Sleeping sickness: pathogens play hide-and-seek

An international research team has discovered that Trypanosoma brucei, the pathogen responsible for sleeping sickness, varies its antigenic surface proteins – so-called variant surface glycoproteins (VSGs) – primarily in tissues outside the bloodstream. These results could lead to new approaches for fighting this life-threatening infection, says Nicolai Siegel. The LMU professor and his team played a significant role in the study, which has now appeared in the highly prestigious journal Nature. Siegel heads the Molecular Parasitology research group (Division of Experimental Parasitology, Department of Veterinary Sciences) at the Biomedical Center Munich.

Transmitted in Africa through the bite of the tsetse fly, sleeping sickness poses a danger to humans and animals alike. Typical symptoms are fever, lethargy, and, in advanced stages, severe neurological disorders. If untreated, the disease causes death. One of the biggest challenges in treating sleeping sickness is the ability of the parasite to evade the host’s immune system by continually changing its surface proteins. Known as antigenic variation, this mechanism protects the parasites against immune attacks, as the immune system has to respond to new, unknown protein variants.

It was previously assumed that these antigenic changes take place primarily in the bloodstream. The new study shows, however, that T. brucei generates most of its VSG variants in extravascular tissues like skin, fatty tissue, and other organs. The immune system is less active in these tissues, which gives the parasite more time to produce a wide variety of new variants, before it goes back into the blood. These “safe zones” in the body give the parasite the opportunity to maintain chronic infection and shield itself against immune attacks.

Main reservoir of antigenic variety

To analyze the VSG diversity of T. brucei, the researchers used a special type of single-cell high-throughput RNA-sequencing, which was established in the Siegel group. They discovered that over 75% of the VSG variants can be found exclusively in extravascular tissues and that the variety there is around two to four times higher than in blood. These findings indicate that extravascular tissues serve as the main reservoir of antigenic variety, which is a decisive component of immune evasion.

The discovery of the role of these tissues opens up new perspectives for the treatment of sleeping sickness. By specifically blocking the entry of T. brucei into these immunologically protected tissues, doctors could stem the infection by reducing the variability of VSGs and helping the immune system recognize and attack the parasite.

These results offer new insights into the complex relationship between host and parasite and could represent an important step toward the development of more effective therapies against sleeping sickness and other diseases in which pathogens protect themselves using immune escape mechanisms.

Alexander K. Beaver, Zhibek Keneskhanova, Raúl O. Cosentino, Brian L. Weiss, Erick O. Awuoche, Gretchen M. Smallenberger, Gracyn Y. Buenconsejo, Nathan P. Crilly, Jaclyn E. Smith, Jill M. C. Hakim, Bailin Zhang, Bryce Bobb, Filipa Rijo-Ferreira, Luisa M. Figueiredo, Serap Aksoy, T. Nicolai Siegel & Monica R. Mugnier: Tissue spaces are reservoirs of antigenic diversity for Trypanosoma brucei. Nature, 2024