Introduction: Patients with type 2 diabetes (T2D) are at increased risk of progression from latent tuberculosis (LTBI) to active tuberculosis (TB) and individuals with TB-T2D co-morbidity are more likely to fail TB treatment and relapse compared to TB patients without co-morbidities, this despite having higher circulating concentrations of Th1 and Th17 cytokines. The aim of this study was to better understand the underlying immunological mechanisms contributing to increased susceptibility of T2D patients to TB and worse TB treatment outcomes.
Methods: Whole blood samples from participants with TB +/- T2D were collected at baseline and end of treatment and from LTBI +/- T2D at a single visit. RNA was extracted from unstimulated and M. tuberculosis antigen (ESAT-6, CFP-10 and TB 7.7) stimulated whole blood and differential expression of 594 genes involved in immune regulation was determined using the Nanostring technology.
Results: We demonstrate that gene transcripts associated with innate and adaptive immune responses are differentially represented in unstimulated and antigen stimulated whole blood from TB and TB-T2D patients at baseline and month 6. Unbiased hierarchical clustering showed clear separation of TB-T2D patients from TB patients and those participants who had transient TB induced hyperglycaemia. Transcripts involved in JAK-STAT signalling pathways were significantly up-regulated in patients with TB-T2D comorbidity, whereas transcripts involved in iNOS and IL-12 signalling pathways were down-regulated. Transcriptomic differences between LTBI +/- T2D were less profound and mainly B-cell driven.
Conclusion: Our results show differential gene expression and activation of immunological pathways in TB +/- T2D and LTBI +/- T2D. Alterations of these immunological pathways may contribute to increased susceptibility of T2D patients to TB as well as delayed M. tuberculosis clearance and unfavourable TB treatment outcomes. These pathways may contain promising targets for host-directed therapeutic approaches to better treat TB-DM comorbidity.