More Plastids in Human Parasites?

54 Update TRENDS in Parasitology Vol.20 No.2 February 2004 More plastids in human parasites? Ross F. Waller1,2, Malcolm J. McConville1 and Geoffrey I. McFadden3 1Department of Biochemistry and Molecular Biology, Genetics Lane, The University of Melbourne, 3010, Australia 2Department of Botany, 3529–6270 University Boulevard, University of British Columbia, Vancouver, BC, Canada V6T 1Z4 3Plant Cell Biology Research Centre, School of Botany, Professors Walk, The University of Melbourne, 3010, Australia Trypanosomatid parasites are disease agents with an acid and isoprenoid synthesis [5]. When the plastid was extraordinarily broad host range including humans, first acquired, several anabolic pathways would have livestock and plants. Recent work has revealed that existed in two places in the new amalgamated cell: the trypanosomatids harbour numerous genes sharing cytosol and the plastid. Subsequent rationalization of this apparent common ancestry with plants and/or bacteria. redundancy apparently led to loss of certain eukaryotic Although there is no evidence of a plastid (chloroplast- pathways with the prokaryotic ones introduced with the like organelle) in trypanosomatids, the presence of such plastid being maintained. This resulted in the apicoplast genes suggests lateral gene transfer from some photo- being integrated beyond the point of no return for these synthetic organism(s) during trypanosomatid evolu- parasites. Thus, these prokaryotic anabolic pathways, tion. Remarkably, many products of these horizontally together with all the prokaryotic-type housekeeping acquired genes now function in the glycosome, a highly functions on which they depend, are excellent targets for modified peroxisome unique to trypanosomatids and drug assault. Apicoplast DNA replication, transcription, their near relatives. translation, fatty acid and isoprenoid biosynthesis have all been validated as drug targets, and this could be just the The holy grail for many parasitologists is to identify tip of the iceberg [6]. Good news for the war on malaria and differences between parasite and host which can be other apicomplexan diseases. exploited for therapy. In principle, any difference provides an opportunity to develop a treatment regime that A shady photosynthetic past for trypanosomatids? selectively targets the parasite as long as the target is We now learn that trypanosomatid parasites bear similar essential. Evolutionary distance is a reliable provider of molecular hints of a possible photosynthetic past [7]. The biological divergence. Thus, the greater the time since two Trypanosomatidae (Kinetoplastida) includes the agents of organisms shared a common ancestor, the greater the African sleeping sickness (Trypanosoma brucei), Chagas divergence as a result of incremental accumulation of disease (Trypanosoma cruzi), and visceral and (muco)cu- small differences. Bacterial pathogens are a case in point. taneous leishmaniasis (Leishmania spp.). Together, these Many antibacterials in use today target unique prokary- pathogens represent a threat to the health of .500 million otic biochemical processes such as cell wall formation. people, infect .100 million people and cause .100 However, other highly successful antibacterials block thousand deaths annually. Hannaert et al. report a ubiquitous and fundamental processes such as transcrip- collection of genes from T. brucei and Leishmania tion and translation, which are sufficiently divergent from mexicana with intriguing plant and/or prokaryotic signa- eukaryotic forms, so that pathogen-specific inhibition can tures [7]. Several of these represent genes involved in occur. Alas, we do not enjoy such an advantage over our carbon metabolism, assigned to either glycolysis or the eukaryotic pathogens because they are our nearer cousins, hexose-monophosphate pathway (HMP). Some of these and this narrows the window of targets considerably. genes are involved in the Calvin cycle in plastids, but are A remarkable twist in the evolution of eukaryotes is employed in either of the above processes in trypanoso- enabling us to reassess our arsenal for some parasites. matids, which do not possess a Calvin cycle. Other genes Plastid organelles (known as chloroplasts in plants) are highlighted by Hannaert et al. are involved in fatty acid the product of an endosymbiotic merger of a cyanobacterial biosynthesis, aromatic amino acid and glycerol metabolism, prokaryote with a eukaryote [1]. Typically, we associate reactive oxygen protection, respiration and proton pumping. plastids with photosynthetic organisms such as plants, Whereas many of these genes are apparently derived from seaweeds and unicellular phytoplankton. However, the prokaryotic sources (perhaps from plastids), others are recent discovery of a plastid (termed apicoplast) in reported to be more closely allied to plants [e.g. sedoheptulose- apicomplexan parasites such as Plasmodium and 1,7-bisphosophatase (SPBase) and cofactor-independent Toxoplasma demonstrates that the rules are not so clear phosphoglycerate mutase (PGAM)] [7]. [2–4]. Although the apicoplast is no longer photosynthetic, Given that apicomplexan parasites contain a plastid, we the parasite has apparently become dependant upon this must ask the question, do trypanosomatids also contain a organelle for other metabolic functions, including fatty plastid? The answer is almost certainly, no. Unlike api- complexans, where a mysterious, but unidentified, organ- Corresponding author: Ross F. Waller ([email protected]). elle was well described at an ultrastructural level before www.sciencedirect.com Update TRENDS in Parasitology Vol.20 No.2 February 2004 55 molecular evidence for a plastid [8], there is no such evi- suggests that only certain euglenids, with specialized dence of a plastid in trypanosomatids. Two explanations cytoskeletal adaptations that allowed for the ingestion of for plant-like genes remain. The simplest explanation, other eukaryotic cells, contain a plastid [13]. Euglenids favoured by Hannaert et al., is that the trypanosomatid lacking these adaptations can only phagocytose bacteria parasites once contained a plastid endosymbiont, but have and lack a plastid [13]. According to this hypothesis, since lost it. Endosymbiont genes were transferred to the euglenid plastids were acquired relatively recently and nucleus during the tenancy of the plastid, but only a trace only by some members of this group. Trypanosomatids of such an organelle now remains. Hannaert et al. note therefore could not have inherited such a plastid if it were that trypanosomatids fall within the phylum Euglenozoa, acquired so recently (Figure 1). However, some kineto- which includes euglenid algae (Figure 1). These algae have plastids contain their own bacterial endosymbionts green plastids surrounded by three membranes, which (e.g. Crithidia oncopelti and Cryptobia vaginalis). Thus, indicates a secondary plastid [i.e. an engulfed eukaryotic it is conceivable that independent endosymbionts could (algal) endosymbiont similar to the apicoplast] [9]. There- have been an alternative source for some of the plastid fore, it is possible that the common ancestor of the and/or prokaryotic-type genes (Figure 1). Euglenozoa contained this plastid, but that it has since An alternative possible source of evolutionarily been lost in several lineages during Euglenozoa diversi- unrelated genes is food items. Ford Doolittle’s ‘You are fication (Figure 1). what you eat’ hypothesis posits rampant gene transfer This hypothesis for an ancient plastid acquisition in from prey to consumer in the microscopic world [14]. Just Euglenozoa followed by plastid loss in the kinetoplastid as a lysing organelle can provide a surge of genetic lineage has some attractive features. Lateral gene transfer material with an opportunity for integration into the is probably accelerated by having an in-house source of nucleus, a partially digested bacterial food particle also foreign DNA such as an endosymbiont [10]. In addition, provides opportunity for gene transfer (Figure 1aii). Many trypanosomatids harbour not only genes found in plastids free-living kinetoplastids, such as bodonids, are bacterio- and bacteria, but also genes (such as SBPase) that are only vores, and a long history of bacterial gene integration known from eukaryotes. While this early eukaryotic during kinetoplastid evolution is possible. In a similar endosymbiont hypothesis requires organelle loss within vein, some modern trypanosomatids parasitize plant the Euglenozoa (from multiple lineages to explain the tissues. If ancestral trypanosomatids also parasitized current occurrence of plastids in this phylum) (Figure 1), plants, they could have directly acquired genes from plastid loss is not without precedent. For instance, their hosts. The question of how trypanosomatids gained secondary plastids have apparently been lost from their plant and prokaryote-type genes will only become oomycetes [11] and possibly ciliates [12]. clear with further molecular data (notably from other Although attractive, the early acquisition hypothesis protists) that will enable more thorough analyses of their (Figure 1ai) should be embraced cautiously at this point. evolutionary affinities. For many of the genes presented by For example, recent ultrastructural analysis of Euglenozoa Hannaert et al., limited taxon representation allows for only preliminary phylogenetic conclusions at this point (http://www.icp.ucl.ac.be/~opperd/supplementary/table.html). (a) (i)Euglenids (ii) Plastid Euglenids

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