Rosette-Disrupting Effect of an Anti-Plasmodial Compound for the Potential Treatment of Plasmodium falciparum Malaria Complications

Ch'ng, Jun‐Hong; Moll, Kirsten; Quintana, Maria del Pilar; Chan, Sherwin; Masters, Ellen K. G.; Moles, Ernest; Liu, Jianping; Eriksson, Anders; Wahlgren, Mats

doi:10.1038/srep29317

Cited by 19 publications

(24 citation statements)

References 33 publications

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“…falciparum . Future studies should strive to understand the pathobiological process behind non-falciparum and possible develop therapeutics that disrupt their formation[ 27 , 28 ].…”

Section: Discussionmentioning

confidence: 99%

Rheopathologic Consequence of Plasmodium vivax Rosette Formation

et al. 2016

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Malaria parasites dramatically alter the rheological properties of infected red blood cells. In the case of Plasmodium vivax, the parasite rapidly decreases the shear elastic modulus of the invaded RBC, enabling it to avoid splenic clearance. This study highlights correlation between rosette formation and altered membrane deformability of P. vivax-infected erythrocytes, where the rosette-forming infected erythrocytes are significantly more rigid than their non-rosetting counterparts. The adhesion of normocytes to the PvIRBC is strong (mean binding force of 440pN) resulting in stable rosette formation even under high physiological shear flow stress. Rosetting may contribute to the sequestration of PvIRBC schizonts in the host microvasculature or spleen.

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“…falciparum . Future studies should strive to understand the pathobiological process behind non-falciparum and possible develop therapeutics that disrupt their formation[ 27 , 28 ].…”

Section: Discussionmentioning

confidence: 99%

Rheopathologic Consequence of Plasmodium vivax Rosette Formation

et al. 2016

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“…30 µl of stained cells were added to 150 µl PBS in 96-well plates and analysed by BD FACSVerse flow cytometer. FITC levels of trophozoite-infected cells were measured after sequential gating as described elsewhere 51 , with only singlet events being measured. GFP+ cells were defined as all events that generated FITC signals above the untransfected NF54 parasites.…”

Section: Methodsmentioning

confidence: 99%

Frequent GU wobble pairings reduce translation efficiency in Plasmodium falciparum

Chan¹,

Ch'ng²,

Wahlgren³

et al. 2017

Sci Rep

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Plasmodium falciparum genome has 81% A+T content. This nucleotide bias leads to extreme codon usage bias and culminates in frequent insertion of asparagine homorepeats in the proteome. Using recodonized GFP sequences, we show that codons decoded via G:U wobble pairing are suboptimal codons that are negatively associated to protein translation efficiency. Despite this, one third of all codons in the genome are GU wobble codons, suggesting that codon usage in P. falciparum has not been driven to maximize translation efficiency, but may have evolved as translational regulatory mechanism. Particularly, asparagine homorepeats are generally encoded by locally clustered GU wobble AAT codons, we demonstrated that this GU wobble-rich codon context is the determining factor that causes reduction of protein level. Moreover, insertion of clustered AAT codons also causes destabilization of the transcripts. Interestingly, more frequent asparagine homorepeats insertion is seen in single-exon genes, suggesting transcripts of these genes may have been programmed for rapid mRNA decay to compensate for the inefficiency of mRNA surveillance regulation on intronless genes. To our knowledge, this is the first study that addresses P. falciparum codon usage in vitro and provides new insights on translational regulation and genome evolution of this parasite.

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“…A, B or AB) patients show higher levels of rosetting than isolates from group O patients in studies from sub-Saharan Africa (Rowe et al ., 1995, 2007) and India (Rout et al ., 2012), although the same result was not seen in one Thai study (Lee et al ., 2014). When parasites are cultured in their ‘preferred’ blood group, they form larger, stronger rosettes that are more resistant to disruption by antibodies or chemical agents than in group O cells (Carlson and Wahlgren, 1992; Barragan et al ., 2000 b ; Ch'ng et al ., 2016). Enzymatic removal of the terminal sugars ( N -acetyl-D-galactosamine for A and D-galactose for B) results in smaller, weaker rosettes, equivalent to those seen in group O erythrocytes (Barragan et al ., 2000 b ).…”

Section: Rosetting Receptors On Host Erythrocytesmentioning

confidence: 99%

Rosetting revisited: a critical look at the evidence for host erythrocyte receptors inPlasmodium falciparumrosetting

McQuaid

Rowe

2019

Parasitology

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Malaria remains a major cause of mortality in African children, with no adjunctive treatments currently available to ameliorate the severe clinical forms of the disease. Rosetting, the adhesion of infected erythrocytes (IEs) to uninfected erythrocytes, is a parasite phenotype strongly associated with severe malaria, and hence is a potential therapeutic target. However, the molecular mechanisms of rosetting are complex and involve multiple distinct receptor–ligand interactions, with some similarities to the diverse pathways involved in P. falciparum erythrocyte invasion. This review summarizes the current understanding of the molecular interactions that lead to rosette formation, with a particular focus on host uninfected erythrocyte receptors including the A and B blood group trisaccharides, complement receptor one, heparan sulphate, glycophorin A and glycophorin C. There is strong evidence supporting blood group A trisaccharides as rosetting receptors, but evidence for other molecules is incomplete and requires further study. It is likely that additional host erythrocyte rosetting receptors remain to be discovered. A rosette-disrupting low anti-coagulant heparin derivative is being investigated as an adjunctive therapy for severe malaria, and further research into the receptor–ligand interactions underlying rosetting may reveal additional therapeutic approaches to reduce the unacceptably high mortality rate of severe malaria.

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Rosette-Disrupting Effect of an Anti-Plasmodial Compound for the Potential Treatment of Plasmodium falciparum Malaria Complications

Cited by 19 publications

References 33 publications

Rheopathologic Consequence of Plasmodium vivax Rosette Formation

Rheopathologic Consequence of Plasmodium vivax Rosette Formation

Frequent GU wobble pairings reduce translation efficiency in Plasmodium falciparum

Rosetting revisited: a critical look at the evidence for host erythrocyte receptors inPlasmodium falciparumrosetting

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