Regulation of Sexual Commitment and Gametocytogenesis in Malaria Parasites

Josling, Gabrielle A.; Williamson, Kim C.; Llinás, Manuel

doi:10.1146/annurev-micro-090817-062712

Cited by 105 publications

(146 citation statements)

References 85 publications

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“…However, it is also possible for commitment to occur in the very early ring stage resulting in parasites developing directly into gametocytes without first passing through schizogony (same cycle conversion) 3 . During the 10-12 day process of gametocytogenesis, the parasite undergoes dramatic morphological changes as it passes through five distinct stages (stages I-V) 4,5 . With the exception of stage V gametocytes, gametocytes are sequestered in host tissues (particularly the bone marrow 6,7 ).…”

Section: The Malaria Parasitementioning

confidence: 99%

Regulation of sexual differentiation is linked to invasion in malaria parasites

Venezia

Orchard

et al. 2019

Preprint

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In the malaria parasite Plasmodium falciparum, the switch from asexual multiplication to sexual differentiation into gametocytes is essential for transmission to mosquitos. One of the key determinants of sexual commitment is the transcription factor PfAP2-G, which has been proposed to orchestrate this crucial cell fate decision by driving expression of gametocyte genes.We show conclusively that PfAP2-G is a transcriptional activator of gametocyte genes and identify the earliest known markers expressed during commitment. Remarkably, we also find that in sexually committed cells, PfAP2-G is associated with the promoters of genes important for red blood cell invasion and activates them through its interactions with a second transcription factor. We thus demonstrate an intriguing transcriptional link between the apparently opposing processes of red blood cell invasion and gametocytogenesis that is coordinated by the master regulator PfAP2-G. This finding has important implications for the development of new antimalarial drugs that block the invasion of red blood cells by sexually committed cells, thereby preventing parasite transmission.

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Section: The Malaria Parasitementioning

confidence: 99%

Regulation of sexual differentiation is linked to invasion in malaria parasites

Venezia

Orchard

et al. 2019

Preprint

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“…The AP2 transcription factors (TFs), comprised of 26 genes in P. berghei , are the best-characterized family of TFs in apicomplexans ( Figure 5A ). AP2s are known to regulate Plasmodium transitions into different developmental stages and have emerged as key factors leading to both sexual commitment and sex differentiation (reviewed in (4)). Unsurprisingly, we observe that AP2 genes with established functions in mosquito stages ( AP2-O , AP2-O2 ) and those involved in sporozoite development ( AP2-SPs ) are downregulated throughout the liver stages ( Figure 5A ).…”

Section: Resultsmentioning

confidence: 99%

“…Transcriptomic studies have been instrumental in revealing gene expression variation that accompanies stage transitions and developmental processes in Plasmodium . Subsequent analyses of these data have also identified transcription factors that are critical for controlling parasite progression at various stages (reviewed in (4)). Yet, only a handful of transcriptome analyses have been completed in the LS relative to other parasite forms, likely owing to the technical challenges associated with studying this stage.…”

Section: Introductionmentioning

confidence: 99%

RNA-Seq Analysis Illuminates the Early Stages ofPlasmodiumLiver Infection

Toro-Moreno¹,

Sylvester

Srivastava³

et al. 2019

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24The apicomplexan parasites Plasmodium spp. are the causative agents of malaria, a disease 25 that poses a significant global health burden. Plasmodium spp. initiate infection of the human host 26 by transforming and replicating within hepatocytes. This liver stage (LS) is poorly understood 27 when compared to other Plasmodium life stages, which has hindered our ability to target these 28 parasites for disease prevention. We conducted an extensive RNA-seq analysis throughout the 29 Plasmodium berghei LS, covering as early as 2 hours post infection (hpi) and extending to 48 hpi. 30Our data revealed that hundreds of genes are differentially expressed at 2 hpi, and that multiple 31 genes shown to be important for later infection are upregulated as early as 12 hpi. Using 32 hierarchical clustering along with co-expression analysis, we identified clusters functionally 33 enriched for important liver-stage processes such as interactions with the host cell and redox 34 homeostasis. Furthermore, some of these clusters were highly correlated to the expression of 35ApiAP2 transcription factors, while showing enrichment of mostly uncharacterized DNA binding 36 motifs. This finding presents potential LS targets for these transcription factors, while also hinting 37 at alternative uncharacterized DNA binding motifs and transcription factors during this stage. Our 38 work presents a window into the previously undescribed transcriptome of Plasmodium upon host 39 hepatocyte infection to enable a comprehensive view of the parasite's LS. These findings also 40 provide a blueprint for future studies that extend hypotheses concerning LS gene function in P. 41 berghei to human-infective Plasmodium parasites. 42 43 IMPORTANCE 44The LS of Plasmodium infection is an asymptomatic yet necessary stage for producing 45 blood-infective parasites, the causative agents of malaria. Blocking the liver stage of the life cycle 46 can prevent clinical malaria, but relatively less is known about the parasite's biology at this stage. 47 Using the rodent model P. berghei, we investigated whole-transcriptome changes occurring as 48 early as 2 hpi of hepatocytes. The transcriptional profiles of early time points (2, 4, 12, and 18 hpi) 49have not been accessible before due to the technical challenges associated with liver-stage 50 infections. Our data now provides insights into these early parasite fluxes that may facilitate 51 establishment of infection, transformation and replication in the liver. 52 INTRODUCTION 54Plasmodium spp., the causative agents of malaria, are eukaryotic parasites with a largely 55 conserved and complex life cycle that begins in the mammalian host by invasion of hepatocytes. 56In these host cells, a single parasite, termed a sporozoite, will transform and then replicate 57 asexually to form thousands of merozoites, or blood-infective forms (1). After maturation and 58 release from the liver, parasites replicate within erythrocytes causing the clinical manifestation of 59 malaria. Some parasites differentiate into sexual forms ...

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“…This is followed by sexual conversion, which according to our recently proposed definitions (Bancells et al, 2019) is marked by expression of gametocyte-specific proteins absent from any replicating blood stages. After sexual conversion, parasites at the sexual ring stage develop through gametocyte stages I 55 to V in a maturation process that lasts for ~10 days (Josling et al, 2018;Ngotho et al, 2019). While immature gametocytes are sequestered in organs such as the bone marrow (Venugopal et al, 2020), mature gametocytes (stage V) are released into the circulation, where they are infectious to mosquitoes for several days or even weeks (Cao et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

“…From an evolutionary perspective, the ability to adjust sexual conversion rates depending on the host conditions would be clearly advantageous for the parasite (Carter et al, 2013;Schneider et al, 2018). In P. 75 falciparum, several specific conditions have been shown to increase sexual conversion rates, and exposure to stress in general was proposed to enhance sexual conversion (Baker, 2010;Bousema & Drakeley, 2011;Dyer & Day, 2000;Josling et al, 2018). The most commonly used method to enhance sexual conversion and obtain large numbers of gametocytes in vitro relies on overgrowing blood stage 80 cultures (the "crash method") (Delves et al, 2016) and/or maintaining the cultures with parasite-conditioned (spent) medium (Brancucci et al, 2015;Fivelman et al, 2007).…”

Section: Introductionmentioning

confidence: 99%