耐药白色念珠菌弥散性感染小鼠模型的建立

The establishment of the drug-resistant Candida albicans disseminated infected mice model

目的为新药筛选建立耐药白色念珠菌弥散性感染小鼠模型。方法对免疫抑制ICR小鼠静脉注射临床耐氟康唑白色念珠菌CaR,通过临床症状、生存情况、组织载菌量、组织病理、细胞因子分析以及药物治疗等方法对模型评价。结果 CaR感染小鼠在接种后第1天出现死亡,相比临床药敏菌株Ca S感染组,16 d观察期内动物死亡率无显著性差异(CaR,90.7%;Ca S,86.2%,P=0.158),但观察早期CaR组死亡比Ca S组快。感染第4天,不同组织均可检测到念珠菌,并发现与Ca S组相比,肾、脑组织载菌量具有显著性差异。真菌引起的典型肉芽肿样是肾、脑、心的主要组织病理学特征。利用流式细胞仪检测肾组织细胞因子,IL-1α、IL-6、TNF-α、IFN-γ等细胞因子变化显著,与Ca S组比较,IL-1α和IFN-γ显著升高,TNF-α显著下降。CaR和Ca S感染小鼠给予10 mg/kg氟康唑治疗,死亡率分别为83.3%、37.5%,具有显著性差异。结论本研究成功建立了耐药白色念珠菌弥散性感染小鼠模型,有望成为抗感染新药研发的重要工具。

Objective Establishing the drug-resistant Candida albicans disseminative infected mice model for new drug screening. Methods The disseminative infected mouse model was generated by intravenously injecting a clinical Drug-resistant Candida albicans strain（ CaR） to immunosuppressive ICR mice. The features of model was evaluated by clinical symptom,survival condition,fungal burden in tissue,histopathology,cytokines assay and medication. Results After infected with CaR（ 0 day）,the death of mice started at the first day,though,compared to clinical drug sensitive strain（ Ca S） infected group,the difference of mortality rate in 16-day observation period was not significant in two groups（ CaR,90. 7%; Ca S,86. 2%,P = 0. 158）,mice in CaR group died faster than those in Ca S group at the early stage; On the fourth day of infection,Candida albicans could be detected in the different tissues,and we found fungal burden inkidney and brain was a significant difference. The typical granuloma caused by fungal infection was the main histopathological feature observed in the kidney, brain and heart. Cytokines in renal tissue were detected by flow cytometry,The changes of IL-1α,IL-6,TNF-αand IFN-γin kidney were significant. Compared with Ca S group,IL-1 and IFN-γ were significantly higher and TNF-αdecreased significantly in CaR group. The mice of groups CaR and Ca S were treated with 10 mg / kg fluconazole,the mortality rates were 83. 3% and 37. 5%,which have a significant difference.Conclusions In this study,we successfully established a drug-resistant Candida albicans disseminative infected mice model which is potential tool for the development of new anti-infectious agent.