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cAMP-ing with sleeping sickness – potential drug target and mode of resistance

Human African trypanosomiasis (HAT), also known as sleeping sickness, is a lethal disease caused by the parasite Trypanosoma brucei. Current treatments cause serious side effects or are ineffective due to drug resistance.
cAMP-ing with sleeping sickness – potential drug target and mode of resistance
Recent evidence indicated a role for cAMP metabolism in parasite proliferation and cell division. Inhibition of the enzymes that synthesise or degrade cAMP kill the parasite, clearly showing that cAMP metabolism comprises an excellent drug target against HAT. However, it is currently unknown how changes in cAMP concentrations translate to an observed cell division defect.

To address this, scientists of the EU-funded TRYPCARPINTERACTORS (Uncovering the components and interactors of a novel cAMP signalling pathway and characterisation of its role in cytokinesis in Trypanosoma brucei) project set out to study the downstream cAMP effector proteins in trypanosomes.

For this purpose, they developed a forward genetics approach that led to the identification of cAMP response proteins (CARPs). When these proteins were knocked down by RNAi, they induced resistance to elevated cAMP. Drug sensitivity assays validated a total of ten CARPs that potentially participate in the cAMP signalling cascades. Repression of at least one CARP resulted in a drastic cell division phenotype, comparable to that seen by genetic or pharmalogical manipulation of the intracellular cAMP concentration.

Overall, researchers identified two phenotypes linked to extreme changes in cAMP concentrations, namely a block in cell division of bloodstream parasite forms and a disruption in social motility of parasite insect stage forms. Further analysis of CARPs and candidate interacting proteins is expected to unravel the pathways that mediate cAMP signaling in trypanosomatids.

Collectively, the results of the TRYPCARPINTERACTORS study support current EU-funded attempts to target the cAMP modulating machinery as a means of treating HAT. The provided mechanistic insight underscores the importance of CARPs in trypanosome biology and their role in development of resistance to drugs modulating cAMP.

Related information

Keywords

Neglected tropical disease, Sleeping sickness, African Trypanosomiasis, Parasite, cell signaling, cyclic adenosine monophosphate, cAMP, cAMP response proteins genetic screening, genome-wide RNAi
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