A sense of direction: cooperative behaviour and chemotaxis in the life cycle of Trypanosoma brucei

Many protozoan parasites have complex life cycles requiring migration through different organs in their hosts.

The current mind-set is that parasites act as individuals and that tissue specificity is largely dictated by receptor-ligand interactions between pathogen and host surface molecules. However, parasites are more autonomous and manipulative than we give them credit for.

I propose that self-steering, a mechanism by which groups of cells migrate in response to gradients that they create and/or modify, is central to their ability to orient themselves and home into host tissues.Trypanosoma brucei, which causes sleeping sickness, cycles between mammals and tsetse flies.

Trypanosomes lack G-protein coupled receptors (GPCR) and heterotrimeric G proteins, which act as sensors and signal transducers in yeast and multicellular eukaryotes, but encode a large number of receptor adenylate cyclases.

We recently discovered that trypanosomes generate pH gradients on semi-solid surfaces and use cyclic AMP (cAMP) signalling to move collectively in response to them. This correlates with their ability to cross barriers and sequentially colonise organs in tsetse flies.

Our newest findings that trypanosomes respond chemotactically to other metabolites, together with evidence from several laboratories that T. brucei is not restricted to the blood and central nervous system in mammals, but also invades other organs, are the focus of this project.My objectives are: to elucidate the intracellular mechanism of cAMP-mediated pH sensing to explore other cues for chemotaxis and determine how signals are transduced to establish whether the expanded family of adenylate cyclase genes in T. brucei plays a role in extravasation and colonisation of different organs in mammalian hosts.This is the first, comprehensive analysis of the mechanisms governing directed migration by a parasite and is a paradigm for new forms of sensing in eukaryotes lacking GPCR.