Transcriptomics and proteomics reveal two waves of translational repression during the maturation of malaria parasite sporozoites

Lindner, Scott E.; Swearingen, Kristian E.; Shears, Melanie J.; Walker, Michael P.; Vrana, Erin N.; Hart, Kevin J.; Minns, Allen M.; Sinnis, Photini; Moritz, Robert L.; Kappe, Stefan H. I.

doi:10.1038/s41467-019-12936-6

Cited by 113 publications

(142 citation statements)

References 86 publications

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“…Translational repression (TR) of hundreds of transcripts has been reported at most stages of the P. berghei life cycle (29). TR is particularly pervasive in the sporozoite transition from the mosquito to the mammalian host (30,31). During this transition, hundreds of transcripts that are highly expressed in sporozoites are stored in mRNA granules, until infection of the host relieves this repression, resulting in protein translation.…”

Section: Discussionmentioning

confidence: 99%

RNA-Seq Analysis Illuminates the Early Stages of Plasmodium Liver Infection

Toro-Moreno

Sylvester

Srivastava

et al. 2020

mBio

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The apicomplexan parasites Plasmodium spp. are the causative agents of malaria, a disease that poses a significant global health burden. Plasmodium spp. initiate infection of the human host by transforming and replicating within hepatocytes. This liver stage (LS) is poorly understood compared to other Plasmodium life stages, which has hindered our ability to target these parasites for disease prevention. We conducted an extensive transcriptome sequencing (RNA-Seq) analysis throughout the Plasmodium berghei LS, covering as early as 2 h postinfection (hpi) and extending to 48 hpi. Our data revealed that hundreds of genes are differentially expressed at 2 hpi and that multiple genes shown to be important for later infection are upregulated as early as 12 hpi. Using hierarchical clustering along with coexpression analysis, we identified clusters functionally enriched for important liver-stage processes such as interactions with the host cell and redox homeostasis. Furthermore, some of these clusters were highly correlated to the expression of ApiAP2 transcription factors, while showing enrichment of mostly uncharacterized DNA binding motifs. This finding indicates potential LS targets for these transcription factors, while also hinting at alternative uncharacterized DNA binding motifs and transcription factors during this stage. Our work presents a window into the previously undescribed transcriptome of Plasmodium upon host hepatocyte infection to enable a comprehensive view of the parasite’s LS. These findings also provide a blueprint for future studies that extend hypotheses concerning LS gene function in P. berghei to human-infective Plasmodium parasites. IMPORTANCE The LS of Plasmodium infection is an asymptomatic yet necessary stage for producing blood-infective parasites, the causative agents of malaria. Blocking the liver stage of the life cycle can prevent clinical malaria, but relatively less is known about the parasite’s biology at this stage. Using the rodent model P. berghei, we investigated whole-transcriptome changes occurring as early as 2 hpi of hepatocytes. The transcriptional profiles of early time points (2, 4, 12, and 18 hpi) have not been accessible before due to the technical challenges associated with liver-stage infections. Our data now provide insights into these early parasite fluxes that may facilitate establishment of infection, transformation, and replication in the liver.

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Section: Discussionmentioning

confidence: 99%

RNA-Seq Analysis Illuminates the Early Stages of Plasmodium Liver Infection

Toro-Moreno

Sylvester

Srivastava

et al. 2020

mBio

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“…Hierarchical clustering of gene expression datasets from different stages of the Plasmodium life cycle (7, 8, 26, 32, 34, 52–54). Datasets generated in this study are in bold.…”

Section: Resultsmentioning

confidence: 99%

“…Translational repression (TR) of hundreds of transcripts has been reported at most stages of the P. berghei life cycle (30). TR is particularly pervasive in the sporozoite transition from the mosquito to the mammalian host (31, 32). During this transition, hundreds of transcripts that are highly expressed in sporozoites are stored in mRNA granules, until infection of the host relieves this repression resulting in protein translation.…”

Section: Discussionmentioning

confidence: 99%

RNA-Seq Analysis Illuminates the Early Stages ofPlasmodiumLiver Infection

Toro-Moreno¹,

Sylvester

Srivastava³

et al. 2019

Preprint

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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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“…In silico translational repression analysis was performed as reported by Lindner et al [34] with modification.…”

Section: Translational Repression Analysismentioning

confidence: 99%

A Tail of Two Structures: Proteomic and Transcriptomic Analysis of Cercarial Heads and Tails of Schistosome Worms

Hagerty¹,

Kim²,

Jolly³

2020

Preprint

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Schistosomes require both molluscan and mammalian hosts for development. The larval stage, cercaria, exits the intermediate snail host and must swim to identify and invade the definitive mammalian host. The cercaria has two macrostructures, the head and the tail. The tail is lost after host invasion, whereas the head develops into a sexually dimorphic adult worm. Translation in the cercaria differs in each macrostructure with higher levels of translation in cercarial tails and little to no translational activity in cercarial heads. We compared the transcriptome and proteome of the cercarial head and tail and observed stark differences between the two macrostructures. We identified unique and differentially expressed transcripts and proteins, including multiple ribosomal components expressed in higher levels in tails than in heads, which may explain the differences in translation levels between heads and tails and reflect the weak correlation between transcription and translation in infectious cercarial heads and tails.

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Transcriptomics and proteomics reveal two waves of translational repression during the maturation of malaria parasite sporozoites

Cited by 113 publications

References 86 publications

RNA-Seq Analysis Illuminates the Early Stages of Plasmodium Liver Infection

RNA-Seq Analysis Illuminates the Early Stages of Plasmodium Liver Infection

RNA-Seq Analysis Illuminates the Early Stages ofPlasmodiumLiver Infection

A Tail of Two Structures: Proteomic and Transcriptomic Analysis of Cercarial Heads and Tails of Schistosome Worms

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