Abstract
Malaria transmission is dependent on the formation of gametocytes in the human blood. The sexual conversion rate, the proportion of asexual parasites that convert into gametocytes at each multiplication cycle, is variable and reflects the relative parasite investment between transmission and maintaining the infection. The impact of environmental factors such as drugs on sexual conversion rates is not well understood. We developed a robust assay using gametocyte-reporter parasite lines to accurately measure the impact of drugs on sexual conversion rates, independently from their gametocytocidal activity. We found that exposure to subcurative doses of the frontline antimalarial drug dihydroartemisinin (DHA) at the trophozoite stage resulted in a ~ fourfold increase in sexual conversion. In contrast, no increase was observed when ring stages were exposed or in cultures in which sexual conversion was stimulated by choline depletion. Our results reveal a complex relationship between antimalarial drugs and sexual conversion, with potential public health implications.
Highlights
Plasmodium falciparum is responsible for the most severe forms of human malaria
The sexual conversion rate was calculated as the proportion of parasites that developed into gametocytes at the cycle after exposure (Figure 1—figure supplement 1A)
ARTs are the key component of Artemisinin-based combination therapies (ACTs), the most widely used treatment for clinical malaria
Summary
Plasmodium falciparum is responsible for the most severe forms of human malaria. Repeated rounds of its ~48 hr intraerythrocytic asexual replication cycle result in an exponential increase in parasite numbers and are responsible for all clinical symptoms of malaria. Sexual commitment is marked by epigenetic activation of the expression of the master regulator PfAP2-G, a transcription factor of the ApiAP2 family (Josling et al, 2020; Kafsack et al, 2014; Llora-Batlle et al, 2020; Poran et al, 2017) This is followed by sexual conversion, which according to our recently proposed definitions (Bancells et al, 2019) is marked by the expression of gametocyte-specific proteins absent from any replicating blood stages. We developed a robust assay based on recently described gametocyte-reporter parasite lines (Portugaliza et al, 2019) to accurately measure the impact of drugs on sexual conversion rates, independently from their gametocytocidal activity Using this assay, we tested the effect of exposing parasites to dihydroartemisinin (DHA, the active metabolite of all ARTs) at different stages and under different metabolic conditions, to provide an accurate and comprehensive description of the direct effect of this drug on sexual conversion rates. We tested the effect of another drug, CQ, and a different type of stress, heat shock, on sexual conversion rates
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
