title: Variant Exported Blood-Stage Proteins Encoded by Plasmodium Multigene Families Are Expressed in Liver Stages Where They Are Exported into the Parasitophorous Vacuole.
abstract: Many variant proteins encoded by Plasmodium-specific multigene families are exported into red blood cells (RBC). P. falciparum-specific variant proteins encoded by the var, stevor and rifin multigene families are exported onto the surface of infected red blood cells (iRBC) and mediate interactions between iRBC and host cells resulting in tissue sequestration and rosetting. However, the precise function of most other Plasmodium multigene families encoding exported proteins is unknown. To understand the role of RBC-exported proteins of rodent malaria parasites (RMP) we analysed the expression and cellular location by fluorescent-tagging of members of the pir, fam-a and fam-b multigene families. Furthermore, we performed phylogenetic analyses of the fam-a and fam-b multigene families, which indicate that both families have a history of functional differentiation unique to RMP. We demonstrate for all three families that expression of family members in iRBC is not mutually exclusive. Most tagged proteins were transported into the iRBC cytoplasm but not onto the iRBC plasma membrane, indicating that they are unlikely to play a direct role in iRBC-host cell interactions. Unexpectedly, most family members are also expressed during the liver stage, where they are transported into the parasitophorous vacuole. This suggests that these protein families promote parasite development in both the liver and blood, either by supporting parasite development within hepatocytes and erythrocytes and/or by manipulating the host immune response. Indeed, in the case of Fam-A, which have a steroidogenic acute regulatory-related lipid transfer (START) domain, we found that several family members can transfer phosphatidylcholine in vitro. These observations indicate that these proteins may transport (host) phosphatidylcholine for membrane synthesis. This is the first demonstration of a biological function of any exported variant protein family of rodent malaria parasites.
authors.affiliation: Leiden Malaria Research Group, Parasitology, Center of infectious Diseases, Leiden University Medical Center (LUMC), Leiden, The Netherlands.|Department of Experimental Medicine, University of Perugia, Italy.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Fougère
authors.affiliation: Department of Infection Biology, Institute of Infection and Global Health, University of Liverpool, Liverpool, UnitedKingdom.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Jackson
authors.affiliation: The Francis Crick Institute, Mill Hill Laboratory, Mill Hill, London, UnitedKingdom.
authors.forename: Dafni Paraskevi
authors.initials: DP
authors.lastname: Bechtsi
authors.affiliation: Leiden Malaria Research Group, Parasitology, Center of infectious Diseases, Leiden University Medical Center (LUMC), Leiden, The Netherlands.
authors.forename: Joanna A M
authors.initials: JA
authors.lastname: Braks
authors.affiliation: Leiden Malaria Research Group, Parasitology, Center of infectious Diseases, Leiden University Medical Center (LUMC), Leiden, The Netherlands.|Department of Department of Parasitology, National Institute of Infectious Diseases (NIID), Tokyo, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Annoura
authors.affiliation: Leiden Malaria Research Group, Parasitology, Center of infectious Diseases, Leiden University Medical Center (LUMC), Leiden, The Netherlands.|Department of Microbiological Diagnostics and Virology, Statens Serum Institute, Copenhagen, Denmark.
authors.forename: Jannik
authors.initials: J
authors.lastname: Fonager
authors.affiliation: Department of Experimental Medicine, University of Perugia, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Spaccapelo
authors.affiliation: Leiden Malaria Research Group, Parasitology, Center of infectious Diseases, Leiden University Medical Center (LUMC), Leiden, The Netherlands.
authors.forename: Jai
authors.initials: J
authors.lastname: Ramesar
authors.affiliation: Leiden Malaria Research Group, Parasitology, Center of infectious Diseases, Leiden University Medical Center (LUMC), Leiden, The Netherlands.
authors.forename: Séverine
authors.initials: S
authors.lastname: Chevalley-Maurel
authors.affiliation: Leiden Malaria Research Group, Parasitology, Center of infectious Diseases, Leiden University Medical Center (LUMC), Leiden, The Netherlands.|Biomedical Primate Research Centre (BPRC), Rijswijk, The Netherlands.
authors.forename: Onny
authors.initials: O
authors.lastname: Klop
authors.affiliation: Department of Molecular Cell Biology, Leiden University Medical Center (LUMC), Leiden, The Netherlands.
authors.forename: Annelies M A
authors.identifier: 0000-0002-6104-2410
authors.initials: AM
authors.lastname: van der Laan
authors.affiliation: Department of Molecular Cell Biology, Leiden University Medical Center (LUMC), Leiden, The Netherlands.
authors.forename: Hans J
authors.initials: HJ
authors.lastname: Tanke
authors.affiliation: Biomedical Primate Research Centre (BPRC), Rijswijk, The Netherlands.
authors.forename: Clemens H M
authors.initials: CH
authors.lastname: Kocken
authors.affiliation: Biomedical Primate Research Centre (BPRC), Rijswijk, The Netherlands.
authors.forename: Erica M
authors.initials: EM
authors.lastname: Pasini
authors.affiliation: Leiden Malaria Research Group, Parasitology, Center of infectious Diseases, Leiden University Medical Center (LUMC), Leiden, The Netherlands.
authors.forename: Shahid M
authors.initials: SM
authors.lastname: Khan
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, UnitedKingdom.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Böhme
authors.affiliation: The Francis Crick Institute, Mill Hill Laboratory, Mill Hill, London, UnitedKingdom.
authors.forename: Christiaan
authors.initials: C
authors.lastname: van Ooij
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, UnitedKingdom.
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Otto
authors.affiliation: Leiden Malaria Research Group, Parasitology, Center of infectious Diseases, Leiden University Medical Center (LUMC), Leiden, The Netherlands.
authors.forename: Chris J
authors.initials: CJ
authors.lastname: Janse
authors.affiliation: Leiden Malaria Research Group, Parasitology, Center of infectious Diseases, Leiden University Medical Center (LUMC), Leiden, The Netherlands.
authors.forename: Blandine
authors.initials: B
authors.lastname: Franke-Fayard
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004912:Erythrocytes / Q000469:parasitology; D005455:Fluorescent Antibody Technique; D022781:Hepatocytes / Q000821:virology*; D006801:Humans; D008099:Liver; D016778:Malaria, Falciparum / Q000378:metabolism* / Q000821:virology; D051379:Mice; D005810:Multigene Family; D030781:Organisms, Genetically Modified; D010802:Phylogeny; D010963:Plasmodium falciparum; D021381:Protein Transport; D015800:Protozoan Proteins / Q000378:metabolism*; D014617:Vacuoles / Q000821:virology
chemical_list: D015800:Protozoan Proteins