Granzyme-mediated regulation of host defense in the liver in experimental Leishmania donovani infection.
Granzyme-mediated regulation of host defense in the liver in experimental Leishmania donovani infection.
复制标题
实验性杜氏利什曼原虫感染中颗粒酶介导的肝脏宿主防御调节。
DOI：
10.1128/iai.02418-14
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发表时间：
2015
影响因子：
3.1
通讯作者：
Ma,Xiaojing
中科院分区：
文献类型：
--
作者：
Murray,HenryW;Mitchell-Flack,Marisa;Zheng,Hua;Ma,Xiaojing
在感染杜氏利什曼原虫的易感C57BL/6(B6)小鼠的肝脏中，CD8+T细胞机制需要肉芽肿聚集、巨噬细胞激活、细胞内寄生虫杀伤和自我治愈。由于穿孔素和颗粒酶A和B(GzmA和GzmB)的基因表达在感染的肝组织中增强，因此缺乏这些颗粒蛋白的B6小鼠被用来检测宿主的防御作用。不需要穿孔素或GzmA；然而，GzmB基因缺陷的小鼠(GzmB−/−、GzmB簇−/−和GzmA×B簇双基因敲除小鼠)既表现出肉芽肿组装延迟，又最初损害了对寄生虫复制的控制。由于B6小鼠的这两个缺陷仅限于早期感染，因此也对天生耐药的129/Sv小鼠进行了测试。在这种遗传环境下，GzmA×B集群DKO小鼠先天和随后的T(Th1)细胞依赖性获得性抗性(包括自愈表型)的表达完全脱轨。这些结果，在对GzmB敏感的B6小鼠和对GzmA和/或GzmB簇具有抵抗力的129/Sv小鼠中，指出了实验性内脏利什曼病肝脏中颗粒酶介导的宿主防御调节。
In the livers of susceptible C57BL/6 (B6) mice infected with Leishmania donovani, CD8+T cell mechanisms are required for granuloma assembly, macrophage activation, intracellular parasite killing, and self-cure. Since gene expression of perforin and granzymes A and B (GzmA and GzmB), cytolytic proteins linked to CD8+cell effector function, was enhanced in infected liver tissue, B6 mice deficient in these granular proteins were used to gauge host defense roles. Neither perforin nor GzmA was required; however, mice deficient in GzmB (GzmB−/−, GzmB cluster−/−, and GzmA×B cluster double knockout [DKO] mice) showed both delayed granuloma assembly and initially impaired control of parasite replication. Since these two defects in B6 mice were limited to early-stage infection, innately resistant 129/Sv mice were also tested. In this genetic setting, expression of both innate and subsequent T (Th1) cell-dependent acquired resistance, including the self-cure phenotype, was entirely derailed in GzmA×B cluster DKO mice. These results, in susceptible B6 mice for GzmB and in resistant 129/Sv mice for GzmA and/or the GzmB cluster, point to granzyme-mediated host defense regulation in the liver in experimental visceral leishmaniasis.