The effects of co-morbidities on blood transcriptomes in tuberculosis patients before and during treatment

The blood transcriptome in tuberculosis (TB) has been well described, it is distinct from healthy controls and other diseases, and is being developed as a biomarker for risk of disease progression, disease severity and treatment response. But TB patients, especially those from high TB-burden countries, often have comorbidities, so the described transcriptomic signature may not be an accurate representation of a typical population. Whether this signature remains constant in different patient phenotypes is an important question. The effect of HIV-1 and also type 2 diabetes (T2DM) on the transcriptomic profile of TB was investigated, using microarray and RNA-seq technology, respectively. Both comorbidities increase the risk of developing active TB, but the underlying mechanism in T2DM is unknown. The potentially beneficial effects of the anti-diabetes drug metformin, on the transcriptome of healthy donors, were also investigated, as existing reports indicate it could behave as an adjuvant for TB therapy. The effect on the TB blood transcriptome signature of HIV-1 coinfection was studied in collaboration with the PanACEA consortium, and T2DM (HbA1c > 6:5) and prediabetes (HbA1c > 5:7 & < 6:5) in the TANDEM consortium. It was found that the TB treatment response transcriptomic signatures could still be observed with HIV-1 coinfection. Both T2DM and pre-diabetes affected the blood transcriptome: increased in ammatory profile with down-regulated type I interferon response genes. This could be indicative of an enhanced immunopathological response in TB/DM and of the important role of type I interferons in susceptibility to TB. Because patients with pre-diabetes had similar transcriptomes to TB/DM, albeit of lower magnitude, it shows that even at intermediate levels of hyperglycaemia there is an immune dysfunction. Metformin had an anti-in ammatory effect in healthy donors in the context of M. tuberculosis stimulation, indicating its potentially beneficial role in TB/DM treatment.