Latent tuberculosis infection in high TB disease burden countries dysregulates cellular and immunological profiles which is further enhanced with uncontrolled hyperglycemia

Abstract

Tuberculosis (TB) and diabetes mellitus (DM) are both highly prevalent in Pakistan. Latent Mycobacterium tuberculosis (Mtb) infection is common however the effect of DM and latent TB infection (LTBI) is less understood. We used RNA arrays to study host transcriptional responses to investigate this. Participants were controls (EC) and with DM, sub-classified to LTBI and DM-LTBI. Host blood transcriptomes were studied using microarrays followed by GO, WikiPathway and reactome pathway analyses. Gene expression compared with EC revealed 187 differentially expressed genes (DEGs) associated with LTBI; 182 DEGs with DM and 13 DEGs with DM-LTBI. In LTBI and DM, downregulation of antigen presentation and upregulation of inflammatory genes was evident whilst in DM, mostly immune related genes were downregulated. Comparison between LTBI-DM and LTBI revealed 321 up- and 12 downregulated DEGs, with upregulated immune response and inflammatory genes whilst a downregulation of genes associated with insulin metabolism and oxidative stress were observed. The impact of uncontrolled hyperglycemia was seen as downregulation in protein synthesis and oxidative phosphorylation in the host. This effect was further enhanced in those with hyperglycemia within the LTBI-DM group. Importantly, our observations of dysregulated pathways observed in diabetic individuals fit with earlier reports. We show that LTBI and DM synergistically increase host inflammatory and metabolic processes whilst reducing innate immunity. Such dysregulation by uncontrolled hyperglyemia highlights increased risk of progression of Mtb infection in this cohort and emphasizes the need for diabetes control in a TB endemic population.