Investigating Matrix Degradation Products in Tuberculosis

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Tuberculosis is a lung infection that spreads by people coughing. It continues to cause disease worldwide, killing over 4,000 people per day, and is becoming progressively more resistant to the antibiotics used to treat it. New innovative approaches to control the disease are urgently needed as standard diagnosis and treatment have remained largely unchanged for the last 30 years. Tuberculosis causes very extensive damage to the lungs and we have shown that this releases small fragments of lung fibrils into the bloodstream. Lung destruction differs between men and women with tuberculosis, and also when tuberculosis occurs in the context of HIV infection. Professor Paul Elkington's research group has previously studied a small number of the fragments released by infection, but as the lung is a highly complex network of interconnected fibrils many fragments will be produced in tuberculosis. This project will measure the full range of fragments using a new type of analytical system called proteomics that can identify all the proteins in a single sample. These fragments can then be used to develop tests to identify patients who are coughing tuberculosis and actively infecting others, and also to monitor the effect of new treatments.I will analyse samples that have been collected as part of other studies and include the important groups for comparison: men and women, HIV uninfected and HIV infected individuals, and patients with other respiratory conditions who have symptoms suggestive of tuberculosis. First, I will measure all the matrix breakdown products in a small number of samples using a highly sensitive but time-intensive testing system comparing patients with active tuberculosis with healthy controls. Next, I will perform detailed computational analysis of all the fragments identified and how they differ between the groups. Once the most interesting fragments are identified, I will measure these using rapid, high-throughput approaches in a much larger number of samples, including individuals with other respiratory conditions that can mimic tuberculosis to characterise the diagnostic potential as a test to exclude tuberculosis. Finally, I will study these fragments in patients of different ethnic origin and various manifestations of tuberculosis. This study will perform the first systematic investigation of lung matrix degradation products in tuberculosis and I will identify fragments that can be used to develop a new diagnostic test to break the cycle of infection. The project will also provide me with an excellent training in cutting edge medical research methods that can be used to address a wide range of human diseases.