A mechanism that is responsible for the drug susceptibility of parasites that cause devastating diseases, known as nagana in cattle and sleeping sickness in humans, has been identified for the first time in a research breakthrough led by the University of Dundee.
African trypanosomiasis is an infection affecting both animals and humans. It can have a devastating impact, particularly in rural areas, and is the most economically important livestock disease in Africa, where it is known as `nagana’.
At present no vaccine is available. Trypanosomiasis can be treated with trypanocidal drugs for therapeutic and prophylactic purposes. However, the effectiveness of these drugs is now questionable following years of use, causing resistance to spread.
Trypanosomosis is usually transmitted through the bite of an infected tsetse fly, which allows parasites to pass into the fluids and tissue of the host animal.
Researchers in the laboratory of Professor David Horn at the University of Dundee, working with colleagues at the University of Glasgow, have discovered the proteins that render these ‘kinetoplastid’ parasites – specifically African trypanosomes that cause nagana in cattle - susceptible to the most important veterinary drugs. These drugs target the kinetoplast itself, a complex DNA structure in the parasites' mitochondrion.
Using a high-throughput genetic approach to identify genes that sensitise cells to drugs, the researchers identified every component of a molecular `rotor’ that is crucial in acidifying compartments within the parasite.
In total, they found that thirty new genes and three protein complexes, including the rotor, are required to maintain kinetoplast-dependent parasite growth.
Professor Horn said, “This is a great example of how a genome-scale genetic screen can yield insight into anti-trypanosomal drug action and, at the same time, reveal unanticipated and novel biology.
“These findings suggest new potential mechanisms of drug resistance. They also indicate that communication between molecular rotors in two separate cellular compartments could be conserved through evolution, reflecting an unanticipated environmental sensing and metabolic control mechanism in nucleated cells.”
The work was funded by grant support from the Wellcome Trust and is published in the journal Proceedings of the National Academy of Sciences USA.