The pre-erythrocytic stage of plasmodium falciparum

Shortt, H. E.; Fairley, N. Hamilton; Covell, G.; Shute, P. G.; Garnhám, P. C. C.

doi:10.1016/s0035-9203(51)80019-1

Cited by 73 publications

(17 citation statements)

References 14 publications

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“…At day 5 post-infection, cryopreserved sporozoites express both PfEBA-175 and PfMSP-1 (Figure 3C). The parasites we observed were similar in size to what has been reported in other in vitro settings (approx.10 to 15μm at day 5) (Mazier et al, 1985; van Schaijk et al, 2008), but smaller than those reported in vivo (Shortt et al, 1951; Shortt and Garnham, 1948; Vaughan et al, 2012), (Figure 2L and 3B). Importantly, we demonstrated that the rate at which parasites progressed to the schizont stage between day 3 to day 6 post-infection was higher in infected MPCCs (33%) relative to the commonly-used hepatoma line, HC04 (14%) (Figure 2K).…”

Section: Resultssupporting

confidence: 88%

“…The infection rates of hepatocytes in MPCC is similar in comparison to the infection rates recently reported in HC04 cells which range from 0.4% to 0.06% (Epstein et al, 2011; Sattabongkot et al, 2006); however, in our system the progression rate from one stage of the life cycle to the other was much higher than in HC04, offering the potential for studying later stages of the liver life cycle more efficiently. Nonetheless, our MPCC infection rates remain low relative to those recorded in in vivo settings (Shortt et al, 1951; Shortt and Garnham, 1948). Experiments done in mice with P. yoelii (Conteh et al, 2010), and nonhuman primates with P. knowlesi (Jiang et al, 2009) have demonstrated that intravenous inoculation of only a few non-cryopreserved sporozoites (10 spz) can lead to a productive malaria infection that results in detectable parasitemia in the blood stage.…”

Section: Discussioncontrasting

confidence: 65%

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A Microscale Human Liver Platform that Supports the Hepatic Stages of Plasmodium falciparum and vivax

March

Velmurugan

et al. 2013

Cell Host & Microbe

189

223

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SUMMARY The Plasmodium liver stage is an attractive target for the development of anti-malarial drugs and vaccines, as it provides an opportunity to interrupt the life cycle of the parasite at a critical early stage. However, targeting the liver stage has been difficult. Undoubtedly, a major barrier has been the lack of robust, reliable and reproducible in vitro liver stage cultures. Here, we establish the liver stages for both Plasmodium falciparum and Plasmodium vivax in a microscale human liver platform composed of cryopreserved, micropatterned human primary hepatocytes surrounded by supportive stromal cells. Using this system, we have successfully recapitulated the full liver stage of P. falciparum including the release of infected merozoites and infection of overlaid erythrocytes, and also the establishment of small forms in late liver stages of P. vivax. Finally, we validate the potential of this platform as a tool for medium-throughput anti-malarial drug screening and vaccine development.

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Section: Resultssupporting

confidence: 88%

Section: Discussioncontrasting

confidence: 65%

A Microscale Human Liver Platform that Supports the Hepatic Stages of Plasmodium falciparum and vivax

March

Velmurugan

et al. 2013

Cell Host & Microbe

189

223

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“…Blood stage infection leads to malaria disease with Plasmodium falciparum alone afflicting more than 500 million people annually (Snow et al, 2005). Plasmodium replication in red blood cells produces between 8 and 36 merozoites with each invasive cycle (Cowman and Crabb, 2006) whereas onetime replication in the infected hepatocyte produces up to 40 000 merozoites (Shortt et al, 1951) -an~2000fold difference. It is currently not well understood to what extent malaria parasites rely on parasitic scavenging of nutrients versus intrinsic synthesis for growth and replication.…”

Section: Introductionmentioning

confidence: 99%

Type II fatty acid synthesis is essential only for malaria parasite late liver stage development

Vaughan

O'Neill

Tarun

et al. 2009

Cellular Microbiology

370

430

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SummaryIntracellular malaria parasites require lipids for growth and replication. They possess a prokaryotic type II fatty acid synthesis (FAS II) pathway that localizes to the apicoplast plastid organelle and is assumed to be necessary for pathogenic blood stage replication. However, the importance of FAS II throughout the complex parasite life cycle remains unknown. We show in a rodent malaria model that FAS II enzymes localize to the sporozoite and liver stage apicoplast. Targeted deletion of FabB/F, a critical enzyme in fatty acid synthesis, did not affect parasite blood stage replication, mosquito stage development and initial infection in the liver. This was confirmed by knockout of FabZ, another critical FAS II enzyme. However, FAS II-deficient Plasmodium yoelii liver stages failed to form exo-erythrocytic merozoites, the invasive stage that first initiates blood stage infection. Furthermore, deletion of FabI in the human malaria parasite Plasmodium falciparum did not show a reduction in asexual blood stage replication in vitro. Malaria parasites therefore depend on the intrinsic FAS II pathway only at one specific life cycle transition point, from liver to blood.

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“…A few hundred sporozoites are then deposited into the skin by an infected mosquito during a blood meal (Jin et al, 2007), enter the bloodstream by means of active locomotion and are transported to the liver to infect hepatocytes (Vanderberg and Frevert, 2004;Amino et al, 2006). Intracellular sporozoites become liver-stage (LS) parasites, which grow and differentiate in order to produce up to 40 000 infectious exo-erythrocytic merozoites (Shortt et al, 1951;Meis et al, 1983;Prudencio et al, 2006;Sturm et al, 2006) that will undergo multiple rounds of intra-erythrocytic growth. While liver infections do not result in overt pathology, they do lead to a massive one-time amplification of parasite numbers whereas replication within infected red blood cells (iRBCs) is cyclic and produces up to a few dozen merozoites after each invasive cycle (Cowman and Crabb, 2006), resulting in malaria-associated pathology.…”

Section: Introductionmentioning

confidence: 99%

“…During exo-erythrocytic schizogony, a single invading sporozoite de-differentiates into a trophozoite before undergoing extensive mitotic division without cytokinesis to form a multinucleated schizont (Meis et al, 1990). The syncytial schizont later undergoes extensive invagination of its plasma membrane, from which tens of thousands of exo-erythrocytic merozoites (Shortt et al, 1951;Bray and Garnham, 1982) are formed. These are eventually released into the bloodstream in parasite-filled vesicles, called merosomes (Sturm et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

APlasmodiumα/β-hydrolase modulates the development of invasive stages

Groat-Carmona

Kain

Brownell

et al. 2015

Cellular Microbiology

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The bud emergence (BEM)46 proteins are evolutionarily conserved members of the α/β-hydrolase superfamily, which includes enzymes with diverse functions and a wide range of substrates. Here, we identified a Plasmodium BEM46-like protein (PBLP) and characterized it throughout the life cycle of the rodent malaria parasite Plasmodium yoelii. The Plasmodium BEM46-like protein is shown to be closely associated with the parasite plasma membrane of asexual erythrocytic stage schizonts and exo-erythrocytic schizonts; however, PBLP localizes to unique intracellular structures in sporozoites. Generation and analysis of P. yoelii knockout (Δpblp) parasite lines showed that PBLP has an important role in erythrocytic stage merozoite development with Δpblp parasites forming fewer merozoites during schizogony, which results in decreased parasitemia when compared with wild-type (WT) parasites. Δpblp parasites showed no defects in gametogenesis or transmission to mosquitoes; however, because they formed fewer oocysts there was a reduction in the number of developed sporozoites in infected mosquitoes when compared with WT. Although Δpblp sporozoites showed no apparent defect in mosquito salivary gland infection, they showed decreased infectivity in hepatocytes in vitro. Similarly, mice infected with Δpblp sporozoites exhibited a delay in the onset of blood-stage patency, which is likely caused by reduced sporozoite infectivity and a discernible delay in exo-erythrocytic merozoite formation. These data are consistent with the model that PBLP has an important role in parasite invasive-stage morphogenesis throughout the parasite life cycle.

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The pre-erythrocytic stage of plasmodium falciparum

Cited by 73 publications

References 14 publications

A Microscale Human Liver Platform that Supports the Hepatic Stages of Plasmodium falciparum and vivax

A Microscale Human Liver Platform that Supports the Hepatic Stages of Plasmodium falciparum and vivax

Type II fatty acid synthesis is essential only for malaria parasite late liver stage development

APlasmodiumα/β-hydrolase modulates the development of invasive stages

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