Plastid-to-nucleus signalling in Plasmodium
Lead Research Organisation:
University of Cambridge
Department Name: Biochemistry
Abstract
Malaria is caused by a single-celled parasite. Very surprisingly, the ancestors of this parasite (and related ones like Toxoplasma, which can also cause disease) were photosynthetic. Like plants and algae, their cells contained chloroplasts, the site of photosynthesis. Although Plasmodium is no longer photosynthetic, it still has the remains of the chloroplast, called the apicoplast, and this is essential for the parasite to live. Many drugs for malaria, such as clindamycin, work by interfering with the the Plasmodium chloroplast. Many of the proteins in the chloroplast are made elsewhere in the cell, from genes present in the nucleus, and imported into the chloroplast after they have been made. We believe that the chloroplast can send a signal to tell the nucleus when it needs these proteins, and we want to test this idea. We know that something similar happens with the chloroplasts of plants and algae, so we know how to test it with Plasmodium. If we can show this signalling happens, we can start to understand how to interfere with it - and this may lead to new drugs for treating malaria.
Technical Summary
Plasmodium and many other apicompexan pathogens have a remnant chloroplast (plastid), the apicoplast, which is essential for the cell's survival. The apicomplexan plastid has a remnant genome encoding an iron-sulphur cluster biosynthesis protein, a chaperone, and components of the transcription and translation machinery. The majority of apicomplexan plastid proteins are nuclear encoded, synthesized in the cytosol and imported into the plastid. It is known that in plants and algae, the chloroplast signals its metabolic state to the nucleus, and this affects the expression of nuclear genes for chloroplast proteins. We believe that this is likely to happen with the apicomplexan plastid, and propose a pilot project to test this. If successful, this will lead to a application for support for a full three-year project. In experiments analogous to those used successfully with plants, we will treat Plasmodium cells at a range of stages in the growth cycle with inhibitors of (i) plastid protein synthesis and (ii) a plastid metabolic pathway. We predict that plastid-to-nucleus signalling will lead to changes in levels of mRNAs from nuclear genes for plastid proteins, and we will test this using molecular biological techniques. We will use microarrays to determine which genes are most affected. Agents that interfere with the signalling process will have potential as antimalarials.
Organisations
People |
ORCID iD |
Christopher Howe (Principal Investigator) |
Publications
Barbrook AC
(2010)
Organization and expression of organellar genomes.
in Philosophical transactions of the Royal Society of London. Series B, Biological sciences
Tarr SJ
(2012)
Transcript level responses of Plasmodium falciparum to antimycin A.
in Protist
Tarr SJ
(2011)
Transcript-level responses of Plasmodium falciparum to thiostrepton.
in Molecular and biochemical parasitology
Description | Our results indicated that there is signaling from the mitochondrion to the nucleus in Plasmodium, but that plastid to nucleus signaling is likely to be through effects on the mitochondrion rather than directly. We also showed that thiostrepton, which is traditionally assumed to interfere with plastid function in Plasmodium, probably interferes with mitochondrial function also. |
Exploitation Route | In developing reagents to interfere with mitochondrial function |
Sectors | Security and Diplomacy |
Description | The findings have been used in helping us and others to understand the importance of mitochondrion and chloroplast to Plasmodium function |
First Year Of Impact | 2010 |
Sector | Retail |
Impact Types | Economic |
Description | RNA metabolism in Plasmodium falciparum |
Amount | £340,000 (GBP) |
Organisation | Wellcome Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 02/2012 |
End | 01/2015 |