A team at the University of Dundee has identified how random genetic decisions allow parasites to survive in their human and animal hosts.
Scientists in the School of Life Sciences have been able to demonstrate the mechanism that allows parasites to switch genes on and off randomly enabling them to survive the defences of the host’s immune system. This behaviour is present in genes within parasites known as trypanosomes, and also in the parasite that causes malaria, which claims hundreds of thousands of lives every year. Changing their cell surface characteristics allows the deadly parasite to escape from the defences of the host’s immune system.
In a paper published in Nature Microbiology, 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.”
Variant surface glycoprotein (VSG) genes are able to activate what the Dundee team have termed a ‘VSG exclusion’, or VEX-complex when only one allele of the gene is expressed. This single expression allows the parasite to change its surface protein coat and escape the immune system defences of its host, however, 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.
Unlike most cellular processes, which are precisely controlled, random patterns of activation are essential for these genes, though until now the mechanisms that promote single gene choice in these parasites have remained unknown. The new discovery shows how two chromosomes interact in a highly selective manner to increase the expression of a single VSG in a single compartment in a trypanosome nucleus. Highly selective gene expression is a key requirement for variation in several pathogens, allowing the parasite to evade host immune responses and maintain persistent infections. 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’.
The breakthrough could benefit research into how other cells make random choices to function effectively. Cells that make up our immune system make distinct antibodies by activating a different gene in each cell and cells in our noses detect distinct odours by each expressing a different odour receptor. The findings could also assist in developing treatments for diseases that use this type of immune evasion strategy.
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”.
The discovery is the result of a collaboration with colleagues at the Ludwig Maximilian University in Munich.