WCAIR scientists have shown how parasitic trypanosomes make random yet ultimately highly selective choices that allow them to survive in their human and animal hosts. They identified a mechanism that allows genes to switch on and off randomly, changing cell surface characteristics and allowing escape from the defences of the host’s immune system. The paper is published in Nature Microbiology.
Joana Faria, a postdoctoral researcher and the first author on the paper said, “This study represents a major advance in our understanding of how trypanosomes express a single variant surface glycoprotein (VSG) from myriad possibilities. In simple terms, we demonstrated that trypanosomes assemble a dedicated expression ‘factory’ to produce a single surface antigen at very high levels. Our findings have a broader impact, revealing a role for inter-chromosomal interactions in gene expression control in simpler eukaryotes”.
David Horn, Professor of Parasite Molecular Biology in the Wellcome Centre for Anti-Infectives Research, said that the findings represent a major advance. “We reported our discovery of the VEX1 protein in 2016 and the VEX2 protein in 2019” he said. “The current study reveals the striking nuclear context within which these protein condensates operate, co-ordinating key interactions between different chromosomes, and also revealing a novel mechanism of gene expression control.”
VSG genes are subject to allelic exclusion, a mechanism that affects the largest gene families in eukaryotes. Typically, only one gene from a family is expressed by each cell. Indeed, parasite survival depends upon only one VSG being expressed at a time by each cell, but the mechanisms underpinning single gene choice have remained mysterious. Linking the ‘VSG exclusion’ or VEX-complex to the process has greatly accelerated progress in understanding the mechanisms at play.
The discovery is the result of a collaboration with colleagues at the Ludwig Maximilian University in Munich. Initial evidence supporting a link between VSG exclusion and a highly specific nuclear organisation emerged simultaneously in both laboratories, using distinct approaches that proved to be highly complementary. The collaborative project then developed following a series of discussions, initially at conferences in the US in June 2018 and in April 2019.
The new discovery shows how two chromosomes interact in a highly selective manner to elevate the expression of a single VSG in a single compartment in a trypanosome nucleus. The VEX-complex occupies this compartment and blocks access for other VSG genes – VEX2 in particular appears to play the role of a highly selective ‘gate-keeper’. Highly selective gene expression is a key requirement for variation in several pathogens, allowing the parasite to evade of host immune responses and maintain persistent infections.
The work in Dundee was funded by grant support from the Wellcome Trust. The research paper can be viewed here.