Accelerated epigenetic ageing linked to detrimental outcomes of combined diabetes-tuberculosis and post-tuberculosis disease

TanDeM-AGE

About this project

Hypothesis

Mycobacterium tuberculosis leads to an estimated 1.6 million deaths annually, more than any other infectious pathogen. Even when cured from a microbiological standpoint, tuberculosis (TB) patients remain under the spectre of ‘post-TB disease’, with chronic respiratory and cardiovascular sequelae and increased mortality. Diabetes mellitus (DM), which affects 1 in 10 adults globally, increases the risk of TB and complicates TB treatment outcomes. As such, the growing burden of DM, coupled with the ongoing TB epidemic has a huge socio-economic and healthcare-associated impact globally, 3 in 4 adults with diabetes living in low- and middle-income countries. In Europe, this is particularly true for Eastern Europe, especially Romania, which continues to have an incidence of 45 per 100.000 individuals. 1–3

To the best of our knowledge, most studies on DM and TB have focused on evaluating epidemiological links and clinical characteristics, but no previous study has examined the potential effects of DM on post-TB complications. Furthermore, no study has analysed the biological mechanisms mediating post-TB complications. Our hypothesis considered the effects of DM on TB progression, as being associated with underlying epigenetic and immune dysregulation. In the light of immune ageing being caused by both TB and DM, we hypothesise that immune ageing is accelerated in patients with TB-DM. 4,5

TanDeM-AGE (2024-2026) aims to address these propositions, by correlating epigenetic and functional data specific to immune ageing, with the long-term disease evolution of TB patients, with/ without DM, in a Romanian cohort. This is one of the first studies to assess epigenetic markers, specific to accelerated ageing in TB and post-TB and the ways in which they are affected by co-existing DM. This project not only explores current themes in the field of TB, but builds upon and recontextualizes two past projects – TANDEM and RID-TB.

Objectives

The overall objective of the project revolves around decoding the underlying mechanisms of epigenetic and immune-mediated ageing, stemming from the combined diagnosis of TB and DM type II.
The specific objectives of TanDeM-AGE include:
1. Assessing the impact of DM on epigenetic aging in TB patients, at the moment of diagnosis;
2. Analysing DM evolution for TB patients during case management, and studying its impact on the progression of post-TB disease;
3. Evaluating epigenetic ageing in “post-TB” – TB patients, several years after the end of anti-tuberculosis therapy;
4. Evaluating epigenetic signatures, in correlation with “post-TB” immune dysregulation;
5. Identifying the immune cells and pathways involved in the immune dysregulation occuring in post-TB patients, in the absence of a DM diagnosis.

The epidemiological data obtained for the long-term effects of post-TB disease, including the risk of DM, will be informative for public health strategies. The mechanistic studies included in TanDeM-AGE will identify long-term methylation profiles of immune dysregulation in TB and post-TB disease and the effect of DM on these patterns; the detailed phenotyping will indicate dysfunctional cell types and affected pathways. We wish for our study to ultimately provide potential targets for mitigating post-infectious complications and accelerated immune aging.

1.     Implications of the global increase of diabetes for tuberculosis control and patient care – Ruslami – 2010 – Tropical Medicine & International Health – Wiley Online Library. https://onlinelibrary.wiley.com/doi/10.1111/j.1365-3156.2010.02625.x.
2.     Facts & figures. International Diabetes Federation https://idf.org/about-diabetes/diabetes-facts-figures/.
3.     TB profile. https://worldhealthorg.shinyapps.io/tb_profiles/?_inputs_&entity_type=%22country%22&lan=%22EN%22&iso2=%22RO%22.
4.     Immune aging in diabetes and its implications in wound healing – PMC. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322932/.
5.     Esmail, H., Macpherson, L., Coussens, A. K. & Houben, R. M. G. J. Mind the gap – Managing tuberculosis across the disease spectrum. EBioMedicine 78, 103928 (2022).

Teams

Our research team at the Medical Genetics Department of UMF Cluj-Napoca studies the mechanisms of inflammatory diseases and their interrelationship with individual genetic susceptibility factors. We are curious how the variance in our genome or epigenome can alter the immunological processes and cause inflammatory disease. We assess immunological functions of primary cells in patient cohorts and in controls and we use multi-omics to assess the different molecular layers that can contribute to inflammatory dysregulation. Currently, we are investigating the mechanisms of immune memory associated to long term proinflammatory effects and accelerated immunological aging in gout, hyperuricemia, systemic sclerosis and other autoinflammatory and autoimmune disorders.

Craiova Human genomics

Cluj Functional Genomics

Cluj Medical Genetics

Cluj Rheumatology

Cluj Infectious Diseases

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