BackgroundMelioidosis is a serious infection caused by the bacterium Burkholderia pseudomallei with a case fatality rate of up to 40% in Northeast Thailand. Diabetes mellitus (DM) increases the risk of developing melioidosis by 12-fold. A similar, but less marked relationship with DM is seen in patients with tuberculosis, with a 3-fold increased risk of developing tuberculosis in people with DM. However, the mechanisms underlying the impact of DM on infection are not fully understood.MethodsEighty-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.ResultsDM 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.ConclusionsDM 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.