Stress kills sleeping sickness parasites

By Dr Matt Wilkinson

- Last updated on GMT

Related tags: Rna

The discovery of a new method of killing the parasite that causes
sleeping sickness could lead to a drug that eliminates the disease.

In the latest issue of EMBO​ Dr Shulamit Michaeli and colleagues in the Life Sciences Department of Bar-Ilan University in Israel, describe a pathway that shuts down the synthesis of spliced leader RNA (SL RNA), leading to the death of the parasite. Exposing the parasite to physiological stress, such as low pH, can trigger the pathway. Sleeping sickness, tyrpanosomiasis, affects both humans and livestock and is endemic in sub-Saharan Africa where it is estimated that there are more than 70,000 sufferers. The disease is caused by the parasite Trypanosoma brucei​ (T. brucei​) and results in neurological damage and ultimately death. The parasite is transmitted by the tsetse fly. Four drugs are currently registered for the treatment of sleeping sickness and are provided free of charge to endemic countries through a WHO private partnership with Sanofi-Aventis (pentamidine, melarsoprol and eflornithine) and Bayer (suramin). However, toxicity issues and undesirable side effects, not to mention administration problems hamper the treatments. Triggering the pathway, which the researchers have named SL-RNA silencing (SLS), halts the production of mRNA molecules and leads to the parasite's death. "If we can find the substance that illicits this pathway we find the ultimate method of eliminating this disease,"​ Michaeli told DrugResearcher.com. The pathway was identified by RNA interference (RNAi) knockdown of the signal recognition particle (SRP) receptor (SR-alpha) using a stem-loop structure. This then causes the accumulation of SRP on ribosomes. Michaeli continued: "Once the SRP binds to the receptor there is no mechanism to release the particle and this is sensed as a major problem and the cells are told to completely shut down, ultimately causing them to commit suicide." ​This accumulation leads to spliced leader (SL) RNA silencing (SLS). The SL RNA is the main RNA molecule in trypaosomes and dictates the SL sequence to all messenger RNA (mRNA) through trans-splicing. To investigate how the SL RNA transcription was silenced proteins present in nuclear extracts from cells before and after SR-alpha knockdown were studied using western analysis. A chromatin immunoprecipitation (CHiP) assay indicated that the SL RNA transcription complex was not formed in SR-alpha depleted cells. The study found that the parasite induces SLS when exposed to low pH. The group are currently investigating the effects of various other physiological stresses on SLS. At present the signalling pathway involved in SLS is unknown. The T. brucei​ parasite is closely related to the Leishmania​ parasite that causes Leishmaniasis and Trypanosoma cruzi​ that causes Chagas disease. Leishmaniasis is estimated to affect millions of individuals throughout the world and leads to skin lesions, tissue damage and death. Chagas disease affects between 16m and 18m people across the Americas and causes intestinal complications, neurological disorders, heart damage and death. According to Michaeli a drug that works to silence the newly discovered pathway should work for all of the related parasites as they share a common cell chemistry.

Related topics: Preclinical Research

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