Artemisinin exposure at the ring or trophozoite stage impacts Plasmodium falciparum sexual conversion differently

Portugaliza, Harvie P.; Miyazaki, Shuichi; Geurten, Fiona J. A.; Pell, Christopher; Rosanas-Urgell, Anna; Janse, Chris J.; Cortés, Alfred

doi:10.7554/elife.60058

Cited by 41 publications

(70 citation statements)

References 75 publications

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“…However, how asexual cells are reprogrammed for gametocyte commitment, and the downstream post‐commitment regulation of sexual development is not well characterized. There are known examples of gametocyte stage genes such as pfsegxp, mdv1, gexp02 and pfs16 that are expressed very early on in the asexual stages, suggesting that programming for gametocytogenesis may begin early in asexual development, and disruption of this program could result in profound effects post‐commitment during sexual development (Furuya et al., 2005; Joice et al., 2014; Nixon et al., 2018; Painter et al., 2017; Portugaliza et al., 2020).…”

Section: Discussionmentioning

confidence: 99%

The PfAP2‐G2 transcription factor is a critical regulator of gametocyte maturation

Singh

Santos

Orchard

et al. 2021

Molecular Microbiology

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Differentiation from asexual blood stages to mature sexual gametocytes is required for the transmission of malaria parasites. Here, we report that the ApiAP2 transcription factor, PfAP2‐G2 (PF3D7_1408200) plays a critical role in the maturation of Plasmodium falciparum gametocytes. PfAP2‐G2 binds to the promoters of a wide array of genes that are expressed at many stages of the parasite life cycle. Interestingly, we also find binding of PfAP2‐G2 within the gene body of almost 3,000 genes, which strongly correlates with the location of H3K36me3 and several other histone modifications as well as Heterochromatin Protein 1 (HP1), suggesting that occupancy of PfAP2‐G2 in gene bodies may serve as an alternative regulatory mechanism. Disruption of pfap2‐g2 does not impact asexual development, but the majority of sexual parasites are unable to mature beyond stage III gametocytes. The absence of pfap2‐g2 leads to overexpression of 28% of the genes bound by PfAP2‐G2 and none of the PfAP2‐G2 bound genes are downregulated, suggesting that it is a repressor. We also find that PfAP2‐G2 interacts with chromatin remodeling proteins, a microrchidia (MORC) protein, and another ApiAP2 protein (PF3D7_1139300). Overall our data demonstrate that PfAP2‐G2 establishes an essential gametocyte maturation program in association with other chromatin‐related proteins.

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Section: Discussionmentioning

confidence: 99%

The PfAP2‐G2 transcription factor is a critical regulator of gametocyte maturation

Singh

Santos

Orchard

et al. 2021

Molecular Microbiology

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“…Furthermore, treatment with sub-curative doses of the widely used drugs chloroquine (36) and sulfadoxine/pyrimethamine ("Fansidar") (39) have been associated with increased gametocyte production in vivo. Using a transgenic reporter cell line for the quantification of sexual conversion rates (40), the Cortés laboratory recently confirmed a gametocytogenesis-inducing effect for the frontline antimalarial dihydroartemisinin (DHA) (38). In this study, short pulses of sub-curative DHA concentrations applied to trophozoites induced sexual commitment in vitro, but this effect was not observed when ring or schizont stage parasites were exposed to the drug.…”

Section: Introductionmentioning

confidence: 72%

“…For example, the different microenvironments that parasites encounter at sequestration sites, including the bone marrow and spleen, may have profound effects on drug kinetics and bioavailability. Furthermore, in recent efforts, Portugaliza and colleagues simulated the short in vivo half-life of artemisinin/DHA by exposing in vitro cultured parasites to short drug pulses and identified stage-specific effects on sexual commitment (38). While ring stage populations exposed to 3hour pulses of DHA responded with decreased SCRs, trophozoites showed elevated SCRs following drug pressure.…”

Section: Discussionmentioning

confidence: 99%

“…Noteworthy, parasites treated with artemisinin or its derivatives dihydroartemisinin (DHA), artemether and artesunate, emitted autofluorescence at various wavelengths including the TRITC channel, making a fluorescence-based quantification of SCRs impossible. To circumvent this issue and evaluate the effect of DHA, for which a sexual commitment-inducing effect has recently been demonstrated (38), we generated the NF54/ap2g-re9h reporter line (Fig. 3A and Fig.…”

Section: Many Antimalarials Induce Sexual Commitment At Growth-limiting Concentrationsmentioning

confidence: 99%

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Revisiting the effect of pharmaceuticals on transmission stage formation in the malaria parasite Plasmodium falciparum

Thommen¹,

Passecker²,

Buser³

et al. 2021

Preprint

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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 provide conclusive evidence for the absence of mechanistic links between the regulation of sexual commitment and the activity of commonly used pharmaceuticals in vitro. Our data hence contradict scenarios in which therapeutic interventions would promote the spread of drug-resistant parasites or malaria transmission in general.

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“…A subsequent in vitro study showed that clinical isolates with K13 mutations had a higher ability to initiate gametocytogenesis and infect mosquitoes under ART drug pressure ( Witmer et al, 2020 ). Actually, exposure of trophozoites to low DHA concentrations promoted sexual conversion ( Portugaliza et al, 2020 ), providing further support for the transmission of resistant parasites after ART treatment. Moreover, ART-resistant parasites can readily infect highly diverse Anopheles mosquitoes including the primary African vector An.…”

Section: Art Resistance: the Unusual Phenotype And Underlying Mechanismsmentioning

confidence: 97%

Plasmodium falciparum resistance to ACTs: Emergence, mechanisms, and outlook

Siddiqui

Liang

2021

International Journal for Parasitology: Drugs and Drug Resistan

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Emergence and spread of resistance in Plasmodium falciparum to the frontline treatment artemisinin-based combination therapies (ACTs) in the epicenter of multidrug resistance of Southeast Asia threaten global malaria control and elimination. Artemisinin (ART) resistance (or tolerance) is defined clinically as delayed parasite clearance after treatment with an ART drug. The resistance phenotype is restricted to the early ring stage and can be measured in vitro using a ring-stage survival assay. ART resistance is associated with mutations in the propeller domain of the Kelch family protein K13. As a pro-drug, ART is activated primarily by heme, which is mainly derived from hemoglobin digestion in the food vacuole. Activated ARTs can react promiscuously with a wide range of cellular targets, disrupting cellular protein homeostasis. Consistent with this mode of action for ARTs, the molecular mechanisms of K13-mediated ART resistance involve reduced hemoglobin uptake/digestion and increased cellular stress response. Mutations in other genes such as AP-2μ (adaptor protein-2 μ subunit), UBP-1 (ubiquitin-binding protein-1), and Falcipain 2a that interfere with hemoglobin uptake and digestion also increase resistance to ARTs. ART resistance has facilitated the development of resistance to the partner drugs, resulting in rapidly declining ACT efficacies. The molecular markers for resistance to the partner drugs are mostly associated with point mutations in the two food vacuole membrane transporters PfCRT and PfMDR1, and amplification of pfmdr1 and the two aspartic protease genes plasmepsin 2 and 3 . It has been observed that mutations in these genes can have opposing effects on sensitivities to different partner drugs, which serve as the principle for designing triple ACTs and drug rotation. Although clinical ACT resistance is restricted to Southeast Asia, surveillance for drug resistance using in vivo clinical efficacy, in vitro assays, and molecular approaches is required to prevent or slow down the spread of resistant parasites.

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Artemisinin exposure at the ring or trophozoite stage impacts Plasmodium falciparum sexual conversion differently

Cited by 41 publications

References 75 publications

The PfAP2‐G2 transcription factor is a critical regulator of gametocyte maturation

The PfAP2‐G2 transcription factor is a critical regulator of gametocyte maturation

Revisiting the effect of pharmaceuticals on transmission stage formation in the malaria parasite Plasmodium falciparum

Plasmodium falciparum resistance to ACTs: Emergence, mechanisms, and outlook

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