Delayed activation of host innate immune pathways in streptozotocin‐induced diabetic hosts leads to more severe disease during infection with Burkholderia pseudomallei

Abstract

Summary Diabetes mellitus is a predisposing factor of melioidosis, contributing to higher mortality rates in diabetics infected with Burkholderia pseudomallei. To investigate how diabetes alters the inflammatory response, we established a streptozotocin (STZ) ‐induced diabetic murine acute‐phase melioidosis model. Viable B. pseudomallei cells were consistently detected in the blood, liver and spleen during the 42‐hr course of infection but the hyperglycaemic environment did not increase the bacterial burden. However, after 24 hr, granulocyte counts increased in response to infection, whereas blood glucose concentrations decreased over the course of infection. A genome‐wide expression analysis of the STZ‐diabetic murine acute melioidosis liver identified ∼ 1000 genes whose expression was altered in the STZ‐diabetic mice. The STZ‐diabetic host transcriptional response was compared with the normoglycaemic host transcriptional response recently reported by our group. The microarray data suggest that the presence of elevated glucose levels impairs the host innate immune system by delaying the identification and recognition of B. pseudomallei surface structures. Consequently, the host is unable to activate the appropriate innate immune response over time, which may explain the increased susceptibility to melioidosis in the STZ‐diabetic host. Nevertheless, a general ‘alarm signal’ of infection as well as defence programmes are still triggered by the STZ‐diabetic host, although only 24 hr after infection. In summary, this study demonstrates that in the face of a B. pseudomallei acute infection, poor glycaemic control impaired innate responses during the early stages of B. pseudomallei infection, contributing to the increased susceptibility of STZ‐induced diabetics to this fatal disease.

Glyburide Reduces Bacterial Dissemination in a Mouse Model of Melioidosis

“…This is consistent with the fact that diabetes is associated with an impaired host response to B. pseudomallei : specifically, it impairs cytokine responses [6]–[8] and macrophage killing of intracellular B. pseudomallei [9].…”

“…Hodgson et al report increased mortality from subcutaneous B. pseudomallei infection in a murine model of diabetes (BKS.Cg-Dock7(m)+/+Lepr(db)/J mice), and found a defect in intracellular killing by peritoneal macrophages taken from diabetic animals compared to non-diabetic animals [9]. The reason behind the increased susceptibility in diabetes is unclear, but may relate to delayed or reduced cytokine production in diabetes [7], [8], [41].…”

Burkholderia pseudomallei Triggers Altered Inflammatory Profiles in a Whole-Blood Model of Type 2 Diabetes-Melioidosis Comorbidity

“…Our data are supported by a recent transcriptome analysis of innate immune responses triggered after infection of B. pseudomallei in a chemically induced diabetic mouse model. Despite comparable bacterial loads in the first 24 h of infection, differential expression profiles for genes involved in PRR signaling pathways were demonstrated for diabetic and nondiabetic mice (13). While 16 h postinfection was the earliest time point assessed in the microarray studies of diabetic mice (13), they provide further support to our data that the presence of very early defects (Ͻ3.5 h) in the ability of phagocytes from diabetic individuals to detect and respond appropriately to B. pseudomallei underlies contrasting disease progression in diabetic and nondiabetic hosts.…”

Impaired Early Cytokine Responses at the Site of Infection in a Murine Model of Type 2 Diabetes and Melioidosis Comorbidity

“…Defective function of bone-marrow derived dendritic cells (BMDC) and peritoneal elicited macrophages (PEC) in response to B. pseudomallei has previously been described using a streptozotocininduced rodent model of type 1 diabetes (T1D) (18,19). However, this model received criticism because the majority of patients with melioidosis have T2D (5), which has an etiology and pathogenesis distinct from those of T1D.…”