Title: Investigating flagellum central pair nucleators in the protozoan pathogen Trypanosoma brucei
Funder: The Academy of Medical Sciences

Abstract: African sleeping sickness is a fatal disease caused by vector-borne trypanosome parasites that threatens 65 million people in 36 sub-Saharan African countries. There are no vaccines available and the current first-line treatment for the late-stage disease suffers from toxic side-effects and requires a 10-day hospitalisation involving twice-daily intravenous infusions and highly trained staff. Trypanosomes also cause economically devastating diseases of cattle, costing rural African farmers ~$1B per year, and making large areas of sub-Saharan Africa unsuitable for livestock production. To achieve the WHO’s goal of eliminating sleeping sickness, safe, effective and practical treatments are urgently needed. The flagellum is critical for the parasite’s movement through the host and vector and thus its ability to transmit and cause disease. Recently, I discovered two proteins, basalin and TZP103.8, that are essential for nucleating the microtubules in the flagellum. Importantly, loss of either of those proteins abolishes parasite motility and viability, making them key players in parasite pathogenicity. To understand basalin and TZP103.8 function, we will address the following questions: •What is their precise localisation? •What is the function of their domains? •Do they form a complex? •What are their interacting partners? •Do they nucleate microtubules in vitro? Using a combination of in vivo and in vitro experiments we will provide mechanistic insight into basalin and TZP103.8 function and identify critical domains and interaction surfaces. This knowledge will enable the development of new, targeted treatments against African trypanosome infections and provide insights into fundamental eukaryotic biology.

Lay abstract: African trypanosomes cause the fatal human disease African Sleeping Sickness that threatens 65 million people in 36-sub-Saharann countries. Cattle diseases caused by trypanosomes are a huge economic burden on African economies and an important factor in keeping rural farmers poor. The recommended treatments for sleeping sickness are often ineffective, toxic and impractical in the isolated and rural settings where the disease occurs. Trypanosomes are transmitted between hosts by tsetse fly. Central to the trypanosome’s ability to spread and cause disease is a protrusion of its surface called the flagellum. The flagellum ‘beats’ and drives the parasite forwards, enabling parasites to move between different human tissues and organs and to navigate towards mouth parts of insects so they can inoculate new hosts. If flagellum function is impaired, trypanosomes and their cousins are unable to cause an infection and unable therefore to cause disease. Recently, I discovered two proteins that are essential for building key structures in the flagellum; without these structures the parasite becomes paralysed and quickly dies. Understanding how these proteins function will pave the way to the development of drugs that block flagellar function as an approach to treating these terrible diseases. Finally, flagella work on common principles: their intrinsic biology and powerful molecular tools make trypanosomes an unrivalled system to investigate flagellum biology. This project therefore provides opportunities to make discoveries that will be important and relevant to those working on flagella of other systems.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION