title: Contrasting Inducible Knockdown of the Auxiliary PTEX Component PTEX88 in P. falciparum and P. berghei Unmasks a Role in Parasite Virulence.
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.
authors.affiliation: School of Medicine, Deakin University, Waurn Ponds, Victoria, Australia.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Chisholm
authors.affiliation: Department of Biochemistry and Molecular Biology, Bio21 Institute, Melbourne, Victoria, Australia.
authors.forename: Emma
authors.initials: E
authors.lastname: McHugh
authors.affiliation: The Burnet Institute, Melbourne, Victoria, Australia.
authors.forename: Rachel
authors.initials: R
authors.lastname: Lundie
authors.affiliation: Department of Biochemistry and Molecular Biology, Bio21 Institute, Melbourne, Victoria, Australia.
authors.forename: Matthew W A
authors.initials: MW
authors.lastname: Dixon
authors.affiliation: School of Medicine, Deakin University, Waurn Ponds, Victoria, Australia.
authors.forename: Sreejoyee
authors.initials: S
authors.lastname: Ghosh
authors.affiliation: The Burnet Institute, Melbourne, Victoria, Australia.
authors.forename: Meredith
authors.initials: M
authors.lastname: O'Keefe
authors.affiliation: Department of Biochemistry and Molecular Biology, Bio21 Institute, Melbourne, Victoria, Australia.
authors.forename: Leann
authors.initials: L
authors.lastname: Tilley
authors.affiliation: School of Medicine, Deakin University, Waurn Ponds, Victoria, Australia.
authors.forename: Ming
authors.initials: M
authors.lastname: Kalanon
authors.affiliation: School of Medicine, Deakin University, Waurn Ponds, Victoria, Australia.
authors.forename: Tania F
authors.initials: TF
authors.lastname: de Koning-Ward
mesh_terms: D000818:Animals; D018955:CD36 Antigens / Q000378:metabolism; D002448:Cell Adhesion; D005260:Female; D055785:Gene Knockdown Techniques; D005944:Glucosamine / Q000378:metabolism; D007109:Immunity; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D008810:Mice, Inbred C57BL; D010271:Parasites / Q000254:growth & development / Q000472:pathogenicity*; D010962:Plasmodium berghei / Q000472:pathogenicity*; D010963:Plasmodium falciparum / Q000472:pathogenicity*; D011485:Protein Binding; D021381:Protein Transport; D015800:Protozoan Proteins / Q000378:metabolism*; D014774:Virulence
chemical_list: D018955:CD36 Antigens; D015800:Protozoan Proteins; D005944:Glucosamine