Caspase-2 mediated apoptotic and necrotic murine macrophage cell death induced by rough Brucella abortus.
Caspase-2 mediated apoptotic and necrotic murine macrophage cell death induced by rough Brucella abortus.
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DOI：
10.1371/journal.pone.0006830
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发表时间：
2009-08-28
期刊：
影响因子：
3.7
通讯作者：
He Y
中科院分区：
文献类型：
--
作者：
Chen F;He Y
布鲁氏菌是引起人畜共患布鲁氏菌病的革兰氏阴性兼性胞内细菌。巨噬细胞内的存活和复制是建立慢性布鲁氏菌感染的关键。强毒光滑流产杆菌2308株可抑制巨噬细胞程序性死亡，并在巨噬细胞内复制。牛流产巴氏杆菌疫苗株RB51是从光滑株2308衍生的一种粗制、脂多糖O抗原缺陷突变株。流产杆菌粗突变体Ra1在2308菌株中含有单一的wboA基因突变。我们的研究表明，活的RB51和Ra1，而不是2308菌株或热灭活的布鲁氏菌，能诱导RAW264.7巨噬细胞和骨髓源性巨噬细胞的凋亡和坏死。在原代小鼠腹膜巨噬细胞中也观察到了同样的现象，这些巨噬细胞是用疫苗株RB51进行腹膜内免疫的，剂量与保护性研究中通常使用的剂量相同。Caspase-2抑制剂(Z-VDVAD-FMK)可抑制RB51和Ra1诱导的巨噬细胞程序性死亡。感染RB51和Ra1的巨噬细胞在感染早期可观察到caspase-2酶的激活和裂解，而2308株未见caspase-2酶的激活和裂解。抑制巨噬细胞死亡促进了粗布氏杆菌细胞在巨噬细胞内的存活。用caspase-2特异的shRNA证实caspase-2在粗制流产杆菌诱导巨噬细胞死亡中的关键作用。毛种布鲁氏菌感染的巨噬细胞线粒体膜通透性增加，细胞色素c释放到细胞质，激活了线粒体的凋亡途径。这些结果表明，流产巴氏杆菌粗品株RB51和Ra1诱导了caspase-2介导的小鼠巨噬细胞的凋亡和坏死。讨论了布鲁氏菌O抗原和caspase-2介导的巨噬细胞死亡在布鲁氏菌发病机制和保护布鲁氏菌免疫中的生物学意义。
Brucella species are Gram-negative, facultative intracellular bacteria that cause zoonotic brucellosis. Survival and replication inside macrophages is critical for establishment of chronic Brucella infection. Virulent smooth B. abortus strain 2308 inhibits programmed macrophage cell death and replicates inside macrophages. Cattle B. abortus vaccine strain RB51 is an attenuated rough, lipopolysaccharide O antigen-deficient mutant derived from smooth strain 2308. B. abortus rough mutant RA1 contains a single wboA gene mutation in strain 2308. Our studies demonstrated that live RB51 and RA1, but not strain 2308 or heat-killed Brucella, induced both apoptotic and necrotic cell death in murine RAW264.7 macrophages and bone marrow derived macrophages. The same phenomenon was also observed in primary mouse peritoneal macrophages from mice immunized intraperitoneally with vaccine strain RB51 using the same dose as regularly performed in protection studies. Programmed macrophage cell death induced by RB51 and RA1 was inhibited by a caspase-2 inhibitor (Z-VDVAD-FMK). Caspase-2 enzyme activation and cleavage were observed at the early infection stage in macrophages infected with RB51 and RA1 but not strain 2308. The inhibition of macrophage cell death promoted the survival of rough Brucella cells inside macrophages. The critical role of caspase-2 in mediating rough B. abortus induced macrophage cell death was confirmed using caspase-2 specific shRNA. The mitochondrial apoptosis pathway was activated in macrophages infected with rough B. abortus as demonstrated by increase in mitochondrial membrane permeability and the release of cytochrome c to cytoplasm in macrophages infected with rough Brucella. These results demonstrate that rough B. abortus strains RB51 and RA1 induce apoptotic and necrotic murine macrophage cell death that is mediated by caspase-2. The biological relevance of Brucella O antigen and caspase-2-mediated macrophage cell death in Brucella pathogenesis and protective Brucella immunity is discussed.
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影响因子：
3.7
作者：
González D;Grilló MJ;De Miguel MJ;Ali T;Arce-Gorvel V;Delrue RM;Conde-Alvarez R;Muñoz P;López-Goñi I;Iriarte M;Marín CM;Weintraub A;Widmalm G;Zygmunt M;Letesson JJ;Gorvel JP;Blasco JM;Moriyón I
通讯作者：
Moriyón I
影响因子：
3.3
作者：
Bricker, BJ
通讯作者：
Bricker, BJ
影响因子：
4.2
作者：
Dahmer, MK
通讯作者：
Dahmer, MK
影响因子：
4.8
作者：
Enoksson, M;Robertson, JD;Orrenius, S
通讯作者：
Orrenius, S
影响因子：
4.4
作者：
Chen, Minjian;Gan, Huixian;Remold, Heinz G.
通讯作者：
Remold, Heinz G.