Activation of the NLRP3 inflammasome by vault nanoparticles expressing a chlamydial epitope.
Activation of the NLRP3 inflammasome by vault nanoparticles expressing a chlamydial epitope.
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表达衣原体表位的穹窿纳米粒子激活 NLRP3 炎症小体。
DOI：
10.1016/j.vaccine.2014.11.028
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发表时间：
2015
期刊：
影响因子：
5.5
通讯作者：
Kelly,KathleenA
中科院分区：
文献类型：
--
作者：
Zhu,Ye;Jiang,Janina;Said-Sadier,Najwane;Boxx,Gale;Champion,Cheryl;Tetlow,Ashley;Kickhoefer,ValerieA;Rome,LeonardH;Ojcius,DavidM;Kelly,KathleenA
疫苗的全部潜力依赖于开发有效的递送系统和佐剂，对于开发成功的候选疫苗至关重要。我们已经证明，设计成包裹微生物表位的重组金库是高度稳定的结构，是不需要包括佐剂的表位递送的理想疫苗载体。我们研究了含有沙眼衣原体免疫原性表位--多形性膜蛋白G(PmpG)的疫苗作为疫苗而内化到人单核细胞的能力，并发挥了“天然佐剂”的作用。我们的研究表明，单核细胞与PmpG-1-vault的孵育通过需要NLRP3炎症体的过程来激活caspase-1并刺激IL-1β的分泌，组织蛋白酶B和Syk参与了炎症体的激活。我们还观察到，PmpG-1-拱顶通过一过性酸性的途径内化，导致溶酶体不稳定。此外，用PmpG-1-vault免疫小鼠，在体外用PmpG多肽再次刺激后，可诱导PmpG-1应答的CD4+细胞，这表明vault疫苗可以被设计成特异性的适应性免疫反应。我们的结论是，PmpG-1-vault疫苗可以刺激NLRP3炎症体，并诱导PmpG特异性T细胞反应。
The full potential of vaccines relies on development of effective delivery systems and adjuvants and is critical for development of successful vaccine candidates. We have shown that recombinant vaults engineered to encapsulate microbial epitopes are highly stable structures and are an ideal vaccine vehicle for epitope delivery which does not require the inclusion of an adjuvant. We studied the ability of vaults which were engineered for use as a vaccine containing an immunogenic epitope ofChlamydiatrachomatis, polymorphic membrane protein G (PmpG), to be internalized into human monocytes and behave as a “natural adjuvant”. We here show that incubation of monocytes with the PmpG-1-vaults activates caspase-1 and stimulates IL-1β secretion through a process requiring the NLRP3 inflammasome and that cathepsin B and Syk are involved in the inflammasome activation. We also observed that the PmpG-1-vaults are internalized through a pathway that is transiently acidic and leads to destabilization of lysosomes. In addition, immunization of mice with PmpG-1-vaults induced PmpG-1 responsive CD4+cells upon re-stimulation with PmpG peptidein vitro, suggesting that vault vaccines can be engineered for specific adaptive immune responses. We conclude that PmpG-1-vault vaccines can stimulate NLRP3 inflammasomes and induce PmpG-specific T cell responses.