Maniam P, Kalimutho M, Embi N, Sidek H M
School of Biosciences and Biotechnology, Faculty of Science and Technology, Universiti Kebangsaan Malaysia 43600 UKM Bangi, Selangor, Malaysia.
Signal Transduction Laboratory, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, QLD 4006, Australia.
Trop Biomed. 2018 Mar 1;35(1):228-238.
Burkholderia pseudomallei, the etiologic agent of melioidosis is a common cause of sepsis mainly in diabetic individuals in South East Asia. Glycogen synthase kinase-3β (GSK3β) plays a pivotal role in modulating inflammatory balance in Gram-negative bacterial infections. In this study, we demonstrate that inhibition of GSK3β significantly improved survival of hyperglycaemic mice acutely infected with B. pseudomallei. With GSK3β inhibition, we found significant modulation between pro- (IL-12, TNF-alpha) and anti-inflammatory (IL10) serum cytokines which may have contributed to bacterial clearance in multiple organs of B. pseudomallei-infected hyperglycaemic mice. Concurrently, an increase in phosphorylation of GSK3β at Ser-9 was observed in the liver of B. pseudomallei-infected hyperglycaemic mice. Likewise, B. pseudomallei-infected non-hyperglycaemic mice upon GSK3β inhibition showed similar trends of bacterial clearance and modulation of serum cytokines; however, the effect of enhanced survival was less substantial than in infected hyperglycaemic mice. Taken together, we demonstrate that inhibition of GSK3β confers survival advantage of hyperglycaemic mice infected with B. pseudomallei and offers a potential therapeutic strategy for the treatment of diabetic patients with melioidosis.
类鼻疽杆菌是类鼻疽病的病原体，主要是东南亚糖尿病患者败血症的常见病因。糖原合酶激酶-3β（GSK3β）在调节革兰氏阴性菌感染中的炎症平衡方面起关键作用。在本研究中，我们证明抑制GSK3β可显著提高急性感染类鼻疽杆菌的高血糖小鼠的存活率。通过抑制GSK3β，我们发现促炎（IL-12、TNF-α）和抗炎（IL10）血清细胞因子之间存在显著调节，这可能有助于清除类鼻疽杆菌感染的高血糖小鼠多个器官中的细菌。同时，在类鼻疽杆菌感染的高血糖小鼠肝脏中观察到Ser-9处GSK3β磷酸化增加。同样，抑制GSK3β后，类鼻疽杆菌感染的非高血糖小鼠也显示出类似的细菌清除和血清细胞因子调节趋势；然而，提高存活率的效果不如感染的高血糖小鼠显著。综上所述，我们证明抑制GSK3β可使感染类鼻疽杆菌的高血糖小鼠具有生存优势，并为治疗类鼻疽病糖尿病患者提供了一种潜在的治疗策略。
