fatal malaria, but their effectiveness is waning due to mosquito insecticide resistance. A new strategy (Paton et al., Nature, 2019) to deliver parasiticidal compounds into mosquitoes to kill transmission-stage parasites could enhance the effectiveness of bed nets and get around the perennial problems of resistance.
Asunto(s)
Anopheles , Antimaláricos , Insecticidas , Parásitos , Plasmodium , Animales , Control de MosquitosRESUMEN
The malaria-causing parasite, Plasmodium, contains a unique non-photosynthetic plastid known as the apicoplast. The apicoplast is an essential organelle bound by four membranes. Although membrane transporters are attractive drug targets, only two transporters have been characterised in the malaria parasite apicoplast membranes. We selected 27 candidate apicoplast membrane proteins, 20 of which are annotated as putative membrane transporters, and performed a genetic screen in Plasmodium berghei to determine blood stage essentiality and subcellular localisation. Eight apparently essential blood stage genes were identified, three of which were apicoplast-localised: PbANKA_0614600 (DMT2), PbANKA_0401200 (ABCB4), and PbANKA_0505500. Nineteen candidates could be deleted at the blood stage, four of which were apicoplast-localised. Interestingly, three apicoplast-localised candidates lack a canonical apicoplast targeting signal but do contain conserved N-terminal tyrosines with likely roles in targeting. An inducible knockdown of an essential apicoplast putative membrane transporter, PfDMT2, was only viable when supplemented with isopentenyl diphosphate. Knockdown of PfDMT2 resulted in loss of the apicoplast, identifying PfDMT2 as a crucial apicoplast putative membrane transporter and a candidate for therapeutic intervention.
Asunto(s)
Apicoplastos/metabolismo , Proteínas de Transporte de Membrana/genética , Plasmodium berghei/genética , Plasmodium falciparum/genética , Proteínas Protozoarias/genética , Animales , Apicoplastos/genética , Transporte Biológico/genética , Técnicas de Inactivación de Genes , Hemiterpenos/biosíntesis , Humanos , Malaria Falciparum/parasitología , Proteínas de Transporte de Membrana/metabolismo , Ratones , Compuestos Organofosforados , Proteínas Protozoarias/metabolismoRESUMEN
Rapid emergence of resistance to atovaquone, which targets electron transport in the malaria parasite mitochondrion, relegated its use to prophylaxis and even cast a shadow over the development of drugs targeting other parasite mitochondrial pathways. Here we argue for a renewed focus on the mitochondrion as a drug target, focusing particularly on the issues of resistance. We posit a hypothesis for why atovaquone resistance emerges so quickly, and we explain how facile acquisition of resistance is apparently offset by an inability of parasites to spread this resistance. We also explore the utility and resistance issues for emerging new drugs targeting parasite mitochondria, concluding that the mitochondrion is indeed an excellent target.