Uncovering the parasite metabolome

Malcolm McConville was studying Antarctic microalgae when he got side-tracked into studying the devastating human parasite Leishmania.

McConville’s PhD involved studying some of the secondary metabolites, particularly the slime-like polysaccharides, made by algae that live under the Antarctic sea-ice.

As he was finishing his PhD at the University of Melbourne, scientists Emanuela Handman and Jim Goding across the road at WEHI were starting to look at some very strange antigens on the surface of Leishmania parasites.

“Their studies suggested that these antigens might be unusual polysaccharides, rather than proteins,” he says. “I joined their team as a post-doc and we showed that the surface coat of Leishmania was indeed composed of an entirely new class of polysaccharides that were tethered to the surface membrane.

“There has been enormous interest in these antigens, both because of their role in helping the parasite to survive in their hosts and as potential vaccine candidates. Quite a journey from Antarctic biology to tropical parasitology.”

One of the advantages of metabolomics, he says, is that you can identify novel metabolites that you wouldn’t anticipate just looking at the genome.

“When we started screening the metabolome of Leishmania more generally we discovered that the major carbohydrate reserve of these parasites is made up of polymers of mannose rather than glucose, which is what most other organisms, including ourselves, make.

“Our major carbohydrate reserve is glycogen, which is made of long chains of glucose, whereas the Leishmania make smaller carbohydrates, made of linear chains of mannose.

“The synthesis of the Leishmania ‘mannogen’ involves a completely novel metabolic pathway and we have recently identified one of the key genes involved in its synthesis.

“We’ve found a gene that was annotated in the genome as being involved in the synthesis of another type of sugar, which we happened to know from our metabolite profiling experiments was not made by these parasites.

“We therefore suspected that this gene might have been conscripted to this new metabolic pathway that we had discovered and acquired a new activity. Fleur Sernee, a post-doc in the lab has recently confirmed this hypothesis by deleting the gene and showing that it is not only required for mannogen synthesis but also for virulence.

“This is a nice example of how metabolite profiling can lead to the identification of new metabolic pathways and the identification of novel genes that might be potential drug targets in microbial pathogens.”

Metabolomics is also bringing the traditionally disparate roles of immunology and biochemistry together. While biochemists tend to look at metabolism in a culture flask and immunologists in an animal system, McConville says it is now becoming clear that the interaction between the parasite and the host is often fundamentally about metabolism.

“It’s about scavenging essential nutrients from the host and a very important part of the immune response is to stop the host cells from giving the parasite the necessary nutrients.

“Leishmania lives inside macrophages, the foot soldiers of the immune system – they should be responsible for clearing these pathogens but Leishmania resides within the most hydrolytic compartment of the macrophages. One way that macrophages kill intracellular pathogens is to prevent them from accessing essential amino acids and sugars.

“Leishmania on the other hand is quite effective at pushing macrophages into a metabolic state where they provide lots of these essential nutrients. So immunology and metabolomics is increasingly being seen as tied together. In fact, the metabolism of the macrophage is a fundamental part of the anti-microbial immune response.

“The flip side is that we can use metabolomics to look at the metabolism of the host cell when it is being invaded. Although it has been extremely useful in looking at the pathogen itself, there is now equal interest in looking at the host cell and how it is responding to the invading pathogen, to see if maybe we can tweak the metabolism of the host cell in such a way that it becomes an inhospitable environment for the microbe.”