【摘要】 肿瘤靶向细菌是一种全新的肿瘤治疗方法,减毒沙门氏菌VNP20009是细菌介导肿瘤治疗的典型代表.VNP20009在野生型沙门氏菌背景上敲除基因msbB和purI后降低了沙门氏菌对宿主的致病力,因而具有良好的抗肿瘤疗效,得到广泛应用.以减毒沙门氏菌VNP20009为研究对象,以免疫缺陷型转基因鼠TNFR1KO小鼠为敏感模型,对VNP20009感染的毒副性及其应用范畴进行评估.研究表明,减毒沙门氏菌VNP20009对正常小鼠无明显毒副性,但对免疫缺陷型小鼠具有致死毒性,出现严重肝脾肥大以及引发全身性感染.通过体外巨噬细胞侵染实验发现,VNP20009在TNFR1敲除的巨噬细胞内能大量增殖并引发巨噬细胞死亡,导致体内巨噬细胞的大幅减少.研究认为,VNP20009仅适用于免疫力正常的宿主,但在免疫力缺陷或低下的宿主中进行应用则无安全性保障.更多还原

【Abstract】 VNP20009 is a genetically modified strain of Salmonella typhimurium and has a good anti-cancer effect wildly used in tumor therapy on animal models.For its clinical application,an accurate bio-safety assessment on sensitive models is necessary.We use TNFR1-KO mice as a susceptive model to assess the virulence of bacterial VNP20009.In this study,we find that VNP20009 restores its virulence in TNFR1-KO mice.By intraperitoneal administration or orally delivery of VNP20009,the increased lethality was observed in TNFR1-KO mice.Higher bacterial replication of VNP20009 in most tissues was found in TNFR1-KO mice than WT mice,especially in the liver and spleen.Macrophages play a critical role in the innate immune response to infection with an intracellular pathogen.We found that the number of macrophages in the spleen was significantly decreased.Then the antimicrobial ability of macrophages was analyzed by bacterial invasion assay in vitro.The macrophages with TNFR1 deficiency exhibited a reduced ability of bacteria clearance.As the extension of infection time,macrophages died.Rapid reproduction of VNP20009 resulted in macrophages to die,which might be the main cause of mortality in TNFR1-KO mice.Taken together,VNP20009 infections display strong toxicity and lethality,and the cause of death in TNFR1-KO mice is due to uncontrolled bacterial replication.The attenuated Salmonella VNP20009 is not suit for bacterial therapy applicable in host response with immunodeficiency.更多还原