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

Hodgson, Kelly A., Govan, Brenda L., Walduck, Anna K., Ketheesan, Natkunam, and Morris, Jodie L. (2013) Impaired early cytokine responses at the site of infection in a murine model of type 2 diabetes and melioidosis comorbidity. Infection and Immunity, 81 (2). pp. 470-477.

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Abstract

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 were compared in our diet-induced polygenic mouse model and a leptin receptor-deficient monogenic model of T2D. The metabolic profile of mice with diet-induced diabetes, 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 72h postinfection 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 24h postinfection, the expression of inflammatory (interleukin-1β [IL-1β], tumor necrosis factor alpha [TNF-α], and IL-6) and T(H)1 (IL-12 and gamma interferon [IFN-γ]) cytokines was impaired in diabetic mice compared to nondiabetic littermates. Early differences in cytokine expression were associated with excessive infiltration of polymorphonuclear neutrophils (PMN) in diabetic mice compared to nondiabetic littermates. This was accompanied by bacteremia, hematogenous dissemination of bacteria to the lungs, and uncontrolled bacterial growth in the spleens of diabetic mice by 72 h postinfection. The findings from our novel model of T2D and melioidosis comorbidity support the role of impaired early immune pathways in the increased susceptibility of individuals with T2D to bacterial infections.

Item ID: 25025
Item Type: Article (Research - C1)
ISSN: 1098-5522
Funders: James Cook University
Date Deposited: 20 Feb 2013 22:49
FoR Codes: 06 BIOLOGICAL SCIENCES > 0605 Microbiology > 060502 Infectious Agents @ 50%
11 MEDICAL AND HEALTH SCIENCES > 1108 Medical Microbiology > 110801 Medical Bacteriology @ 50%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920109 Infectious Diseases @ 100%
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