Contrasting Inducible Knockdown of the Auxiliary PTEX Component PTEX88 in P. falciparum and P. berghei Unmasks a Role in Parasite Virulence.

Scott A Chisholm,Emma Mchugh,Ming Kalanon,Leann Tilley,Tania F De Koning-Ward,Meredith O’Keefe,Sreejoyee Ghosh,Rachel Lundie,Matthew W A Dixon,Gordon Langsley

doi:10.1371/journal.pone.0149296

Scott A Chisholm, Emma Mchugh + Show 8 more

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https://doi.org/10.1371/journal.pone.0149296

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Journal: PloS one	Publication Date: Feb 17, 2016
Citations: 34	License type: CC BY 4.0

Affiliation: Deakin University, Burnet Institute

Abstract

Pathogenesis of malaria infections is linked to remodeling of erythrocytes, a process dependent on the trafficking of hundreds of parasite-derived proteins into the host erythrocyte. Recent studies have demonstrated that the Plasmodium translocon of exported proteins (PTEX) serves as the central gateway for trafficking of these proteins, as inducible knockdown of the core PTEX constituents blocked the trafficking of all classes of cargo into the erythrocyte. However, the role of the auxiliary component PTEX88 in protein export remains less clear. Here we have used inducible knockdown technologies in P. falciparum and P. berghei to assess the role of PTEX88 in parasite development and protein export, which reveal that the in vivo growth of PTEX88-deficient parasites is hindered. Interestingly, we were unable to link this observation to a general defect in export of a variety of known parasite proteins, suggesting that PTEX88 functions in a different fashion to the core PTEX components. Strikingly, PTEX88-deficient P. berghei were incapable of causing cerebral malaria despite a robust pro-inflammatory response from the host. These parasites also exhibited a reduced ability to sequester in peripheral tissues and were removed more readily from the circulation by the spleen. In keeping with these findings, PTEX88-deficient P. falciparum-infected erythrocytes displayed reduced binding to the endothelial cell receptor, CD36. This suggests that PTEX88 likely plays a specific direct or indirect role in mediating parasite sequestration rather than making a universal contribution to the trafficking of all exported proteins.

Highlights

Malaria remains a significant global health issue, resulting in approximately 584,000 deaths and 200 million clinical cases annually [1]
We show that while loss of PTEX88 in P. falciparum does not alter the maintenance of normal parasite growth in vitro, it reduces the cytoadhesive capacity of infected erythrocytes
Protein material extracted from treated parasites was analysed by Western blot using anti-HA antibodies to detect PTEX88 expression, with EXP2 serving as a loading control (Fig 1C)

Summary

Introduction

Malaria remains a significant global health issue, resulting in approximately 584,000 deaths and 200 million clinical cases annually [1]. The pathogenicity of P. falciparum is attributed to its ability to drastically modify the host erythrocyte, both physically and biochemically, primarily by the synthesis and trafficking of hundreds of parasite proteins beyond the parasitophorous vacuole membrane (PVM)(for reviews, see [2,3]). These exported proteins play vital roles in a number of essential parasite processes, including nutrient acquisition and exchange of solutes, and the modification of the erythrocyte to reduce host cell deformability [4,5,6,7]. The adhesion of infected erythrocytes to blood vessels is a major contributor to the pathogenesis and severity of malaria infections [11,13]

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