Liver‐specific protein 2: a <scp>P</scp>lasmodium protein exported to the hepatocyte cytoplasm and required for merozoite formation

Orito, Yuki; Ishino, Tomoko; Iwanaga, Shiro; Kaneko, Ikuyo; Kato, Tomomi; Ménard, Robert; Chinzei, Yasuo; Yuda, Masao

doi:10.1111/mmi.12083

Cited by 69 publications

(126 citation statements)

References 41 publications

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“…EXP-1 belongs to a short list of parasite-derived proteins that have been shown to localize at the intrahepatic host-parasite interface, which includes LISP1/2, IBIS1, UIS3/4, and components of the PTEX translocon (23,24,33,(50)(51)(52)(53). Although it was identified >30 y ago and is abundantly expressed during blood-and liver-stage parasite development (28,32), the function of Plasmodium EXP-1 largely remained elusive.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…One additional protein exported during liver infection is P. berghei liver-specific protein 2 (LISP2) (Orito et al, 2013) (Fig. 1).…”

Section: Host Nucleus Host Nucleusmentioning

confidence: 99%

“…By immunofluorescence LISP2 can be detected in the cytoplasm and nucleus of the infected host cells beginning 36 h post-infection when P. berghei parasites are in early schizogony. In contrast, fluorescently tagged LISP2 remains associated with the PV suggesting that LISP2 processing results in a PV localization of the C-terminal fragment and the export of a cleavage product (Orito et al, 2013). Although LISP2 lacks a canonical N-terminal PEXEL/HT motif, there is a pentameric amino acid sequence at positions 373-377 that matches the PEXEL/HT motif (RxLxE).…”

Section: Host Nucleus Host Nucleusmentioning

confidence: 99%

Feeling at home from arrival to departure: protein export and host cell remodelling duringPlasmodiumliver stage and gametocyte maturation

et al. 2014

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SummaryObligate intracellular pathogens actively remodel their host cells to boost propagation, survival, and persistence. Plasmodium falciparum, the causative agent of the most severe form of malaria, assembles a complex secretory system in erythrocytes. Export of parasite factors to the erythrocyte membrane is essential for parasite sequestration from the blood circulation and a major factor for clinical complications in falciparum malaria. Historic and recent molecular reports show that host cell remodelling is not exclusive to P. falciparum and that parasite-induced intraerythrocytic membrane structures and protein export occur in several Plasmodia. Comparative analyses of P. falciparum asexual and sexual blood stages and imaging of liver stages from transgenic murine Plasmodium species show that protein export occurs in all intracellular phases from liver infection to sexual differentiation, indicating that mammalian Plasmodium species evolved efficient strategies to renovate erythrocytes and hepatocytes according to the specific needs of each life cycle phase. While the repertoire of identified exported proteins is remarkably expanded in asexual P. falciparum blood stages, the putative export machinery and known targeting signatures are shared across life cycle stages. A better understanding of the molecular mechanisms underlying Plasmodium protein export could assist in designing novel strategies to interrupt transmission between Anopheles mosquitoes and humans.

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“…Here we investigated Plasmodium berghei parasites lacking a gene, LISP2 (for liver specific protein 2), which is specifically expressed in liver stages25 and exported from the parasite to the host cell26. The partial disruption of this gene yielded severely impaired, but not completely attenuated liver stages2627.…”

mentioning

confidence: 99%

“…The partial disruption of this gene yielded severely impaired, but not completely attenuated liver stages2627. For this reason the gene would not be listed as a potential GAP candidate.…”

mentioning

confidence: 99%

Protective efficacy and safety of liver stage attenuated malaria parasites

Kumar

Sattler

Singer

et al. 2016

Sci Rep

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During the clinically silent liver stage of a Plasmodium infection the parasite replicates from a single sporozoite into thousands of merozoites. Infection of humans and rodents with large numbers of sporozoites that arrest their development within the liver can cause sterile protection from subsequent infections. Disruption of genes essential for liver stage development of rodent malaria parasites has yielded a number of attenuated parasite strains. A key question to this end is how increased attenuation relates to vaccine efficacy. Here, we generated rodent malaria parasite lines that arrest during liver stage development and probed the impact of multiple gene deletions on attenuation and protective efficacy. In contrast to P. berghei strain ANKA LISP2(–) or uis3(–) single knockout parasites, which occasionally caused breakthrough infections, the double mutant lacking both genes was completely attenuated even when high numbers of sporozoites were administered. However, different vaccination protocols showed that LISP2(–) parasites protected better than uis3(–) and double mutants. Hence, deletion of several genes can yield increased safety but might come at the cost of protective efficacy.

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Liver‐specific protein 2: a Plasmodium protein exported to the hepatocyte cytoplasm and required for merozoite formation

Cited by 69 publications

References 41 publications

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

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

Feeling at home from arrival to departure: protein export and host cell remodelling duringPlasmodiumliver stage and gametocyte maturation

Protective efficacy and safety of liver stage attenuated malaria parasites

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