Host Cell Phosphatidylcholine Is a Key Mediator of Malaria Parasite Survival during Liver Stage Infection

Itoe, Maurice A.; Sampaio, Júlio L.; Cabal, Ghislain G.; Real, Eliana; Zuzarte‐Luís, Vanessa; March, Sandra; Bhatia, Sangeeta N.; Frischknecht, Friedrich; Thiele, Christoph; Shevchenko, Andrej; Mota, Maria M.

doi:10.1016/j.chom.2014.11.006

Cited by 104 publications

(100 citation statements)

References 50 publications

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“…In support of a role in parasite growth within the host cell, we found that several Fam-A members transfer phosphatidylcholine (PC) in vitro . Since host cell PC has been shown to be key for malaria liver stage development [41], these observations indicate that Fam-A proteins may mediate the transfer of PC from the host cell into the parasite for membrane synthesis. This is the first demonstration of a biological function of any exported variant protein family of rodent malaria parasites.…”

Section: Introductionmentioning

confidence: 99%

Variant Exported Blood-Stage Proteins Encoded by Plasmodium Multigene Families Are Expressed in Liver Stages Where They Are Exported into the Parasitophorous Vacuole

et al. 2016

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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.

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Section: Introductionmentioning

confidence: 99%

Variant Exported Blood-Stage Proteins Encoded by Plasmodium Multigene Families Are Expressed in Liver Stages Where They Are Exported into the Parasitophorous Vacuole

et al. 2016

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“…PC was acquired from the HC, among others via lyso-PC, and mouse hepatocytes impaired in de novo PC synthesis via the Kennedy or the PEMT pathway showed reduced infection with Plasmodium. The host-derived PC was found in most membranes of the infected hepatocytes, like the host cell membrane (HCM), the PPM and the PVM, where it plays a role in membrane integrity (Itoe et al, 2014). In accordance with these findings, proteins of the fam-a variant multigene family of malaria parasites were demonstrated to be transported into the cytoplasm of iRBCs as well as into the parasitophorous vacuole in infected hepatocytes.…”

Section: Membrane Dynamics and Lipid Turnover In Plasmodial Parasitessupporting

confidence: 61%

“…The larger proportion of PC present in trophozoite-compared to gametocyte-iRBCs might reflect the need for these lipids in these stages, for instance to maintain the exo-membrane system. A previous study investigated the changes in lipid compositions in hepatocytes infected with the rodent malaria parasite P. berghei (Itoe et al, 2014). Upon infection, the NL levels increase, but subside during the late liver phase (approximately 45 hours after infection).…”

Section: Membrane Dynamics and Lipid Turnover In Plasmodial Parasitesmentioning

confidence: 99%

Phospholipases during membrane dynamics in malaria parasites

Flammersfeld

Lang

Flieger

et al. 2018

International Journal of Medical Microbiology

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A B S T R A C TPlasmodium parasites, the causative agents of malaria, display a well-regulated lipid metabolism required to ensure their survival in the human host as well as in the mosquito vector. The fine-tuning of lipid metabolic pathways is particularly important for the parasites during the rapid erythrocytic infection cycles, and thus enzymes involved in lipid metabolic processes represent prime targets for malaria chemotherapeutics. While plasmodial enzymes involved in lipid synthesis and acquisition have been studied in the past, to date not much is known about the roles of phospholipases for proliferation and transmission of the malaria parasite. These phospholipid-hydrolyzing esterases are crucial for membrane dynamics during host cell infection and egress by the parasite as well as for replication and cell signaling, and thus they are considered important virulence factors. In this review, we provide a comprehensive bioinformatic analysis of plasmodial phospholipases identified to date. We further summarize previous findings on the lipid metabolism of Plasmodium, highlight the roles of phospholipases during parasite life-cycle progression, and discuss the plasmodial phospholipases as potential targets for malaria therapy.

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“…The intracellular parasite then transforms into round exoerythrocytic forms (EEFs), which undergo repeated closed mitosis, ultimately leading to the formation of several thousand progenies. This development is exceptional for an obligate eukaryotic intracellular pathogen and likely depends on the extensive acquisition of lipids and nutrients from its host cell, while also relying on the parasite's own metabolism to ensure its survival and replication within host cells (7,8).…”

mentioning

confidence: 99%

“…Despite being metabolically active itself, the parasite has been shown to scavenge a plethora of host-cell molecules, such as glucose, cholesterol, fatty acids, phosphatidylcholine, or lipoic acids (8)(9)(10)(11)(12). Because Plasmodium parasites do not reside freely in the host cell cytoplasm or in endocytic compartments, but, rather, inside a vacuole formed de novo during the active invasion process, required nutrients have to cross the parasite plasma membrane as well as the PV membrane (PVM).…”

mentioning

confidence: 99%

Plasmodium berghei EXP-1 interacts with host Apolipoprotein H during Plasmodium liver-stage development

Cunha

Nyboer

Heiß

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The first, obligatory replication phase of malaria parasite infections is characterized by rapid expansion and differentiation of single parasites in liver cells, resulting in the formation and release of thousands of invasive merozoites into the bloodstream. Hepatic Plasmodium development occurs inside a specialized membranous compartment termed the parasitophorous vacuole (PV). Here, we show that, during the parasite's hepatic replication, the C-terminal region of the parasitic PV membrane protein exported protein 1 (EXP-1) binds to host Apolipoprotein H (ApoH) and that this molecular interaction plays a pivotal role for successful Plasmodium liver-stage development. Expression of a truncated EXP-1 protein, missing the specific ApoH interaction site, or down-regulation of ApoH expression in either hepatic cells or mouse livers by RNA interference resulted in impaired intrahepatic development. Furthermore, infection of mice with sporozoites expressing a truncated version of EXP-1 resulted in both a significant reduction of liver burden and delayed blood-stage patency, leading to a disease outcome different from that generally induced by infection with wildtype parasites. This study identifies a host-parasite protein interaction during the hepatic stage of infection by Plasmodium parasites. The identification of such vital interactions may hold potential toward the development of novel malaria prevention strategies. malaria | Plasmodium liver stages | host-parasite interaction | ApoH | EXP-1

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Host Cell Phosphatidylcholine Is a Key Mediator of Malaria Parasite Survival during Liver Stage Infection

Cited by 104 publications

References 50 publications

Variant Exported Blood-Stage Proteins Encoded by Plasmodium Multigene Families Are Expressed in Liver Stages Where They Are Exported into the Parasitophorous Vacuole

Variant Exported Blood-Stage Proteins Encoded by Plasmodium Multigene Families Are Expressed in Liver Stages Where They Are Exported into the Parasitophorous Vacuole

Phospholipases during membrane dynamics in malaria parasites

Plasmodium berghei EXP-1 interacts with host Apolipoprotein H during Plasmodium liver-stage development

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