cAMP signalling in trypanosomatids: role in pathogenesis and as a drug target

Despite recent research linking cAMP signalling to virulence in trypanosomatids and detailed studies of trypanosomatid adenylyl cyclases (ACs) and phosphodiesterases (PDEs) since their discoveries 40 years ago, downstream components of the pathway and their biological functions have remained remarkably elusive. However, in recent years, significant discoveries have been made: a role for parasite ACs has been proposed in cytokinesis, evasion of the host immune response, and social motility. cAMP phosphodiesterases PDEB1 and PDEB2 were found to be essential for survival and virulence of Trypanosoma brucei and, in Trypanosoma cruzi, PDEC2 was shown to be required for normal osmoregulation. As we discuss here, these breakthroughs have led to an ongoing surge in the development of PDE inhibitors as lead compounds for trypanocidal drugs.