Impaired early cytokine responses at the site of infection in a murine model of type 2 diabetes and melioidosis comorbidity

Bacterial infections are a common and serious complication of type 2 diabetes (T2D). The prevalence of melioidosis, an emerging tropical infection caused by the Gram negative bacterium, Burkholderia pseudomallei, is increased in people with T2D. This is the first study to compare murine models of T2D and melioidosis. Susceptibility and disease progression following infection with B. pseudomallei was compared in our diet-induced polygenic mouse model and a leptin receptor deficient monogenic model of T2D. The metabolic profile of diet-induced diabetic mice, including body weight, blood glucose, cholesterol, triglycerides, insulin resistance and baseline levels of inflammation, closely resembled that of clinical T2D. Following subcutaneous infection with B. pseudomallei, bacterial loads at 24 and 72 hours post-infection in the blood, spleen, liver, lungs and subcutaneous adipose tissue (SAT) at the site of infection were compared in parallel with the expression of inflammatory cytokines and tissue histology. As early as 24 hours post-infection, the expression of inflammatory (IL-1ß, TNF-a, IL-6) and T(H)1 cytokines (IL-12 and IFN-?) was impaired in diabetic mice compared to non-diabetic littermates. Early differences in cytokine expression were associated with excessive infiltration of polymorphonuclear neutrophils (PMN) in diabetic mice compared to non-diabetic littermates. This was accompanied by bacteraemia, haematogenous dissemination of bacteria to the lungs and uncontrolled bacterial growth in the spleen of diabetic mice by 72 hours post-infection. The findings from our novel model of T2D and melioidosis comorbidity supports the role of impaired early immune pathways in the increased susceptibility of individuals with T2D to bacterial infections