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 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.

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.