Revisiting the Effect of Pharmaceuticals on Transmission Stage Formation in the Malaria Parasite Plasmodium falciparum

Abstract

Malaria parasites rely on specialized stages, called gametocytes, to ensure human-to-human transmission. The formation of these sexual precursor cells is initiated by commitment of blood stage parasites to the sexual differentiation pathway. Plasmodium falciparum, the most virulent of six parasite species infecting humans, employs nutrient sensing to control the rate at which sexual commitment is initiated, and the presence of stress-inducing factors, including antimalarial drugs, has been linked to increased gametocyte production in vitro and in vivo. These observations suggest that therapeutic interventions may promote gametocytogenesis and malaria transmission. Here, we engineered a P. falciparum reporter line to quantify sexual commitment rates after exposure to antimalarials and other pharmaceuticals commonly prescribed in malaria-endemic regions. Our data reveal that some of the tested drugs indeed have the capacity to elevate sexual commitment rates in vitro. Importantly, however, these effects are only observed at drug concentrations that inhibit parasite survival and only rarely result in a net increase of gametocyte production. Using a drug-resistant parasite reporter line, we further show that the gametocytogenesis-promoting effect of drugs is linked to general stress responses rather than to compound-specific activities. Altogether, we did not observe evidence for mechanistic links between the regulation of sexual commitment and the activity of commonly used pharmaceuticals in vitro. Our data hence does not support scenarios in which currently applied therapeutic interventions would promote the spread of drug-resistant parasites or malaria transmission in general.

Adapt or Die: Targeting Unique Transmission-Stage Biology for Malaria Elimination

“…This has often raised a concern as to potential increased transmission of the parasite under sub-optimal treatment conditions. Indeed, quantitative data on sexual commitment rates after drug (including antimalarials) exposure indicated elevated sexual commitment as a general stress response at a narrow window around the IC 50 and in the case of mefloquine and pyrimethamine, resulted in a net increase in gametocyte production ( Thommen et al., 2022 ). Whether this translates to therapeutic induction of gametocytes is unclear, but it would be a concern if antimalarials are not used at effective doses, as can often be the case in some endemic regions.…”

“…However, beyond the above evidence of drugs inducing gametocytogenesis when used on ABS parasites, no reports of drugs preventing gametocyte commitment by targeting the molecular role players are available, possibly due to the difficulty associated with detecting committed ring and schizont stages that precludes large scale investigations. The development of new P. falciparum reporter lines to detect commitment ( Thommen et al., 2022 ) may open up investigations of new antimalarial leads blocking this process. Genetic manipulation have indeed resulted in several gametocyte deficient cell lines [e.g.…”

Plasmodium falciparum sexual conversion rates can be affected by artemisinin-based treatment in naturally infected malaria patients

“…However, the conditions of the environment can enhance sexual conversion rates, possibly as an adaptive response to stress conditions. 2 , 6 , 7 , 8 , 9 , 10 , 11 Parasite commitment to sexual development depends on the transcription factor PfAP2-G, which is the master regulator of the process. 12 , 13 , 14 , 15 , 16 In asexually growing parasites, the pfap2-g gene is silenced by epigenetic mechanisms.…”

“…In a recent carefully conducted study in which parasites were exposed to different drugs for the duration of a full asexual replication cycle (48 h), no effect of ART or the majority of other drugs tested on sexual conversion rates was observed. 11 However, the long exposure time implied that even very low ART concentrations resulted in high parasite mortality. We recently measured the impact of chloroquine and dihydroartemisinin (DHA), the active metabolite of all ARTs, on P. falciparum sexual conversion.…”

Streamlined and Robust Stage-Specific Profiling of Gametocytocidal Compounds Against Plasmodium falciparum

“…In such scenarios, transmission will not be blocked, and the parasite will continue to be spread. Moreover, this is of particular concern given the presence of same cycle sexual conversion, i.e., induction of gametocytogenesis within the first cycle of ABS proliferation ( Bancells et al., 2019 ) and evidence that some ABS actives (chloroquine, antifolates, and mefloquine) can shift the parasite population into sexual differentiation and increase the gametocytaemia of immature stages in vivo ( Buckling et al., 1999 ; Price et al., 1999 ; Sowunmi and Fateye, 2003 ; Sowunmi et al., 2006 ; Fehintola et al., 2012 ; Thommen et al., 2022 ).…”