A Specific PfEMP1 Is Expressed in P. falciparum Sporozoites and Plays a Role in Hepatocyte Infection

Zanghì, Gigliola; Vembar, Shruthi S.; Baumgarten, Sebastian; Ding, Shibin; Guizetti, Julien; Bryant, Jessica M.; Mattei, Denise; Jensen, Anja T. R.; Rénia, Laurent; Goh, Yun Shan; Sauerwein, Robert W.; Hermsen, Cornelus C.; Franetich, Jean‐François; Bordessoulles, Mallaury; Silvie, Olivier; Soulard, Valérie; Scatton, Olivier; Chen, Patty; Mécheri, Salaheddine; Mazier, Dominique; Scherf, Artur

doi:10.1016/j.celrep.2018.02.075

Cited by 104 publications

(109 citation statements)

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“…For instance, in both P. yoelii and P. falciparum , CelTOS, GEST and SPELD were not detected or were only weakly expressed in oocyst sporozoites, but were among the most abundant proteins in salivary gland sporozoites (Table 2, Table S1). Moreover, the presence/absence of cellular regulators such as specific ApiAP2s, histone modifiers, RNA-binding proteins and other proteins (Table S1) agree with previous reports describing how these types of regulation may be used by the sporozoite 32, 40, 48 .…”

Section: Resultssupporting

confidence: 90%

“…py17x_0208200 , py17x_0835500 , py17x_1354300 ) undergo the same extreme swings in transcript abundance between these stages as does pyuis4 (>1000-fold). Finally, we found that a recently described sporozoite var gene (SpzPfEMP1) is robustly expressed in not only oocyst sporozoites as previously reported, but also in salivary gland sporozoites and thus may simplify the recently described model of how this interesting var gene is regulated (Table 1) 32 . Given the transcript abundance of the novel and uncharacterized genes of these lists, they warrant a prioritized assessment.…”

Section: Resultssupporting

confidence: 73%

“…In response to this, we have developed a scalable, discontinuous density gradient purification approach for sporozoites that greatly reduces contamination from the mosquito and its microbes 25 . The resulting fully infectious sporozoites have allowed extensive ChIP, transcriptomic (RNA-seq) and proteomic (nanoLC-MS/MS) analyses of sporozoites from both rodent-infectious ( P. yoelii ) and human-infectious ( P. falciparum , P. vivax ) parasites 26–32 . Taken together, these studies demonstrate that ‘omics’ level efforts on sporozoites are now experimentally practical, and thus reopen long standing questions of mechanisms underlying critical sporozoite functions.…”

Section: Introductionmentioning

confidence: 99%

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Extensive Transcriptional and Translational Regulation Occur During the Maturation of Malaria Parasite Sporozoites

Lindner

Swearingen

Shears

et al. 2019

Preprint

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22 Introduction: 41Malaria remains one of the great global health problems today, taking a large toll on people in the 42 tropics and subtropics. This disease, caused by Plasmodium parasites, affects over 200 million people 43 annually and kills over 400,000 (WHO World Malaria Report 2018). While a protein-based subunit 44 vaccine (RTS,S) has recently been licensed and is being used for pilot implementation in three Saharan African countries, its protection has been limited and relatively short-lived in clinical trials 1 . 46 Identifying and fully testing an effective and long-lasting malaria vaccine remains a chief goal that has 47 yet to be achieved. Accomplishing this will require greater knowledge of the basic biology of the pre-48 erythrocytic sporozoite and liver stage parasites. Promising new whole-parasite vaccine candidates, 49 based upon the sporozoite form of the parasite, are on the horizon and hopefully will meet these needs 50 2 . 51Plasmodium parasites are transmitted between hosts by an infected female Anopheles mosquito 52 (reviewed in 3 ). Following uptake of male and female gametocytes by the mosquito during a blood meal 53 of an infected host, these parasites activate into male and female gametes in the midgut, fuse into a 54 zygote, and develop into a motile ookinete, which burrows through the midgut wall and establishes an 55 oocyst under the basal lamina. Within the oocyst, the parasite undergoes sporogony to produce up to 56 five thousand oocyst sporozoites 4 . These oocyst sporozoites are weakly infectious if injected directly 57 into a naïve mammalian host 5 , but become highly infectious following proteolytic rupture of the oocyst 58 wall and transit through the mosquito hemocoel. Sporozoites further gain infectivity after invasion of 59 the salivary glands 5,6 . Interestingly, the gain of infectivity for the mammalian host is concomitant with a 60 loss of infectivity for the salivary glands. Within the glands, the sporozoites await transmission as 61 salivary gland sporozoites, which occurs when the mosquito takes its next blood meal. Infection of a 62 host begins with the injection of salivary gland sporozoites into the skin. Following this, sporozoites exit 63 the bite site in the skin, locate and enter the vasculature, and passively travel to the liver, where 64 sporozoites can productively infect hepatocytes, which initiates the life cycle progression in the 65 mammalian host 7 . Moreover, because relatively few sporozoites are injected during a mosquito bite 8 , 66 this transmission event bottleneck has been the focus of intervention efforts using drugs, subunit 67 vaccines, and attenuated whole parasite vaccines 2 . 68Fundamental studies of sporozoite biology have informed efforts to inhibit and/or arrest the parasite 69 during development. To date, genetically-attenuated parasite (GAP) vaccine candidates were generated 70 by the deletion of genes whose transcripts are Up-regulated in Infective (Salivary Gland) Sporozoites 71 (UIS). The UIS gene family was originally determi...

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Section: Resultssupporting

confidence: 90%

Section: Resultssupporting

confidence: 73%

Section: Introductionmentioning

confidence: 99%

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Extensive Transcriptional and Translational Regulation Occur During the Maturation of Malaria Parasite Sporozoites

Lindner

Swearingen

Shears

et al. 2019

Preprint

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“…H3K9ac is a universal histone mark associated with active promoters across the animal kingdom, including P. falciparum ABS, oocysts and sporozoites (12, 61, 62). We investigated the relationship between H3K9ac distribution and gene transcription across the three P. berghei developmental stages.…”

Section: Resultsmentioning

confidence: 99%

Epigenetic regulation underlying Plasmodium berghei gene expression during its developmental transition from host to vector

Witmer

Fraschka²,

Vlachou

et al. 2019

Preprint

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Epigenetic regulation of gene expression is an important attribute in the survival and adaptation of the malaria parasite Plasmodium in its human host. Our understanding of epigenetic regulation of gene expression in Plasmodium developmental stages beyond asexual replication in the mammalian host is sparse. We used chromatin immune-precipitation (ChIP) and RNA sequencing to create an epigenetic and transcriptomic map of the murine parasite Plasmodium berghei development from asexual blood stages to male and female gametocytes, and finally, to ookinetes. We show that heterochromatin 1 (HP1) almost exclusively associates with variantly expressed gene families at subtelomeric regions and remains stable across stages and various parasite lines. Variant expression based on heterochromatic silencing is observed only in very few genes. In contrast, the active histone mark histone 3 Lysine 9 acetylation (H3K9ac) is found between heterochromatin boundaries and occurs as a sharp peak around the start codon for ribosomal protein genes. H3K9ac occupancy positively correlates with gene transcripts in asexual blood stages, male gametocytes and ookinetes. Interestingly, H3K9ac occupancy does not correlate with transcript abundance in female gametocytes. Finally, we identify novel DNA motifs upstream of ookinete-specific genes thought to be involved in transcriptional activation upon fertilization.

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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%

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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A Specific PfEMP1 Is Expressed in P. falciparum Sporozoites and Plays a Role in Hepatocyte Infection

Cited by 104 publications

References 44 publications

Extensive Transcriptional and Translational Regulation Occur During the Maturation of Malaria Parasite Sporozoites

Extensive Transcriptional and Translational Regulation Occur During the Maturation of Malaria Parasite Sporozoites

Epigenetic regulation underlying Plasmodium berghei gene expression during its developmental transition from host to vector

RNA-Seq Analysis Illuminates the Early Stages ofPlasmodiumLiver Infection

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