The silent path to thousands of merozoites: the Plasmodium liver stage

Prudêncio, Miguel; Rodrı́guez, Ana; Mota, Maria M.

doi:10.1038/nrmicro1529

Cited by 422 publications

(388 citation statements)

References 83 publications

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“…4 Malariaassociated pathology originates during the blood stage of Plasmodium life cycle while the liver stage is asymptomatic and offers opportunities for early intervention and vaccine development. 5 Relatively little is known about molecular interactions in either the parasite or the host during the liver stage. The residency and maturation of sporozoites inside host cells require the formation of a membrane-bound vacuole around the parasite.…”

Section: Introductionmentioning

confidence: 99%

Evidence from NMR interaction studies challenges the hypothesis of direct lipid transfer from L‐FABP to malaria sporozoite protein UIS3

et al. 2013

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UIS3 is a malaria parasite protein essential for liver stage development of Plasmodium species, presumably localized to the membrane of the parasitophorous vacuole formed in infected cells. It has been recently proposed that the soluble domain of UIS3 interacts with the host liver fatty acid binding protein (L-FABP), providing the parasite with a pathway for importing exogenous lipids required for its rapid growth. This finding may suggest novel strategies for arresting parasite development. In this study, we have investigated the interaction between human L-FABP and the soluble domain of Plasmodium falciparum UIS3 by NMR spectroscopy. The amino acid residuespecific analysis of 1 H, 15 N-2D NMR spectra excluded the occurrence of a direct interaction between L-FABP (in its unbound and oleate-loaded forms) and Pf-UIS3. Furthermore, the spectrum of Pf-UIS3 was unchanged when oleate or phospholipids were added. The present investigation entails a reformulation of the current model of host-pathogen lipid transfer, possibly redirecting research for early intervention against malaria.

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Section: Introductionmentioning

confidence: 99%

Evidence from NMR interaction studies challenges the hypothesis of direct lipid transfer from L‐FABP to malaria sporozoite protein UIS3

et al. 2013

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“…Plasmodium sporozoites invade hepatocytes actively by forming a membrane-bound compartment called the parasitophorous vacuole (PV), where the parasite resides for further intracellular development (2,3). The nature of the molecular interactions mediating sporozoite invasion still remains elusive.…”

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confidence: 99%

The Ig Domain Protein CD9P-1 Down-regulates CD81 Ability to Support Plasmodium yoelii Infection

Charrin

Yalaoui

Bartosch

et al. 2009

Journal of Biological Chemistry

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Invasion of hepatocytes by Plasmodium sporozoites is a prerequisite for establishment of a malaria natural infection. The molecular mechanisms underlying sporozoite invasion are largely unknown. We have previously reported that CD81 is required on hepatocytes for infection by Plasmodium falciparum and Plasmodium yoelii sporozoites. CD81 belongs to the tetraspanin superfamily of transmembrane proteins. By interacting with each other and with other transmembrane proteins, tetraspanins may play a role in the lateral organization of membrane proteins. In this study, we investigated the role of the two major molecular partners of CD81 in hepatocytic cells, CD9P-1/EWI-F and EWI-2, two transmembrane proteins belonging to a novel subfamily of immunoglobulin proteins. We show that CD9P-1 silencing increases the host cell susceptibility to P. yoelii sporozoite infection, whereas EWI-2 knock-down has no effect. Conversely, overexpression of CD9P-1 but not EWI-2 partially inhibits infection. Using CD81 and CD9P-1 chimeric molecules, we demonstrate the role of transmembrane regions in CD81-CD9P-1 interactions. Importantly, a CD9P-1 chimera that no longer associates with CD81 does not affect infection. Based on these data, we conclude that CD9P-1 acts as a negative regulator of P. yoelii infection by interacting with CD81 and regulating its function.Malaria remains the most important parasitic human disease, responsible for nearly one million deaths each year (1). Plasmodium natural infection is initiated by the inoculation of sporozoites in the host by a female Anopheles mosquito.Within the first hours of infection the motile sporozoites reach the liver and invade hepatocytes, where they further differentiate into a replicative exo-erythrocytic form (EEF) 5 that will ultimately give rise to thousands of merozoites that initiate the pathogenic erythrocytic cycle. Plasmodium sporozoites invade hepatocytes actively by forming a membrane-bound compartment called the parasitophorous vacuole (PV), where the parasite resides for further intracellular development (2, 3). The nature of the molecular interactions mediating sporozoite invasion still remains elusive. Two well-characterized sporozoite surface proteins, the circumsporozoite protein and the thrombospondin-related adhesive protein, are known to interact with the liver heparan sulfate proteoglycans (HSPGs) (2, 3). HSPGs play a role in the initial sequestration of the sporozoites in the liver sinusoids (4, 5), and activate sporozoites for productive invasion, leading to proteolytic processing of the circumsporozoite protein (6). Two sporozoite proteins, P36 and P36p/ P52, were shown to play a major role during infection of hepatocytes (7-9). Both belong to a Plasmodium-specific family characterized by the presence of domains with six conserved cysteines, but their precise function during sporozoite invasion and/or maintenance of the PV early after invasion remains unknown.To date, the only host molecule clearly identified as being essential for sporozoite invasion is CD81. ...

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“…It invades the hepatocytes and transforms into liver-stage parasites. These ex(o)erythrocytic forms undergo multiple divisions to form thousands of merozoites which invade erythrocytes (9). Within erythrocytes the parasite develops and multiplies asexually.…”

Section: Introductionmentioning

confidence: 99%

Benzothiophene carboxamide derivatives as novel antimalarials

et al. 2011

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SummaryBromo-benzothiophene carboxamide derivatives have been shown in the preceding article to inhibit Plasmodium falciparum Enoyl-ACP reductase. Here, we report bromo-benzothiophene carboxamide derivatives as potent inhibitors of Plasmodium asexual blood-stages in vitro as well as in vivo in the mouse model. These compounds specifically impair the development of metabolically active trophozoite stage of intraerythrocytic cycle and the intravenous administration of 3-bromo-N-(4-fluorobenzyl)-benzo[b]thiophene-2-carboxamide (compound 6) enhances the longevity of P. berghei infected mice by 2 weeks compared to disease control animals thereby preventing the onset of ataxia and convulsions in treated mice. These compounds thus hold promise for the development of potent antimalarials.

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The silent path to thousands of merozoites: the Plasmodium liver stage

Cited by 422 publications

References 83 publications

Evidence from NMR interaction studies challenges the hypothesis of direct lipid transfer from L‐FABP to malaria sporozoite protein UIS3

Evidence from NMR interaction studies challenges the hypothesis of direct lipid transfer from L‐FABP to malaria sporozoite protein UIS3

The Ig Domain Protein CD9P-1 Down-regulates CD81 Ability to Support Plasmodium yoelii Infection

Benzothiophene carboxamide derivatives as novel antimalarials

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