Extensive Shared Chemosensitivity between Malaria and Babesiosis Blood-Stage Parasites

Abstract

The apicomplexan parasites that cause malaria and babesiosis invade and proliferate within erythrocytes. To assess the potential for common antiparasitic treatments, we measured the sensitivities of multiple species of Plasmodium and Babesia parasites to the chemically diverse collection of antimalarial compounds in the Malaria Box library. We observed that these parasites share sensitivities to a large fraction of the same inhibitors and we identified compounds with strong babesiacidal activity.T he apicomplexan phylum of eukaryotic microbial parasites is important in human and veterinary medicine. Apicomplexans cause malaria (Plasmodium spp.), babesiosis (Babesia spp.), toxoplasmosis (Toxoplasma gondii), and cryptosporidiosis (Cryptosporidium spp.), among other diseases. The Plasmodium and Babesia genera are relatively closely related among the apicomplexans (1) (last common ancestor, ϳ55 million years ago [2]) ( Fig. 1A) and share similar features in their biology, including mechanisms for host cell invasion and metabolism (3-6). Both Plasmodium and Babesia spp. are pathogenic during the stage of infection when parasites colonize host erythrocytes. Historically, drug development has focused more strongly on inhibitors for Plasmodium sp. parasites (7). Researchers have found that some antimalarial drugs also reduce proliferation of Babesia sp. parasites in erythrocytes as well (8, 9). The antimalarial atovaquone, a ubiquinone analog, is the preferred clinical treatment for human babesiosis in combination with azithromycin (10) and is used also in veterinary practice for babesiosis in dogs (11).A renewed focus on malaria eradication has led to the identification of an unprecedented number of bioactive compounds that block proliferation of Plasmodium falciparum in erythrocytes (12). In 2011, the nonprofit group Medicines for Malaria Venture (MMV) made available to the research community the Malaria Box, a collection of 400 chemically diverse, previously uncharacterized blood-stage antimalarials (13). Researchers have screened the antiparasitic activities of the Malaria Box compounds in nonerythrocytic host cells for the apicomplexans T. gondii, Cryptosporidium parvum, and Theileria annulata and identified a limited number of inhibitors (Ͻ3% of the library) active against each of these species (14-16). Here, we measured the susceptibilities of multiple blood-stage Plasmodium and Babesia parasite species to the Malaria Box compounds and found that erythrocyte-specific apicomplexans share considerable chemical sensitivities during the clinically relevant stages of parasitic infection.To determine the species-specific action of the Malaria Box compounds, we measured the chemical susceptibility of Plasmodium knowlesi in parallel with the reference species P. falciparum (13) (see Dataset S1 in the supplemental material). Endemic to macaque monkeys in southeast Asia and an emerging zoonosis in humans, P. knowlesi is distinguished from P. falciparum by its shorter blood-stage cell cycle and reduced rate of parasite mult...

Comparison of the susceptibility of Plasmodium knowlesi and Plasmodium falciparum to antimalarial agents

“…A recent study reported the in vitro activity of the 400 compound Malaria Box against P. falciparum 3D7 and showed that 90% were also active against P. knowlesi yH-1 strain. 29 Closer examination of those data show that EC 50 estimates for 52 compounds were at least 3-fold higher or lower for P. knowlesi than for P. falciparum .…”

Establishment of a continuous in vitro culture of Babesia duncani in human erythrocytes reveals unusually high tolerance to recommended therapies

“…Unlike B. duncani, the bovine Babesia parasites B. bovis and B. divergens have been shown to be highly susceptible to atovaquone with IC 50 values between 12 and 32 nM (29). It remains unknown whether the low susceptibility of B. duncani to atovaquone and other anti-babesiosis drugs is due to the molecular nature of their respective targets or to a general detoxification process unique to this parasite.…”

Fussing About Fission: Defining Variety Among Mainstream and Exotic Apicomplexan Cell Division Modes

“…divergens strain Rouen 1987, a kind gift from Drs. Kirk Deitsch and Laura Kirkman (Weill Cornell Medical College), was grown in human erythrocytes as described (Paul et al, 2016). Human erythrocytes were purchased from Research Blood Components (Boston, USA).…”