KILLING OF MYCOBACTERIUM TUBERCULOSIS IN MACROPHAGES VIA THE P2X7 RECEPTOR

结核病仍然是一个巨大的全球健康问题。约32%的世界人口受到感染，每年有100多万人死亡。受感染个体一生中发生临床疾病的风险为2-23%。我们知道，环境因素（如社会经济条件下降）和遗传风险因素（如HLA类型）都会导致个体发生疾病的可能性，但目前已知的因素不足以充分解释遗传风险。这个项目的目的是调查另一个潜在的危险因素参与结核病的发展，P2X7受体功能。一种天然化合物，ATP，当加入巨噬细胞时，能够杀死巨噬细胞内的结核菌。这个过程发生在ATP激活P2X7受体时。我们最近发现了P2X7受体的突变，它会导致受体功能的丧失。有这种突变的个体无法对ATP产生反应，因此可能无法杀死结核病。我们的研究将确定我们在P2X7受体中发现的突变是否阻止或抑制ATP介导的分枝杆菌杀伤。此外，我们将确定这种突变在结核病患者和一般人群中的频率，以确定P2X7受体中的这种突变是否是结核病发展的一个危险因素。

Tuberculosis remains an enormous global health problem. Some 32% of the world population are infected, with over 1 million persons dying each year. The risk of an infected individual developing clinical disease ranges from 2-23% for their lifetime. We know that both environmental factors, such as declining socio-economic conditions, and genetic risk factors such as HLA type contribute to the likelihood of an individual developing disease, but current known factors are insufficient to fully account for the risk attributed to genetics. The aim of this project is to investigate another potential risk factor involved in the development of tuberculosis, that of P2X7 receptor function. A natural compound, ATP, when added to macrophages is able to kill tuberculosis organisms residing within the macrophage. This process occurs when ATP activates the P2X7 receptor. We have recently identified a mutation in the P2X7 receptor, which causes a loss of receptor function. Individuals who have this mutation are unable to respond to ATP and hence may be unable to kill tuberculosis. Our studies will determine if the mutation we have identified in the P2X7 receptor prevents or inhibits ATP mediated killing of mycobacteria. Furthermore we will determine the frequency of this mutation in TB patients and the general population to determine if this mutation in the P2X7 receptor is a risk factor for the development of tuberculosis disease.