Differentiation is a central aspect of the parasite life cycle and encompasses adaptation to both host and environment. If we accept that evolution cannot anticipate an organism's needs as it enters a new environment, how do parasite differentiation pathways arise? The transition between vertebrate and insect stage African trypanosomes is probably one of the better studied and involves a cell-cycle arrested or 'stumpy' form that activates metabolic pathways advantageous to the parasite in the insect host. However, a range of stimuli and stress conditions can trigger similar changes, leading to formation of stumpy-like cellular states. We propose that the origin and optimisation of this differentiation program represents repurposing of a generic stress response to gain considerable gain-of-fitness associated with parasite transmission.

School of Life Sciences University of Dundee Dundee DD1 5EH UK; Biotechnology and Biomedicine Centre of the Academy of Sciences and Charles University Průmyslová 595 252 50 Vestec Czech Republic

School of Life Sciences University of Dundee Dundee DD1 5EH UK; Institute of Parasitology Biology Centre Czech Academy of Sciences 37005 Ceske Budejovice Czech Republic

Wellcome Centre for Integrative Parasitology College of Medical Veterinary and Life Sciences Glasgow Biomedical Research Centre University of Glasgow Glasgow UK; School of Life Sciences University of Dundee Dundee DD1 5EH UK

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Phenotypic screening reveals a highly selective phthalimide-based compound with antileishmanial activity

Heme-deficient metabolism and impaired cellular differentiation as an evolutionary trade-off for human infectivity in Trypanosoma brucei gambiense