Association of Diabetes Mellitus With a Shared Hyperinflammatory Immune Response in Patients With Melioidosis and Patients With Tuberculosis: An Observational Case-Control Study.

Background: Melioidosis is a serious infection caused by the bacterium Methods: Eighty-one patients with acute melioidosis from Northeast Thailand and 151 patients with tuberculosis from South Africa, Indonesia, Romania, and Peru, along with uninfected control cohorts, were studied by whole-blood RNA sequencing. Both supervised and unsupervised data analysis approaches, were performed including differential gene expression, pathway, and weighted gene coexpression network analyses. Results: DM status was associated with a hyperinflammatory response to both melioidosis and tuberculosis, with increased neutrophil and platelet degranulation and exaggerated activation of coagulation and scavenger activation pathways, along with decreased phosphoinositide 3-kinase protein kinase B signaling. In melioidosis, changes with DM were subtle but also included increased tumor necrosis factor signaling via nuclear factor κB and enhancement of endoplasmic reticulum stress and unfolded protein responses. DM-related changes were more distinct in tuberculosis, with marked reduction of interferon signaling responses. Conclusions: DM is associated with enhanced nonspecific inflammatory responses in both melioidosis and tuberculosis and an impaired interferon-mediated response to tuberculosis, with implications for future host-directed therapies.