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

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.

The C1q Complement component has been separately implicated in (TB), where it is upregulated in blood, and in T2DM where the proportion of free C1q is elevated due to a reduction in circulating adiponectin which usually complexes with C1q. This project will investigate C1q as a potential biological mechanism linking TB susceptibility and T2DM.

C1Q gene expression (Cliff et al, JID 2013) and protein expression is elevated in TB patients' blood but its effects on macrophages are unclear. In healthy donors in the UK, we propose to 1) determine the human cellular source of C1q and whether expression is up-regulated by M. tuberculosis, and 2) determine whether C1q regulates macrophage function, including differentiation and polarisation to an alternatively activated M2 phenotype, M. tuberculosis phagocytosis and growth restriction, and cytokine production. We will exploit RNASeq technology to investigate the intracellular impact of exogenous C1q.

T2DM patients reportedly have elevated circulating free C1q, which might interfere with macrophage control of M. tuberculosis. In Bandung we propose to 1) compare C1q, C1q-adiponectin and related factors in plasma from a cohort of TB, T2DM, TB-T2DM patients and HC, to determine whether a synergistic elevation in exists in comorbidity, and 2) investigate C1q involvement in macrophage control of M. tuberculosis in T2DM patients and HC, to determine whether the results obtained in healthy donors are clinically relevant.

There is a strong capacity development component to the project, as a research assistant from Indonesia will spend 6 months receiving training in immunological laboratory skills in London. Assays will be transferred to Universitas Padjadjaran, so that immunology research can be further strengthened there to complement existing strengths in clinical and epidemiological research.

This research is intended to increase our understanding of why some people are more susceptible to developing active TB disease, whereas most people are able to contain the infection and remain healthy. In particular, people living with type 2 diabetes are three times more likely to develop TB disease once they are infected than the general population. By increasing our understanding of why some people are more likely to develop disease, we are aiming firstly to develop ways to identify those people and intervene by giving them anti-tuberculosis medicines before they become ill, and secondly to develop new host-directed treatments which boost the correct protective immune response, so that those people are able to resist the infection. The research also has far-reaching implications for TB vaccine development, as we do not really understand why the current vaccine, BCG, fails to protect against adult pulmonary TB in most TB-endemic countries, and we may gain insight into the role of a previously under-researched component of the immune system in TB.