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

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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.