The BBSome Complex – A novel virulence factor in Leishmania

News article 13 Dec 2013

LSTM’s seminar series continued this week with a presentation by Dr Helen Price of the School of Life Sciences, Keele University. “The BBSome Complex – A novel virulence factor in Leishmania” was introduced by LSTM’s Dr Alvaro Acosta-Serrano.

Dr Price started by explaining that her work had begun by looking at the cell biology of the protozoan parasite, Trypanosoma brucei, which is transmitted by the tsetse fly and causes sleeping sickness, and Leishmania spp., which is transmitted by the sand fly and causes leishmaniasis. She described her work to validate the enzyme N-myristoyltranferase (NMT) as a drug target given that it is essential for parasite viability.

The use of two high throughput screens led to the discovery of some potent inhibitors to NMT and she described the most effective inhibitor for the T. bruceiparasite. Parasites overexpressing the NMT protein have an increase in resistance to the inhibitor, showing on-target action of this molecule.

She illustrated how this work had led her to discover that the Leishmania orthologue of the gene BBS1 from the BBSome protein complex is essential for the survival of the parasite within the host. She explained that in humans, BBS1 is one of eight subunits of the BBSome protein complex which is associated with regulation of molecular trafficking to and from the primary cilia. Mutations within the genes encoding the BBSomes subunits are implicated in the genetic disorder Bardet-Biedl syndrome. In Leishmania the BBS1 gene is associated with parasite virulence in the host.

Dr Price and her team generated null and complemented mutants of BBS1 in the Leishmania parasites, and while they showed no apparent defects in vitro, there is an accumulation of vacuoles and the infectivity of the BBS1 null parasites was severely compromised.

Dr Price concluded by looking at her next areas of research, which include further research into how the Leishmania BBSome is organised, where the complex localises and what its structure reveals about its function within the parasite. A greater understanding of which it is hoped will lead to the identification and validation of new drug targets.