Trypanosomiasis: Parasite, kinetoplast

The parasite has only one nucleus, is elongated, contains a giant mitochondrion and has a single flagellum. At the base of the flagellum is the basal body. This lies adjacent to the kinetoplast. The latter is a compact DNA (deoxyribonucleic acid) structure, located in the very long mitochondrion. This mitochondrion is almost as long as the entire trypanosome. The name of the Order to which the parasite belongs – Kinetoplastida - refers to this organelle. Between the basal body and the flagellum there is an undulating membrane which is required for movement. The microscopic recognition of all these structures is important, for example when in doubt about a suspect structure in a microscopy preparation. In a buffy coat and/or a fresh blood slide preparation the parasites can be seen to move rapidly ("trypanon" = to drill or bore and "soma" = body). In the form of the parasite such as it occurs in man (trypomastigote), the kinetoplast lies in a posterior position and the flagellum points towards the front, rather like a bowsprit on a large sailing vessel. The parasite occurs in the salivary glands of the tsetse fly as an epimastigote (kinetoplast located just in front of the nucleus). The varying location of the kinetoplast is possibly related to different metabolic requirements in the various hosts.

The DNA in the kinetoplast (kDNA) stains like that of the nucleus (recognizable on a smear). The structure of the DNA in this kinetoplast is very complex. There are numerous (about 40) large DNA loops ("maxicircles") and even more (some 5,000-10,000) small DNA loops ("minicircles"). These form a gigantic tangle. For replication the parasite requires a specific "disentanglement enzyme" (type II topoisomerase). This latter enzyme could be a target in the development of new drugs.

Several mitochondrial genes appear to be incomplete. In 1986 it was discovered that “editing” of the genetic information takes place in pre-messenger RNA (ribonucleic acid) after transcription of the maxicircle-DNA. Certain RNA-bases (uridines) are removed or inserted in order to form a "mature" mRNA. In 1990 it was discovered that very small, so-called guide-RNA or gRNA molecules play a major role in this editing. Most gRNAs are coded in the minicircles. After the discovery of kRNA-editing, RNA-editing was also found in other organisms.

One hypothesis is that kRNA-editing has a regulatory function in gene expression and in mitochondrial metabolism. Some transcripts are found principally in the procyclic (insect) forms, others mainly in the blood stages. The mitochondria of the parasite in the bloodstream contain no cytochromes and lack various enzymes of the Krebs cycle. There are significant differences in the energy production of the parasite: (1) in glucose-rich mammalian blood (principally anaerobic glycolysis in glycosomes [cellular organelles which contain the first 7 enzymes of glycolysis and which are unique to the Kinetoplastida. In most Eukaryota glycolysis takes place in the cytosol]) and (2) in the insect, which lacks glucose, the parasite’s energy comes mainly from aminoacids (e.g. proline) and the metabolism is mainly aerobic. Hence, there is possibly a cyclic activation and repression of various metabolic pathways in the mitochondria, depending on the host. There is, clearly, insufficient understanding of the details. If a glycosome inhibitor could be developed, this might eventually open up new therapeutic possibilities.

Another illustration of the importance of the mitochondrion in trypanosomes is found in Trypanosoma evansi. This trypanosome causes "surra", a disease in camels and horses. The kDNA of this parasite has a different structure in its mitochondrion (for example, it has no maxicircles). As the maxicircles play a crucial role in the functioning of the mitochondrion, it is reasonable to assume that T. evansi cannot go through a maturation cycle in an insect. A consequence of this may be that a change of host cannot occur here. Indeed, the parasite appears to be transmitted only by a mechanical vector, e.g. biting flies (Tabanidae) or vampire bats.

More than a billion years ago the ancestor of trypanosomes probably merged with a type of green algae. This would have enabled it to harness the Sun's energy. This would have had a tremendous advantage. When trypanosomes became parasites, they no longer needed to photosynthesize. The symbiont degenerated and some of its genes passed to those of the trypanosome. At this moment, the genes are vital for the survival of trypanosomes. Several microorganisms, including the malaria parasite, seem to have absorbed others in the past. Both the cellular powerhouses called mitochondria and chloroplasts, which plants use to turn sunlight into chemical energy, are thought to have originally been free-living bacteria. The leftover plant genes were found by analysing the genomes of T. brucei. So far 16 genes have been found that have their closest relatives in plants. Researchers suspect that more wait to be discovered. Plants use the equivalent genes to photosynthesize, using carbon dioxide to make sugars. Trypanosomes use them to break sugars down, in a unique cellular system.

Category: Medicine Notes