RNA-Seq Analysis Illuminates the Early Stages of <italic toggle="yes">Plasmodium</italic> Liver Infection

ABSTRACT 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 compar...

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Autores principales:	Maria Toro-Moreno, Kayla Sylvester, Tamanna Srivastava, Dora Posfai, Emily R. Derbyshire
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	P. berghei Plasmodium RNA sequencing liver stage malaria transcription Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/453cc204e3344120afb0e2bde561d652
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spelling	oai:doaj.org-article:453cc204e3344120afb0e2bde561d6522021-11-15T15:56:57ZRNA-Seq Analysis Illuminates the Early Stages of <italic toggle="yes">Plasmodium</italic> Liver Infection10.1128/mBio.03234-192150-7511https://doaj.org/article/453cc204e3344120afb0e2bde561d6522020-02-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.03234-19https://doaj.org/toc/2150-7511ABSTRACT 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.Maria Toro-MorenoKayla SylvesterTamanna SrivastavaDora PosfaiEmily R. DerbyshireAmerican Society for MicrobiologyarticleP. bergheiPlasmodiumRNA sequencingliver stagemalariatranscriptionMicrobiologyQR1-502ENmBio, Vol 11, Iss 1 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	P. berghei Plasmodium RNA sequencing liver stage malaria transcription Microbiology QR1-502
spellingShingle	P. berghei Plasmodium RNA sequencing liver stage malaria transcription Microbiology QR1-502 Maria Toro-Moreno Kayla Sylvester Tamanna Srivastava Dora Posfai Emily R. Derbyshire RNA-Seq Analysis Illuminates the Early Stages of <italic toggle="yes">Plasmodium</italic> Liver Infection
description	ABSTRACT 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.
format	article
author	Maria Toro-Moreno Kayla Sylvester Tamanna Srivastava Dora Posfai Emily R. Derbyshire
author_facet	Maria Toro-Moreno Kayla Sylvester Tamanna Srivastava Dora Posfai Emily R. Derbyshire
author_sort	Maria Toro-Moreno
title	RNA-Seq Analysis Illuminates the Early Stages of <italic toggle="yes">Plasmodium</italic> Liver Infection
title_short	RNA-Seq Analysis Illuminates the Early Stages of <italic toggle="yes">Plasmodium</italic> Liver Infection
title_full	RNA-Seq Analysis Illuminates the Early Stages of <italic toggle="yes">Plasmodium</italic> Liver Infection
title_fullStr	RNA-Seq Analysis Illuminates the Early Stages of <italic toggle="yes">Plasmodium</italic> Liver Infection
title_full_unstemmed	RNA-Seq Analysis Illuminates the Early Stages of <italic toggle="yes">Plasmodium</italic> Liver Infection
title_sort	rna-seq analysis illuminates the early stages of <italic toggle="yes">plasmodium</italic> liver infection
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/453cc204e3344120afb0e2bde561d652
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RNA-Seq Analysis Illuminates the Early Stages of <italic toggle="yes">Plasmodium</italic> Liver Infection

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