title: Host PI(3,5)P2 activity is required for Plasmodium berghei growth during liver stage infection.
abstract: Malaria parasites go through an obligatory liver stage before they infect erythrocytes and cause disease symptoms. In the host hepatocytes, the parasite is enclosed by a parasitophorous vacuole membrane (PVM). Here, we dissected the interaction between the Plasmodium parasite and the host cell late endocytic pathway and show that parasite growth is dependent on the phosphoinositide 5-kinase (PIKfyve) that converts phosphatidylinositol 3-phosphate [PI(3)P] into phosphatidylinositol 3,5-bisphosphate [PI(3,5)P2 ] in the endosomal system. We found that inhibition of PIKfyve by either pharmacological or non-pharmacological means causes a delay in parasite growth. Moreover, we show that the PI(3,5)P2 effector protein TRPML1 that is involved in late endocytic membrane fusion, is present in vesicles closely contacting the PVM and is necessary for parasite growth. Thus, our studies suggest that the parasite PVM is able to fuse with host late endocytic vesicles in a PI(3,5)P2 -dependent manner, allowing the exchange of material between the host and the parasite, which is essential for successful infection.
authors.affiliation: CEDOC, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, 1169-056, Lisboa, Portugal; IGC, Instituto Gulbenkian de Ciência, 2780-156, Oeiras, Portugal.
authors.forename: Carolina
authors.initials: C
authors.lastname: Thieleke-Matos
authors.forename: Mafalda Lopes
authors.initials: ML
authors.lastname: da Silva
authors.forename: Laura
authors.initials: L
authors.lastname: Cabrita-Santos
authors.forename: Cristiana F
authors.initials: CF
authors.lastname: Pires
authors.forename: José S
authors.initials: JS
authors.lastname: Ramalho
authors.forename: Ognian
authors.initials: O
authors.lastname: Ikonomov
authors.forename: Elsa
authors.initials: E
authors.lastname: Seixas
authors.forename: Assia
authors.initials: A
authors.lastname: Shisheva
authors.forename: Miguel C
authors.initials: MC
authors.lastname: Seabra
authors.forename: Duarte C
authors.initials: DC
authors.lastname: Barral
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004705:Endocytosis; D008099:Liver / Q000378:metabolism* / Q000469:parasitology; D051379:Mice; D059208:Parasite Load; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010962:Plasmodium berghei / Q000472:pathogenicity* / Q000502:physiology; D021381:Protein Transport; D050051:Transient Receptor Potential Channels / Q000378:metabolism
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D018129:Phosphatidylinositol Phosphates; D000081082:Phosphoinositide-3 Kinase Inhibitors; D050051:Transient Receptor Potential Channels; C512321:Mcoln1 protein, mouse; C106336:phosphatidylinositol 3,5-diphosphate; C116930:Pikfyve protein, mouse
keywords: PI(3,5)P2; PIKfyve; Plasmodium berghei; TRPML1; liver stage infection; malaria