Adenovirus E1B 19-kilodalton protein modulates innate immunity through apoptotic mimicry.
Adenovirus E1B 19-kilodalton protein modulates innate immunity through apoptotic mimicry.
复制标题
腺病毒 E1B 19 千道尔顿蛋白通过凋亡拟态调节先天免疫。
DOI：
10.1128/jvi.02372-13
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发表时间：
2014
影响因子：
5.4
通讯作者：
Cook,JamesL
中科院分区：
文献类型：
--
作者：
Radke,JayR;Grigera,Fernando;Ucker,DavidS;Cook,JamesL
对化学或物理刺激进行细胞凋亡的细胞抑制炎症反应，但对这些刺激进行非凋亡性死亡的细胞缺乏这种活性。病毒感染后死亡的细胞是否对炎症反应表现出细胞死亡型调节作用尚不清楚。我们比较了腺病毒感染导致细胞凋亡或非凋亡性死亡对巨噬细胞炎症反应的影响。结果与传统范式的预测完全相反。由5型腺病毒（Ad 5）E1 B 19-千道尔顿（E1 B 19 K）基因缺失突变体感染诱导的细胞凋亡而死亡的细胞不抑制巨噬细胞NF-κB活化或对促炎刺激的细胞因子应答，而由E1 B 19 K感受态，野生型Ad 5抑制这些巨噬细胞炎症反应以及响应于化学损伤而经历经典凋亡的细胞。免疫抑制，E1 B 19 K相关的细胞死亡活动依赖于直接接触的病毒感染的尸体与响应巨噬细胞。用哺乳动物Bcl-2基因替换病毒E1 B19 K基因，可恢复病毒感染细胞的非凋亡、免疫抑制性细胞死亡活性。这些结果定义了抗凋亡腺病毒E1 B 19 K蛋白的新功能，其可以在病毒感染细胞在感染部位的积累期间限制局部宿主先天性免疫炎症，并表明E1 B 19 K缺失的复制型腺病毒载体可能比E1 B 19 K阳性载体诱导更大的对病毒感染细胞的炎症反应，因为他们失去了...重要提示：我们观察到腺病毒感染诱导的非凋亡性细胞死亡抑制了巨噬细胞的促炎反应，而E1 B 19 K缺失突变病毒感染诱导的凋亡性细胞死亡并不抑制巨噬细胞的促炎反应。巨噬细胞促炎反应和增强一些细胞因子反应。我们的研究结果定义了一个新的功能，抗凋亡，腺病毒蛋白E1 B 19 K，我们称之为“凋亡模拟。”我们的研究表明，E1 B 19 K功能的存在或缺失可能会改变自然和治疗性腺病毒感染的免疫结果。例如，新出现的高免疫致病性腺病毒血清型可能由于E1 B 19 K功能或表达的改变而诱导宿主炎症反应增加。还可能的是，在腺病毒载体设计期间可以产生E1 B 19 K表达/功能的工程化变化，这将增加用于肿瘤细胞的疫苗或溶瘤病毒靶向的复制腺病毒载体的治疗功效。
Cells that undergo apoptosis in response to chemical or physical stimuli repress inflammatory reactions, but cells that undergo nonapoptotic death in response to such stimuli lack this activity. Whether cells dying from viral infection exhibit a cell death-type modulatory effect on inflammatory reactions is unknown. We compared the effects on macrophage inflammatory responses of cells dying an apoptotic or a nonapoptotic death as a result of adenoviral infection. The results were exactly opposite to the predictions from the conventional paradigm. Cells dying by apoptosis induced by infection with an adenovirus type 5 (Ad5) E1B 19-kilodalton (E1B 19K) gene deletion mutant did not repress macrophage NF-κB activation or cytokine responses to proinflammatory stimuli, whereas cells dying a nonapoptotic death from infection with E1B 19K-competent, wild-type Ad5 repressed these macrophage inflammatory responses as well as cells undergoing classical apoptosis in response to chemical injury. The immunorepressive, E1B 19K-related cell death activity depended upon direct contact of the virally infected corpses with responder macrophages. Replacement of the viral E1B 19K gene with the mammalian Bcl-2 gene incisrestored the nonapoptotic, immunorepressive cell death activity of virally infected cells. These results define a novel function of the antiapoptotic, adenoviral E1B 19K protein that may limit local host innate immune inflammation during accumulation of virally infected cells at sites of infection and suggest that E1B 19K-deleted, replicating adenoviral vectors might induce greater inflammatory responses to virally infected cells than E1B 19K-positive vectors, because of the net effect of their loss-of-function mutation.IMPORTANCEWe observed that cells dying a nonapoptotic cell death induced by adenovirus infection repressed macrophage proinflammatory responses while cells dying by apoptosis induced by infection with an E1B 19K deletion mutant virus did not repress macrophage proinflammatory responses and enhanced some cytokine responses. Our results define a new function of the antiapoptotic, adenoviral protein E1B 19K, which we have termed “apoptotic mimicry.” Our studies suggest the possibility that the presence or absence of this E1B 19K function could alter the immunological outcome of both natural and therapeutic adenoviral infections. For example, emerging, highly immunopathogenic adenovirus serotypes might induce increased host inflammatory responses as a result of altered E1B 19K function or expression. It is also possible that engineered variations in E1B 19K expression/function could be created during adenovirus vector design that would increase the therapeutic efficacy of replicating adenovirus vectors for vaccines or oncolytic viral targeting of neoplastic cells.