Diabetes mellitus is associated with a shared hyper-inflammatory immune response in melioidosis and tuberculosis patients: an observational case-control study

Background: Melioidosis is a serious infection caused by the bacterium Burkholderia pseudomallei with a case fatality rate of up to 40% in Northeast Thailand. Diabetes increases the risk of developing melioidosis by 12-fold. A similar, but less marked, relationship with diabetes is seen in tuberculosis (TB) patients, with a 3-fold increased risk of developing TB in people with diabetes. However, the mechanisms underlying increased susceptibility are not fully understood. Methods: 81 acute melioidosis patients from Northeast Thailand and 151 TB patients from South Africa, Indonesia, Romania and Peru alongside uninfected control cohorts were studied by whole blood RNA sequencing. Both supervised and unsupervised data analysis approaches were performed including differential gene expression (DGE) analysis, pathway analyses, and weighted gene co-expression network analysis (WGCNA). Results: Diabetes status was associated with a hyper-inflammatory response to both melioidosis and TB, with increased neutrophil and platelet degranulation, and exaggerated activation of coagulation and scavenger activation pathways, alongside decreased phosphoinositide-3-kinase protein kinase B (P13K-Akt) signalling. In melioidosis, changes with diabetes were subtle but also included increased tumour necrosis factor (TNF) signalling via nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) and enhancement of endoplasmic reticulum stress and unfolded protein responses. Diabetes-related changes were more distinct in TB, with marked reduction of interferon signalling responses. Conclusion: Diabetes is associated with enhanced non-specific inflammatory responses in both melioidosis and TB and an impaired interferon-mediated response to TB, with implications for future host-directed therapies.