Priming and Activation of Inflammasome by Canarypox Virus Vector ALVAC via the cGAS/IFI16-STING-Type I IFN Pathway and AIM2 Sensor.
Priming and Activation of Inflammasome by Canarypox Virus Vector ALVAC via the cGAS/IFI16-STING-Type I IFN Pathway and AIM2 Sensor.
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DOI：
10.4049/jimmunol.1700698
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发表时间：
2017-11-01
期刊：
影响因子：
--
通讯作者：
Hu H
中科院分区：
文献类型：
--
作者：
Liu F;Niu Q;Fan X;Liu C;Zhang J;Wei Z;Hou W;Kanneganti TD;Robb ML;Kim JH;Michael NL;Sun J;Soong L;Hu H
来源于不同病毒家族的病毒载体，包括痘病毒(金丝雀痘病毒载体ALVAC)和腺病毒(人Ad5载体)，已被广泛用于包括HIV/AIDS在内的一系列人类疾病的疫苗开发。关于宿主对这些载体的先天反应机制，我们知之甚少。来自测试不同病毒载体的临床疫苗试验的越来越多的证据表明，了解宿主-病毒载体相互作用的基本要素的重要性。在这项研究中，我们研究了抗原提呈细胞(APC)与两个常用的HIV疫苗载体ALVAC和Ad5的天然相互作用，并在此报告了AIM2是ALVAC在人和小鼠APC中引发强烈炎症小体激活的固有传感器。基因芯片和全面的基因敲除分析(CRISPR/Cas9)证实，ALVAC刺激cGAS/IFI16-STING-I型干扰素途径启动AIM2，这是ALVAC诱导的炎症体激活所必需的功能。我们还提供了与ALVAC不同的证据，Ad5载体本身不能诱导炎性小体激活，这与其不能刺激刺激型I型干扰素途径和提供炎性小体启动信号有关。在预适应的APC中，Ad5载体可通过AIM2非依赖机制刺激炎性小体激活。因此，我们的研究确定AIM2炎症体和cGAS/IFI16-STING-I型干扰素途径是宿主对ALVAC疫苗载体天然免疫的新机制。
Viral vectors derived from different virus families, including poxvirus (canarypox virus vector ALVAC) and adenovirus (human Ad5 vector), have been widely used in vaccine development for a range of human diseases including HIV/AIDS. Less is known about mechanisms underlying host innate response to these vectors. Increasing evidence from clinical vaccine trials testing different viral vectors has suggested the importance of understanding basic elements of host-viral vector interactions. In this study, we investigated the innate interactions of antigen presenting cells (APCs) with two commonly used HIV vaccine vectors, ALVAC and Ad5, and herein reported identification of AIM2 as an innate sensor for ALVAC triggering strong inflammasome activation in both human and mouse APCs. Microarray and comprehensive gene knockout analyses (CRISPR/Cas9) identified that ALVAC stimulated the cGAS/IFI16-STING-Type I IFN pathway to prime AIM2, which was functionally required for ALVAC-induced inflammasome activation. We also provided evidence that different from ALVAC, Ad5 vector itself was unable to induce inflammasome activation, which was related to its inability to stimulate STING-Type I IFN pathway and to provide inflammasome priming signals. In pre-conditioned APCs, Ad5 vector could stimulate inflammasome activation through AIM2-independent mechanism. Therefore, our study identifies AIM2 inflammasome and cGAS/IFI16-STING-Type I IFN pathway as novel mechanism for host innate immunity to ALVAC vaccine vector.
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DOI：
10.4049/jimmunol.1302569
发表时间：
2014-05-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
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DOI：
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发表时间：
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影响因子：
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