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Parasitology: The fatty liver stage of malaria parasites

Christiaan van Ooij

The discovery of a type II fatty-acid biosynthesis pathway (FAS-II) in malaria parasites has raised hopes that these enzymes could form a new target for therapeutic intervention. Two groups now report in Cell Host & Microbe and Cellular Microbiology on the requirement for the FAS-II system in the parasite's life cycle.
ParasitologyThe fatty liver stage of malaria parasites
Immunofluorescence microscopy image showing a host cell infected with Plasmodium yoelii. The FabI enzyme of the parasite is shown in green inside the elaborately branching apicoplast of liver stages 30 hours post-infection, the parasitophorous vacuole membrane protein UIS4 is shown in red, and parasite and host cell nuclei are shown in blue. Image courtesy of A. M. Vaughan, Seattle Biomedical Research Institute, Washington, USA.

Parasites are introduced into the skin of a mammalian host by a mosquito bite, and subsequently infect the liver and invade hepatocytes. This leads to the production of merozoites that are competent to infect erythrocytes, which results in the symptoms of malaria. Subsequent sexual stages and transmission to the mosquito complete the life cycle.

The parasites rely on the hosts for many nutrients, but the discovery of components of the FAS-II system in Plasmodium species indicated that the parasite could synthesize its own fatty acids. The ability of the FAS-II inhibitor triclosan to block erythrocytic growth had suggested a requirement for the FAS-II system at this stage and established the FAS-II system as a potential drug target, but members of the Fidock and Kappe laboratories now reveal that the requirement for FAS-II is limited to the asymptomatic liver stage.

Vaughan and colleagues provide evidence that parasites only produce specific FAS-II enzymes in the late mosquito and liver stages, but not in the erythrocytic stage, which is consistent with data from Yu and colleagues. Together the groups show that deletion of FAS-II genes fabBF, fabZ or fabI did not affect the erythrocytic stage and only led to a measurable phenotype during growth in the liver. In vitro and in mice, mutant parasites invaded liver cells and grew normally but then became arrested. They did not produce the late-stage marker MSP1 (merozoite surface protein 1) and were unable to divide into daughter cells. In addition, Yu and colleagues observed that the fabI mutant was unable to induce the dissociation of infected hepatocytes from the surface of the culture dish. In murine models, infection with the fabBF and fabZ mutants failed to produce blood-stage parasites, whereas the fabI mutant produced blood-stage parasites at severely reduced levels compared with the wild type. However, the difference between the mutants could simply reflect differences in the mouse models used.

Why then does triclosan affect the erythrocytic stage? Yu and colleagues showed that certain derivatives of triclosan inhibited parasite growth better than triclosan itself, but no longer inhibited FabI activity in vitro. Furthermore, parasites that produced a triclosan-insensitive version of FabI were as sensitive to the drug as wild-type parasites. This elegant approach proved that triclosan must affect a different parasitic process.

It remains unclear why the FAS-II system is only required for part of the parasite's life cycle. Possibly, the prolific division of parasites inside hepatocytes that produces up to 5,000-30,000 merozoites (compared with 8-20 per infected erythrocyte) raises the fatty-acid requirement of the parasites above the levels that can be produced by the host cell, requiring the malaria parasite to synthesize its own.



References and links
ORIGINAL RESEARCH PAPERS

1.

Yu, M. et al. The fatty acid biosynthesis enzyme FabI plays a key role in the development of liver stage malaria parasites. Cell Host Microbe 4, 567-578 (2008)
* Article
* PubMed
* ChemPort
2.

Vaughan, A. M. et al. Type II fatty acid synthesis is essential only for malaria parasite late liver stage development. Cell. Microbiol. 3 Dec 2008 (doi: 10.1111/j.1462-5822.2008.01270.x)

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Hepatic fatty metamorphosis in latent exoerythrocytic malaria
Authors: F K Ghishan, M G Myers, K Younoszai

We report a child with asymptomatic latent exoerythrocytic Plasmodium vivax malaria whose initial presentation was only hepatomegaly and elevated serum lipids. Histology of the liver showed severe fatty metamorphosis. Liver size and the severe fatty metamorphosis decreased markedly with the return of serum lipids to normal after successful treatment of P. vivax. Although this association has been reported in monkeys infected with P. knowlesi, this is the first report of such an association in humans.

The American journal of gastroenterology.1980/12;74(6):532-5.
ISSN: 0002-9270

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