Malaria Parasite Liver Infection and Exoerythrocytic Biology

Vaughan, Ashley M.; Kappe, Stefan H. I.

doi:10.1101/cshperspect.a025486

Cited by 114 publications

(98 citation statements)

References 118 publications

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“…Genes in this cluster are highly expressed in sporozoites, and thus appear to be strongly downregulated during infection ( Figure 4C ). In agreement with this result, this cluster includes genes that have been previously shown to play an important role during invasion ( CELTOS, SPECT1, TRAP ), interactions with the host liver cell ( UIS3, UIS4, CSP, p36, p52 ), and translational control of liver-stage specific transcripts ( UIS2, PUF1, PUF2 ) (16).…”

Section: Resultssupporting

confidence: 80%

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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Section: Resultssupporting

confidence: 80%

RNA-Seq Analysis Illuminates the Early Stages ofPlasmodiumLiver Infection

Toro-Moreno¹,

Sylvester

Srivastava³

et al. 2019

Preprint

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“…These so-called Plasmodium sporozoites develop in oocysts at the midgut wall of mosquitoes and enter the salivary glands of the insect from where they are transmitted to a vertebrate host (Ménard et al, 2013;Frischknecht & Matuschewski, 2017; Fig 1A). Sporozoites are highly flexible and motile cells that need to pass several tissue barriers including the salivary glands, the skin and blood vessel endothelium before they infect liver cells to differentiate into thousands of merozoites, which then infect red blood cells (Frischknecht & Matuschewski, 2017;Vaughan & Kappe, 2017). Sporozoites are the target of the first approved malaria vaccine, which contains part of the major sporozoite surface protein as an antigen (Clemens & Moorthy, 2016;Olotu et al, 2016).…”

Section: Of 22mentioning

confidence: 99%

Microtubule number and length determine cellular shape and function in Plasmodium

et al. 2019

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Microtubules are cytoskeletal filaments essential for many cellular processes, including establishment and maintenance of polarity, intracellular transport, division and migration. In most metazoan cells, the number and length of microtubules are highly variable, while they can be precisely defined in some protozoan organisms. However, in either case the significance of these two key parameters for cells is not known. Here, we quantitatively studied the impact of modulating microtubule number and length in Plasmodium , the protozoan parasite causing malaria. Using a gene deletion and replacement strategy targeting one out of two α‐tubulin genes, we show that chromosome segregation proceeds in the oocysts even in the absence of microtubules. However, fewer and shorter microtubules severely impaired the formation, motility and infectivity of Plasmodium sporozoites, the forms transmitted by the mosquito, which usually contain 16 microtubules. We found that α‐tubulin expression levels directly determined the number of microtubules, suggesting a high nucleation barrier as supported by a mathematical model. Infectious sporozoites were only formed in parasite lines featuring at least 10 microtubules, while parasites with 9 or fewer microtubules failed to transmit.

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“…This affords the parasite the protection and resources to multiply from 1 initial infectious parasite into thousands of daughter merozoites. These are then released to the bloodstream and go on to infect erythrocytes, commencing the symptomatic, cyclic, and pathogenic blood stage of infection (2). Although clinically silent, the liver stage of infection is a research priority because it is the first stage for stopping infection before fulminant disease.…”

Section: Introductionmentioning

confidence: 99%