Researchers Identify Key Protein in Sleeping Sickness Parasite

A research team from the University of York has identified a protein that regulates gene expression in the parasite Trypanosoma brucei, the cause of African sleeping sickness. The findings, published in Nature Microbiology, suggest a potential new target for developing treatments for the disease.

The Parasite's Defense Mechanism

Trypanosoma brucei evades detection by the human immune system through a constantly renewing outer coat made of proteins called variant surface glycoproteins (VSG). This molecular cloak allows the parasite to avoid being recognized and destroyed.

A long-standing question in parasitology has been how the parasite sustains this high level of VSG production without overloading its cellular machinery with the production of other, non-essential proteins.

Discovery and Function of ESB2

The protein, named ESB2, selectively degrades specific RNA molecules, enabling the parasite to maintain high production of the surface proteins it uses to evade the human immune system.

The research team discovered ESB2 by tagging proteins within the parasite's cells and identifying them using mass spectrometry. Their investigation revealed that ESB2 functions by selectively intercepting and degrading RNA molecules that encode for other, non-essential "helper" proteins. This process allows RNA molecules encoding the critical VSG coat to pass through unimpeded.

To confirm ESB2's role, researchers genetically removed the protein from T. brucei. In its absence, production levels of the helper proteins increased to match the high levels of VSG production.

Researcher Statements

Lianne Lansink, the study's first author, stated that observing the protein's specific location under a microscope indicated a significant finding.

Senior author Joana Correia Faria described the mechanism as "a remarkably efficient way to downregulate genes at the source." Faria also noted the discovery suggests a shift in perspective, where survival for some organisms may depend more on how they destroy genetic instructions than how they issue them.

Implications for Sleeping Sickness

Sleeping sickness, or African trypanosomiasis, is transmitted by the tsetse fly and can affect the central nervous system. While case numbers have decreased in recent years, hundreds of people are affected annually. Existing treatments can have severe side effects and are not always accessible or effective.

The discovery of ESB2's regulatory role suggests it could be a potential new target for treatments. Disrupting ESB2's activity could impair the parasite's ability to maintain its protective coat, potentially making it more visible to the immune system.

Future Research Directions

The research team plans to further investigate how ESB2 identifies different RNA molecules for degradation and what other proteins it interacts with within the parasite's cells. This work aims to provide a more detailed understanding of the regulatory mechanism.