A surface transporter family conveys the trypanosome differentiation signal

• Published in: Nature 2009-05, Vol.459 (7244), p.213-217
• Main Authors: Dean, Samuel, Marchetti, Rosa, Kirk, Kiaran, Matthews, Keith R.
• Format: Article
• Language: English
• Subjects: Aconitic Acid - analogs & derivatives; Aconitic Acid - metabolism; African trypanosomiasis; Animals; Biological and medical sciences; Carrier proteins; Cell Differentiation; Cell differentiation, maturation, development, hematopoiesis; Cell physiology; Citric Acid - metabolism; Disease transmission; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation, Developmental; Genes; Genetic aspects; Glossina; Health aspects; Humanities and Social Sciences; Hypersensitivity; Insect Vectors - parasitology; Low temperature; Mammals; Molecular and cellular biology; multidisciplinary; Natural history; Oocytes; Parasites; Proteins; Protozoan Proteins - genetics; Protozoan Proteins - metabolism; RNA Interference; RNA, Messenger - genetics; RNA, Messenger - metabolism; RNA, Protozoan - genetics; RNA, Protozoan - metabolism; Science; Science (multidisciplinary); Statistical analysis; Temperature; Transducers; Trypanosoma; Trypanosoma brucei brucei - cytology; Trypanosoma brucei brucei - genetics; Trypanosoma brucei brucei - growth & development; Trypanosoma brucei brucei - metabolism; Trypanosomiasis, African - parasitology; Tsetse Flies - parasitology; Vector-borne diseases; Xenopus laevis
• ISSN: 0028-0836; 1476-4687; 1476-4679
• DOI: 10.1038/nature07997

Microbial pathogens use environmental cues to trigger the developmental events needed to infect mammalian hosts or transmit to disease vectors. The parasites causing African sleeping sickness respond to citrate or cis -aconitate (CCA) to initiate life-cycle development when transmitted to their tsetse fly vector. This requires hypersensitization of the parasites to CCA by exposure to low temperature, conditions encountered after tsetse fly feeding at dusk or dawn. Here we identify a carboxylate-transporter family, PAD (proteins associated with differentiation), required for perception of this differentiation signal. Consistent with predictions for the response of trypanosomes to CCA, PAD proteins are expressed on the surface of the transmission-competent ‘stumpy-form’ parasites in the bloodstream, and at least one member is thermoregulated, showing elevated expression and surface access at low temperature. Moreover, RNA-interference-mediated ablation of PAD expression diminishes CCA-induced differentiation and eliminates CCA hypersensitivity under cold-shock conditions. As well as being molecular transducers of the differentiation signal in these parasites, PAD proteins provide the first example of a surface marker able to discriminate the transmission stage of trypanosomes in their mammalian host. Trypanosomes differentiation The sleeping sickness pathogen Trypanosoma brucei , like many other parasites, has a complex life cycle involving insect and mammalian hosts. It has been long known that differentiation from the human blood to the tsetse-fly stage requires two signals, low temperature and citrate and/or cis -aconitate, but how these signals were perceived was not clear. Now the cell surface molecules that convey the environmental signal responsible for trypanosome differentiation have been identified as members of the trypanosome carboxylate-transporter family PAD. Significantly, it is the transmission-competent 'stumpy' forms of the blood-borne parasite — more robust than slender forms and competent to differentiate— that carry PAD proteins. The differentiation of the parasite Trypanosoma brucei , the cause of sleeping sickness, from the human blood to the tsetse fly stage is known to require two signals – low temperature and citrate and/or cis -aconitate – but how these signals were perceived was unknown. The trypanosome carboxylate-transporter family PAD is now revealed to be essential in this process.