Research: Section IV

Outline of one of our main research areas.

Once differentiation is complete, how is the differentiated state maintained?

Once parasites differentiate from bloodstream to procyclic forms, mechanisms must operate to maintain the differentiated state. However, although there is extensive evidence for stage-regulated mRNA control, the signals responsible for this have remained cryptic.

We have recently focussed on the control of molecules specifically expressed in stumpy forms. These are interesting because most genes are down-regulated or held translationally silent in stumpy forms. Hence, those that are actively translated at this stage are particularly interesting because, despite being in the same physiological environment, their regulation is different from most other molecules.

We believe the signals that govern the expression of such genes will be informative in understanding development, rather than environmental, regulation (distinguishing them from molecules differentially expressed between bloodstream forms and tsetse midgut forms). This will help us to understand what is important for controlling transmission and hence spread of the parasite.

We have dissected the regulation of components of the differentiation regulator, PAD1, and also a novel family of molecules strongly expressed in stumpy forms, but of unknown function. These are known as expression site associated gene 9 (ESAG9). Detailed dissection of these genes has revealed that they exhibit distinct regulatory mechanisms and signals, despite their co-regulated expression.

A surface transporter family conveys the trypanosome differentiation signal - article in Nature

Developmental regulation and extracellular release of a VSG expression-site-associated gene product from Trypanosoma brucei bloodstream forms (article in Journal of Cell Science)

In a new theme, pursued together with Nick Savill within our Centre for Immunity, Infection and Evolution, we have exploited the differential expression of these genes, specifically PAD1, to mathematically model the contribution of stumpy forms to the overall infection dynamics of trypanosomes in their mammalian host. This has emphasised the importance of stumpy forms in regulating the parasite load within a chronic infection and revealed how this regulates the frequency of antigenic variation in the population, thereby assisting infection longevity.

Nick Savill - profile on Edinburgh Research Explorer

Centre for Immunity, Infection and Evolution website (ciie.bio.ed.ac.uk)