The Role of Complement Component C1Q in Tuberculosis and Diabetes Co-morbidity

2型糖尿病（T2DM）患者在感染后发生结核病（TB）的风险是一般人群的三倍。由于2型糖尿病的全球负担正在迅速增加，并且与结核病流行日益重叠，特别是在低收入和中等收入国家，迫切需要制定新的干预策略。将这两种疾病联系起来的潜在因果机制尚不清楚。补体系统是免疫系统的一部分，它增强免疫细胞和抗体的作用，使病原体能够更好地杀死和清除。补体在结核病中的作用尚未得到充分研究。补体由几种蛋白质组分组成，它们在级联途径中对下游组分发挥作用。在经典通路中被激活的第一个成分是C1。最近，人们发现结核病患者血液中C1q基因和蛋白的表达上调，尽管其确切作用尚不清楚。它可能增强了吞噬细胞对结核分枝杆菌的杀伤，但也可能通过下调吞噬细胞的杀伤能力使杆菌逃脱杀伤，因为已知C1q在其他疾病中发挥调节作用。C1q活性也与T2DM有关，在T2DM中，C1q的自由循环浓度升高。在这个项目中，我们将探讨C1q是否作为结核和T2DM之间的机制联系，因此T2DM患者游离C1q的升高使他们易患结核病。此外，我们将通过研究其对巨噬细胞的作用来研究C1q的作用机制，巨噬细胞是结核分枝杆菌感染的主要细胞类型。总之，这些研究将揭示C1q是否是结核病发展的重要调节因子，作为连接结核病易感性与T2DM发病机制的共同途径的一部分。此外，该项目将作为加强伦敦卫生与热带医学学院与Padjadjaran大学之间科学联系的平台，并促进印度尼西亚实验室的能力建设，特别是细胞和分子免疫学技术的能力建设。

People with type 2 diabetes mellitus (T2DM) have a three-fold enhanced risk of developing tuberculosis (TB) following infection than the general population. As the global burden of T2DM is rapidly growing, and increasingly overlapping with the TB epidemic particularly in low and middle income countries, there is an urgent need to develop new intervention strategies. The underlying causal mechanism linking the two diseases is unknown.The Complement system is part of the immune system which enhances the actions of immune cells and antibodies, enabling better killing and clearance of pathogens. The role of Complement in TB has not been fully investigated. Complement consists of several protein components, which can exert their effect on downstream components in a cascade pathway. The first component which is activated in the classical pathway is C1. Recently, it has been discovered that expression of C1q genes and proteins are upregulated in blood in TB patients, although its exact role is unclear. It may be acting to enhance killing of Mycobacterium tuberculosis bacilli by phagocytes, but it may also be allowing the bacilli to escape killing by down-regulating the killing ability of the phagocytes, as C1q is known to carry out a regulatory role in other diseases. C1q activity has also been implicated in T2DM, in which free circulating concentrations of C1q are elevated.In this project, we will ask whether C1q acts as a mechanistic link between TB and T2DM, such that elevated free C1q in T2DM patients predisposes them to develop TB disease. Further, we will investigate how C1q might act, by investigating its effects on macrophages, which are the main cell type infected by M. tuberculosis. Together, the studies will reveal whether C1q is an important regulator of TB disease development, as part of a common pathway linking TB disease susceptibility with T2DM pathogenesis.Additionally, the project will serve as a platform for enhancing scientific links between the London School of Hygiene & Tropical Medicine and Padjadjaran University, and facilitate capacity development particularly in cellular and molecular immunological techniques in the Indonesian laboratory.