Host transcriptome of diabetic individuals with latent tuberculosis indicates increased downregulation of immune activation and host metabolic genes
Kiran Iqbal Masood1, Maliha Yameen1, Nanik Ram1, Qamar Masood1, Bushra Jamil1, Amina Ajmal1, Muhammad Irfan1, Jackie Cliff2, Saba Shahid1 and Zahra Hasan1*
1The Aga Khan University, Stadium Road, P.O.Box 3500, Karachi 74800, Pakistan; 2London School of Hygiene and Tropical Medicine, UK.
Submitting author email; Zahra.firstname.lastname@example.org
One third of the world’s population is thought to have latent disease (LTB) caused by infection with Mycobacterium tuberculosis (MTB). Diabetes causes a change in immune activation genes and is thought to result in unfavourable outcomes in tuberculosis (TB). We investigated the impact of LTB on DM cases in a TB endemic region using a host blood transcriptome approach.
We studied host blood transcriptome analysis in healthy endemic controls (EC), those with latent TB (LTB), diabetic individuals (DM) and DM with LTB using the Clariom S Array 21,448 gene set, Affymetrix. Cellular pathway analysis of significant differentially expressed genes (DEGs) up- or down-regulated (log FC (fold change) < -2 or > 2; FDR adjusted P value <0.05) were identified using anova test.
We found 117 differentially regulated genes (DEGs) between EC and LTB. Functional analysis of DEGs identified those related to gene regulation (56%), immune activation and cytokine signaling (20%), metabolic (16%) and host defense responses (8%); with downregulation of toll-like receptors (TLR1, TLR8 and TLR10) and HLA genes. On comparison of transcriptomes of DM with EC groups, there were 337 upregulated and 653 downregulated DEGs in DM. These were related to cell death and apoptosis (60%), gene regulation (22%), metabolic pathways, host defenses (6%) and immune activation. Upregulated genes included JAK2 and genes involved in oxidative metabolism, there was downregulation of metabolic pathways related genes. Comparison of transcriptomes between LTB-DM and DM cases showed; 1171 upregulated in DM-LTB and 1523 downregulated genes when compared with DM. Most DEGs were immune activation and cytokine signaling genes (29%), followed by Gene regulatory (11%), Metabolic (8%) pathways such as, triglyceride metabolism, insulin processing and glucose metabolism. There was upregulation of inflammatory cytokine pathways IL-1, IL-18, TNF, IL-12 and also type 2 responses such as, IL13, IL5, GMCSF and TGF beta.
We identify a combination of increased inflammation together with downregulation of metabolic pathway genes in individuals with DM who have LTB, suggesting that this modulation of function may lead to increased chance of disease progression to active TB.
This work was supported by a National Research Program University Grant #5218, Higher Education Commission, Pakistan.