Awakening news towards the treatment of sleeping sickness

25/08/2014

Sleeping sickness threatens millions of people in 36 Sub-Saharan Africa countries: The disease caused by the parasite Trypanosoma brucei is spread primarily by the tsetse fly and is – if not treated – eventually fatal. Due to its antigenic plasticity and repertoire, the parasite stays ahead of the host immune response, and T. brucei infections are therefore very difficult to treat.

The group of Gang Dong at the Max F. Perutz Laboratories (MFPL) of the University of Vienna and the Medical University of Vienna has recently made progress in the fight against T. brucei by identifying a potential drug target in one specific region of a protein located in the parasite’s surface membrane: BILBO1.

BILBO1 has been identified as indispensable to the health and pathogenicity of T. brucei. This cytoskeletal protein is a crucial component of the so-called flagellar pocket collar (FPC) located at the neck of the flagellar pocket (FP). “Analogically speaking, the flagellar pocket is similar to our mouth – it is essential for the survival of the parasite, because it is the sole site for all endo- and exocytic activity in the cell and is crucial for the parasite’s metabolism and removal of host antibodies”, explains Gang Dong. Neither BILBO1 nor the FPC is present in mammals. Therapeutics could thus be focused on interfering with flagellar pocket function and biogenesis, as they would not cause unpredicted reactions in the parasite’s host.

A high resolution structure of the N-terminal domain of T. brucei BILBO1 determined by Gang Dong’s group showed that it forms a variant ubiquitin-like fold with a distinct conserved surface patch. Mutagenesis of this patch caused cell death in vivo. “We therefore suggest that the surface patch on the N-terminal domain of BILBO1 could be a potential drug target”, adds Gang. These findings were published early this year in The Journal of Biological Chemistry.

In another recent paper in The Journal of Biological Chemistry, the scientists from MFPL provide further structural dissections of the other three constituent domains of T. brucei BILBO1, which will help elucidate the molecular mechanism for BILBO1 assembly at the flagellar pocket collar.

Gang Dong’s group is now teaming up with the Robinson/Bonhivers group from the Laboratory of Fundamental Microbiology and Pathogenicity at the University Bordeaux (France), who originally identified BILBO1 in 2008. “Our collaboration partners in France have identified several FPC proteins in addition to BILBO1, and together we are now aiming at characterizing these proteins in detail, both structurally and functionally”, says Gang.

Their work and findings provide hope that in the future drugs may be developed that help treat and prevent infection by Trypanosoma brucei.

Original publications in The Journal of Biological Chemistry:
Keni Vidilaseris, Brooke Morriswood, Georg Kontaxis and Gang Dong: Structure of the TbBILBO1 protein N-terminal domain from Trypanosoma brucei reveals an essential requirement for a conserved surface patch. In: J. Biol. Chem. (February 2014).
DOI:
http://dx.doi.org/10.1074/jbc.M113.529032

Keni Vidilaseris, Ekaterina Shimanovskaya, Heather J. Esson, Brooke Morriswood and Gang Dong: Assembly mechanism of Trypanosoma brucei BILBO1, a multidomain cytoskeletal protein. In: J. Biol. Chem. (July 2014).
DOI: http://dx.doi.org/10.1074/jbc.M114.554659