Delayed activation of host innate immune pathways in streptozotocin-induced diabetic hosts leads to more severe disease during infection with Burkholderia pseudomallei
Delayed activation of host innate immune pathways in streptozotocin-induced diabetic hosts leads to more severe disease during infection with Burkholderia pseudomallei
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DOI：
10.1111/j.1365-2567.2011.03544.x
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发表时间：
2012-04-01
期刊：
影响因子：
6.4
通讯作者：
Nathan, Sheila
中科院分区：
文献类型：
--
作者：
Chin, Chui-Yoke;Monack, Denise M.;Nathan, Sheila
糖尿病是类鼻疽的诱发因素，导致感染鼻疽伯克霍尔德菌的糖尿病患者死亡率较高。为了研究糖尿病如何改变炎症反应，我们建立了链脲佐菌素（STZ）诱导的糖尿病小鼠急性期类鼻疽模型。在 42 小时的感染过程中，在血液、肝脏和脾脏中始终检测到与假鼻疽细胞类似的活 B. 菌，但高血糖环境并未增加细菌负荷。然而，24小时后，粒细胞计数因感染而增加，而血糖浓度在感染过程中下降。对 STZ 糖尿病小鼠急性类鼻疽肝脏的全基因组表达分析发现，在 STZ 糖尿病小鼠中，有 1000 个类似基因的表达发生了改变。将 STZ 糖尿病宿主转录反应与我们小组最近报道的正常血糖宿主转录反应进行了比较。微阵列数据表明，升高的葡萄糖水平的存在会延迟对类似于假鼻疽表面结构的 B. 的识别和识别，从而损害宿主先天免疫系统。因此，随着时间的推移，宿主无法激活适当的先天免疫反应，这可能解释了 STZ 糖尿病宿主对类鼻疽的易感性增加。尽管如此，STZ-糖尿病宿主仍然会触发感染的一般警报信号以及防御程序，尽管仅在感染后 24 小时。总之，本研究表明，面对类鼻疽伯克氏菌急性感染，血糖控制不佳会损害类鼻疽伯克氏菌感染早期的先天反应，导致 STZ 诱导的糖尿病患者对这种致命疾病的易感性增加。
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.similar to 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 similar to 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.similar to 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.similar to pseudomallei acute infection, poor glycaemic control impaired innate responses during the early stages of B.similar to pseudomallei infection, contributing to the increased susceptibility of STZ-induced diabetics to this fatal disease.