The role of platelets in the innate inflammatory response to TB.

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Tuberculosis (TB) causes over 1.5 million deaths each year and there is increasing resistance to antibiotics used to treat the disease. There are few new anti-TB drugs, and new approaches to treating patients are required. In TB the immune system is overactive, and inflammation damages the lung tissues. This is a complex process involving a range of our own immune cells. Understanding this process better should help to identify opportunities to develop new treatments that reduce inflammation and tissue damage. There is evidence that platelets, cells in the blood that are usually associated with blood clotting, are also important in regulating the immune system. They have been shown to be important in many different diseases that involve inflammation including cancer and arthritis, but very little is known about their role and their importance in TB.Background work for this project shows that platelets increase levels of markers of inflammation that are produced by cells of the immune system when they are infected with TB. I also found that patients with TB have higher concentrations of platelet-derived factors in their blood compared to healthy controls, and these levels decreased when the patients were given TB treatment. The main idea behind my research, which is that platelets are important in regulating the human immune system's response to tuberculosis, is supported by these results.My project has 2 parts:1. I shall study the effect of platelets on production of markers of inflammation by monocytes, which are cells of the human immune system. Using techniques I have used in my previous work, I will obtain monocytes and platelets from blood taken from healthy donors. I will measure inflammatory markers produced by monocytes with and without platelets following TB infection, as well as measuring gene expression from these cells using a technique called qPCR. I will look at how platelets may affect the immune cells including studying the importance of direct contact between the platelets and the immune cells as a way of regulating inflammation and TB bacterial growth. 2. I shall then focus on the clinical importance of platelet activation in patients with TB before, during, and after anti-TB treatment. I will examine targets suggested by the work above to confirm that their effects can be demonstrated in patients as well as in cells in laboratory experiments. I shall recruit 120 adult TB patients (drug-sensitive disease only) and the same number of age- and sex-matched healthy controls. All subjects will be HIV-negative. I will collect clinical and X-ray data about the patients and any scarring left by infection with tuberculosis. Patients will have a test called spirometry to measure lung function. This will be done for TB patients at the end of their treatment, and in healthy controls for comparison. 30mls blood will be taken from patients before treatment, after 14 and 56 days, and at the end of treatment. The blood will be used to measure platelet activation and some will be frozen at -70C for later measurement of platelet factors, and the remainder used to obtain platelet and white blood cell counts. Some patients will have a procedure called a bronchoscopy as part of their clinical care. Fluid from the lungs will be obtained from these patients, and the cells and fluid tested for evidence of platelet activity. Together, these results will allow me to understand what is happening in terms of platelets and the immune response in TB patients. In summary, this project will produce data about the role of platelets in TB. This is a new and exciting area that might affect TB treatment in the future. It will also provide me with an excellent clinical and laboratory science training that I need to progress as a clinical academic.