The Plasmodium NOT1-G paralogue is an essential regulator of sexual stage maturation and parasite transmission

Hart, Kevin J.; Power, B. Joanne; Rios, Kelly T.; Sebastian, Aswathy; Lindner, Scott E.

doi:10.1371/journal.pbio.3001434

Cited by 18 publications

(32 citation statements)

References 59 publications

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“…mRNA targets are bound by Pf Puf2, the disruption of which results in translation and the increased production of the associated protein ( Miao et al., 2013 ). Those transcripts not stabilized are regulated by the CAF1/CCR4/NOT complex causing mRNA decay and thereby translational repression ( Figure 3 ) ( Hart et al., 2019 ; Hart et al., 2021 ).…”

Section: Maturation Of Gametocytes To Transmissible Formsmentioning

confidence: 99%

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

Watt

Reader

Birkholtz

2022

Front. Cell. Infect. Microbiol.

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Plasmodium parasites have a complex life cycle that includes development in the human host as well as the Anopheles vector. Successful transmission of the parasite between its host and vector therefore requires the parasite to balance its investments in asexual replication and sexual reproduction, varying the frequency of sexual commitment to persist within the human host and generate future opportunities for transmission. The transmission window is extended further by the ability of stage V gametocytes to circulate in peripheral blood for weeks, whereas immature stage I to IV gametocytes sequester in the bone marrow and spleen until final maturation. Due to the low gametocyte numbers in blood circulation and with the ease of targeting such life cycle bottlenecks, transmission represents an efficient target for therapeutic intervention. The biological process of Plasmodium transmission is a multistage, multifaceted process and the past decade has seen a much deeper understanding of the molecular mechanisms and regulators involved. Clearly, specific and divergent processes are used during transmission compared to asexual proliferation, which both poses challenges but also opportunities for discovery of transmission-blocking antimalarials. This review therefore presents an update of our molecular understanding of gametocyte and gamete biology as well as the status of transmission-blocking activities of current antimalarials and lead development compounds. By defining the biological components associated with transmission, considerations for the development of new transmission-blocking drugs to target such untapped but unique biology is suggested as an important, main driver for transmission-blocking drug discovery.

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Section: Maturation Of Gametocytes To Transmissible Formsmentioning

confidence: 99%

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

Watt

Reader

Birkholtz

2022

Front. Cell. Infect. Microbiol.

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“…Gene models were created with two alternative methodologies using Nanopore direct RNA-seq long reads alone or in combination with our previously published Illumina short-read RNA-seq of mixed asexual and sexual blood stage parasites (Figure 2) (37). These parallel approaches are both informative, given the strengths and limitations of both sequencing techniques.…”

Section: Nanopore Direct Rna Sequencing Provides New Information To P...mentioning

confidence: 99%

“…The predicted genes were annotated using reciprocal BLAST against P. yoelii 17X proteins. Illumina RNA-seq reads were previously reported (37).…”

Section: Data Availabilitymentioning

confidence: 99%

“…The library preparation methods and sequencing devices used for each sample are also indicated. The Illumina RNA-seq data utilized in this study was previously published by our laboratories and was retrieved from the GEO depository (Accession #GSE136674) (37). The amino acid sequence for the central repeat region of circumsporozoite protein (CSP) is shown for P. yoelii 17X, P. yoelii 17XNL, and P. yoelii YM.…”

Section: Fundingmentioning

confidence: 99%

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Long-Read Genome Assembly and Gene Model Annotations for the Rodent Malaria ParasitePlasmodium yoelii17XNL

Godin

Sebastian

Albert

et al. 2023

Preprint

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Malaria causes over 200 million infections and over 600 thousand fatalities each year, with most cases attributed to a human-infectious Plasmodium species, Plasmodium falciparum. Many rodent-infectious Plasmodium species, like Plasmodium berghei, Plasmodium chabaudi, and Plasmodium yoelii, have been used as genetically tractable model species that can expedite studies of this pathogen. In particular, P. yoelii is an especially good model for investigating the mosquito and liver stages of parasite development because key attributes closely resemble those of P. falciparum. Because of its importance to malaria research, in 2002 the 17XNL strain of P. yoelii was the first rodent malaria parasite to be sequenced. While sequencing and assembling this genome was a breakthrough effort, the final assembly consisted of >5000 contiguous sequences that impacted the creation of annotated gene models. While other important rodent malaria parasite genomes have been sequenced and annotated since then, including the related P. yoelii 17X strain, the 17XNL strain has not. As a result, genomic data for 17X has become the de facto reference genome for the 17XNL strain while leaving open questions surrounding possible differences between the 17XNL and 17X genomes. In this work, we present a high-quality genome assembly for P. yoelii 17XNL using HiFi PacBio long-read DNA sequencing. In addition, we use Nanopore long-read direct RNA-seq and Illumina short-read sequencing of mixed blood stages to create complete gene models that include not only coding sequences but also alternate transcript isoforms, and 5′and 3′ UTR designations. A comparison of the 17X and this new 17XNL assembly revealed biologically meaningful differences between the strains due to the presence of coding sequence variants. Taken together, our work provides a new genomic and gene expression framework for studies with this commonly used rodent malaria model species.

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“…Recently, it is reported that transcription factors of Apicomplexan Apetala 2 family (ApiAP2) member AP2-O3, also specifically active in the female gametocytes, is a transcription repressor that regulates the formation of female gamete ( Li et al., 2021 ). In addition, recently, Plasmodium yoelii negative on TATA-less1-G ( Py NOT1-G) was discovered to play dual and opposed sexual functions - reducing gametocyte commitment but supporting male (exflagellation) and female (preparing the female gamete for further development) gametogenesis ( Hart et al., 2021 ). Though Py NOT1-G is a key part of mRNA de-adenylation complex (Ccr4p-associated factor/carbon catabolite repression4/negative on TATA-less (CAF1/CCR4/NOT)) and plays a fundamental role in preserving the mRNAs that are critical to Plasmodium sexual and early mosquito stage development, the mRNAs is regulated by the complex during gametogenesis is yet to be found ( Hart et al., 2021 ).…”

Section: The Criticality Of Gametogenesis and Its Biologymentioning

confidence: 99%

Gametogenesis in Plasmodium: Delving Deeper to Connect the Dots

Dash

Sachdeva²,

Bansal³

et al. 2022

Front. Cell. Infect. Microbiol.

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In the coming decades, eliminating malaria is the foremost goal of many tropical countries. Transmission control, along with an accurate and timely diagnosis of malaria, effective treatment and prevention are the different aspects that need to be met synchronously to accomplish the goal. The current review is focused on one of these aspects i.e., transmission control, by looking deeper into the event called gametogenesis. In the Plasmodium life cycle, gametocytes are the first life forms of the sexual phase. The transmission of the parasite and the disease is critically dependent on the number, viability and sex ratio of mature gametocytes and their further development inside mosquito vectors. Gametogenesis, the process of conversion of gametocytes into viable gametes, takes place inside the mosquito midgut, and is a tightly regulated event with fast and multiple rounds of DNA replication and diverse cellular changes going on within a short period. Interrupting the gametocyte-gamete transition is ought to restrict the successful transmission and progression of the disease and hence an area worth exploring for designing transmission-blocking strategies. This review summarizes an in-depth and up-to-date understanding of the biochemical and physiological mechanism of gametogenesis in Plasmodium, which could be targeted to control parasite and malaria transmission. This review also raises certain key questions regarding gametogenesis biology in Plasmodium and brings out gaps that still accompany in understanding the spectacular process of gametogenesis.

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The Plasmodium NOT1-G paralogue is an essential regulator of sexual stage maturation and parasite transmission

Cited by 18 publications

References 59 publications

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

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

Long-Read Genome Assembly and Gene Model Annotations for the Rodent Malaria ParasitePlasmodium yoelii17XNL

Gametogenesis in Plasmodium: Delving Deeper to Connect the Dots

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