Scientists map a giant parasite machine to fight tropical diseases

A study conducted between the University of Liège and Rockefeller University reveals, with near-atomic precision, the three-dimensional structure and function of a gigantic molecular machine essential to the survival of trypanosomatid parasites, which cause serious diseases in humans, animals and plants. This discovery sheds light on a biological mechanism that has remained a mystery for nearly forty years and reveals several features specific to these organisms.

Trypanosomatids are parasites responsible for numerous diseases affecting humans, animals and plants. In humans, they cause tropical diseases such as leishmaniasis, sleeping sickness and Chagas' disease, which affect several million people worldwide. Treatments exist, but they remain limited by their efficacy, toxicity or the development of resistance. And this problem extends beyond human health. Other trypanosomatids infect livestock, causing major economic losses, while some species infect crops and significantly reduce agricultural yields.

What makes these parasites so unusual? In our cells, genetic information is first copied into RNA, a kind of draft that must be processed before it can serve as instructions for making proteins. One of the steps in this maturation process is RNA splicing, during which certain sequences, known as introns, are cut out and removed. "Trypanosomatids use a very specific form of this process, known as Spliced Leader (SL) RNA trans-splicing," explains Arnaud Vanden Broeck, a biologist heading the Laboratory of RNA Structural Biology and Biochemistry at the University of Liège. "In these organisms, conventional intron splicing is extremely rare. Instead, virtually all of their messenger RNAs receive the same short RNA sequence, known as the SL RNA, at their 5' end. This step is essential for the maturation of their RNAs and therefore for the functioning of their cells." Two factors make this mechanism particularly interesting: it is absolutely essential for the parasite's survival, and it does not exist in this form in humans. This is precisely what makes it a promising target for new treatments, as blocking this step could neutralise the parasite without disrupting our own cells.

A mechanism finally observed in action

The machine responsible for this process, known as the trans-spliceosome, is a true molecular factory. Although it was discovered nearly forty years ago, how it works has remained largely mysterious. "We didn't know precisely how its various components were organised or how they worked together to carry out this reaction," the researcher continues. "To obtain high-resolution snapshots of this machine in action, we used cryogenic electron microscopy (cryo-EM), a technique that involves freezing molecules very rapidly and then reconstructing their three-dimensional structure from hundreds of thousands of images." Using this method, the scientists were able to capture two successive stages in the machine's activity: the moment when the SL RNA is attached to the messenger RNA, and the state immediately afterwards, once this reaction is complete.

These structures reveal, with unprecedented precision, the organisation of the machine's core, the way in which the various RNAs are positioned during the reaction, and the role of several proteins unique to trypanosomatids and absent in humans. "Despite some similarities with the splicing machinery found in our own cells, the trans-spliceosome has numerous distinctive adaptations." These findings show how this very ancient molecular machine has been profoundly remodelled to perform a different function, thereby shedding light on the evolutionary history of such machinery in eukaryotic organisms.

By revealing the architecture of the trans-spliceosome at near-atomic resolution, this study achieves a goal that the scientific community has been pursuing for decades. "Beyond advancing our fundamental understanding of the evolution of life, our study provides a concrete basis for designing molecules capable of specifically disrupting this machinery in parasites, whilst sparing human cells," concludes Arnaud Vanden Broeck. An encouraging avenue of research in the face of diseases that remain difficult to treat.