Conference Agenda

Recently published whole-genome analyses of the two closely related parasites, Plasmodium ovale curtisi and P. ovale wallikeri, which cause human ovale malaria, provide compelling evidence that the nuclear genomes of these two organisms do not recombine and are therefore perfectly dimorphic at all loci examined. The same pattern is observed when comparing the two 4.3 kb mitochondrial genomes. Here, we present an analysis of new sequencing data from the tufa locus, encoded in the plastid-derived apicoplast organelle, that provides evidence that this third parasite genome is also dimorphic and co-segregates with specific dimorphs of the nuclear and mitochondrial genomes. These findings, together with other recent studies, support full species status for the two causative agents of ovale malaria in humans, necessitating a revision of the nomenclature used up until now. We propose redefining the original species name Plasmodium ovale Stephens by designating a neotype from Kenya for what was previously referred to as ‘P. ovale curtisi’. A new species, Plasmodium wallikeri sp. n., is also described using a type specimen from West Africa. Morphological descriptions will be provided and sequence information defined for three genetic loci that distinguish these two species at nuclear, mitochondrial and apicoplast genome levels, respectively.

The combination of atovaquone and proguanil (e.g., Malarone^®) has been used for decades for malaria prevention and treatment. Atovaquone inhibits cytochrome bc₁ (complex III), a component of the Plasmodium mitochondrial electron transport chain (mETC). Proguanil is a biguanide prodrug that is metabolized in vivo by liver cytochrome P450 (CYP2C19) enzymes into cycloguanil, a dihydrofolate reductase (DHFR) inhibitor that blocks the synthesis of pyrimidines which are required for nucleic acid synthesis. Proguanil can potentiate the activity of atovaquone in vitro, and we demonstrated that this drug also has slow action in vitro activity against P. falciparum (e.g., Pf3D7 96h IC₅₀ 0.1 µM) that is independent of DHFR inhibition and isoprenoid metabolism and does not appear to be directly linked to pyrimidine synthesis. However, our understanding of the clinical implications of proguanil’s intrinsic activity are complicated by an incomplete understanding of the slow action mechanism of this drug and the lack of information on clinical resistance to proguanil. To address this, we have utilised a range of approaches to investigate resistance mechanisms associated with proguanil, including generation of proguanil-resistant P. falciparum lines and examining differences in sensitivity to proguanil by P. falciparum lab lines, field isolates and the zoonotic P. cynomolgi species. These data will be discussed in the context of clinical use of proguanil in the atovaquone and proguanil combination.