BBSome trafficking: investigating a novel pathway associated with virulence in Leishmania The microscopic parasite Leishmania causes a tropical infectious disease called leishmaniasis, which is particularly found in regions of extreme poverty, war and population displacement. The disease affects millions of people worldwide and causes an estimated 50,000 deaths per year. The most severe form of leishmaniasis is known as kala-azar or black fever which develops when parasites invade internal organs including the liver and spleen, causing them to swell. Kala-azar is fatal unless treated but the handful of available drugs to treat this condition are highly toxic, extremely expensive or difficult to administer, and therefore inaccessible to many infected people. The disease is spread by the bite of a sand fly, which injects thousands of tiny parasites into the skin of a human or animal host. The parasites survive inside the hostile environment of the host by rapidly invading and hiding inside cells of the immune system called macrophages. These immune cells normally engulf and kill harmful microbes but Leishmania are able to block normal responses by the macrophages and instead are able to grow and multiply inside these cells. Understanding the survival strategies of the parasite would enable us to design ways of interfering with this process and may underpin new research into development of new drugs to treat the disease. My previous research has identified a group of proteins called the BBSome which are needed for the Leishmania parasite to survive inside the host. The same set of proteins are found in humans and are known to be important in structures called primary cilia. Cilia are long slender structures that protrude from some cells in the human body which act as 'antennae' for sensing the environment and communicating with other cells. Small changes in the BBSome proteins due to genetic mutations can have a big impact, preventing the primary cilia from transmitting signals. People with these mutations have a condition called Bardet-Biedl syndrome and develop blindness, kidney problems and obesity from an early age. My experimental results suggest that the parasite BBSome may be important in communicating important signals from the parasite in a similar way to the equivalent proteins in humans. Studying how these proteins work will give us specific insights into the biology of the parasite and may also provide valuable information that is generally applicable to primary cilia in mammals. I propose to study this group of proteins in detail using a range of cutting-edge technologies to find out which molecules they interact with in the cell. Genetic engineering will be used to make specific changes to, or completely remove, selected BBSome proteins in Leishmania. The resulting microbes will be studied to find out whether they have any obvious defects in cell shape and their ability to grow. Biochemical analysis will be done to give a detailed picture of where hundreds of different proteins, carbohydrates and lipids are found within these parasites. This information will help construct a model of how the BBSome proteins help to transport molecules (including those involved in communication) from where they are made to where they are needed. I will also develop new methods for studying these microbes in the laboratory, including a new way of testing if two proteins in the cell bind to each other. Findings from the proposed research will enable us to understand more about the mechanisms the Leishmania parasite uses in order to survive and may in the long term contribute to the development of new treatments for this deadly disease. The Global Challenges Research Fund (GCRF) supports cutting-edge research to address challenges faced by developing countries. The fund addresses the UN sustainable development goals. It aims to maximise the impact of research and innovation to improve lives and opportunity in the developing world.