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

补体成分 C1Q 在结核病和糖尿病合并症中的作用

• 批准号: MR/P017568/1
• 负责人: Jacqueline Cliff
• 金额: $ 44.93万
• 依托单位: London School of Hygiene & Tropical Medicine
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FP017568%2F1
• 关键词: Role; Complement; Component; C1Q; Tuberculosis

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.

2型糖尿病（T2DM）患者在感染后患结核病（TB）的风险是普通人群的三倍。随着T2DM的全球负担迅速增加，特别是在低收入和中等收入国家，与结核病流行日益重叠，迫切需要制定新的干预策略。补体系统是免疫系统的一部分，它可以增强免疫细胞和抗体的作用，从而更好地杀死和清除病原体。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，它们可以在级联途径中对下游组分发挥作用。在经典途径中被激活的第一个组分是C1。最近，已经发现C1q基因和蛋白质的表达在TB患者的血液中上调，尽管其确切作用尚不清楚。C1q可以增强吞噬细胞对结核分枝杆菌的杀伤作用，但也可以通过下调吞噬细胞的杀伤能力使结核分枝杆菌逃避杀伤，因为已知C1q在其他疾病中发挥调节作用。C1q活性也与2型糖尿病有关，2型糖尿病患者游离循环中C1q浓度升高，在本项目中，我们将探讨C1q是否作为结核病和2型糖尿病之间的机制联系，从而使2型糖尿病患者游离C1q升高使他们易于患结核病。此外，我们将通过研究C1q对巨噬细胞的影响来研究C1q可能如何起作用，巨噬细胞是被M.结核总之，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，该项目将作为一个平台，加强伦敦卫生与热带医学学院和Padjadaran大学之间的科学联系，并促进能力发展，特别是在印度尼西亚实验室的细胞和分子免疫技术。

项目成果

Transcriptional profiles predict treatment outcome in patients with tuberculosis and diabetes at diagnosis and at two weeks after initiation of anti-tuberculosis treatment.

• DOI: 10.1016/j.ebiom.2022.104173
• 发表时间: 2022-08
• 期刊: EBIOMEDICINE
• 影响因子: 11.1
• 作者: van Doorn, Cassandra L. R.;Eckold, Clare;Ronacher, Katharina;Ruslami, Rovina;van Veen, Suzanne;Lee, Ji-Sook;Kumar, Vinod;Kerry-Barnard, Sarah;Malherbe, Stephanus T.;Kleynhans, Leanie;Stanley, Kim;Hill, Philip C.;Joosten, Simone A.;van Crevel, Reinout;Wijmenga, Cisca;Critchley, Julia A.;Walzl, Gerhard;Alisjahbana, Bachti;Haks, Marielle C.;Dockrell, Hazel M.;Ottenhoff, Tom H. M.;Vianello, Eleonora;Cliff, Jacqueline M.
• 通讯作者: Cliff, Jacqueline M.

Impact of Intermediate Hyperglycemia and Diabetes on Immune Dysfunction in Tuberculosis.

• DOI: 10.1093/cid/ciaa751
• 发表时间: 2021-01-23
• 期刊: Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
• 作者: Eckold C;Kumar V;Weiner J;Alisjahbana B;Riza AL;Ronacher K;Coronel J;Kerry-Barnard S;Malherbe ST;Kleynhans L;Stanley K;Ruslami R;Ioana M;Ugarte-Gil C;Walzl G;van Crevel R;Wijmenga C;Critchley JA;Dockrell HM;Cliff JM;TANDEM consortium
• 通讯作者: TANDEM consortium

Impaired resolution of blood transcriptomes through tuberculosis treatment with diabetes comorbidity

合并糖尿病合并症的结核病治疗导致血液转录组分辨率受损

• DOI: 10.1101/2022.02.07.22269422
• 发表时间: 2022
• 作者: Eckold C

Impaired resolution of blood transcriptomes through tuberculosis treatment with diabetes comorbidity.

• DOI: 10.1002/ctm2.1375
• 发表时间: 2023-09
• 期刊: Clinical and translational medicine
• 影响因子: 10.6

Host transcriptional response to TB preventive therapy differentiates two sub-groups of IGRA-positive individuals.

• DOI: 10.1016/j.tube.2020.102033
• 发表时间: 2021-03
• 期刊: Tuberculosis (Edinburgh, Scotland)
• 作者: Broderick C;Cliff JM;Lee JS;Kaforou M;Moore DA
• 通讯作者: Moore DA