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首页> 外文期刊>Vaccine >Novel lipopeptides of ESAT-6 induce strong protective immunity against Mycobacterium tuberculosis: Routes of immunization and TLR agonists critically impact vaccine's efficacy
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Novel lipopeptides of ESAT-6 induce strong protective immunity against Mycobacterium tuberculosis: Routes of immunization and TLR agonists critically impact vaccine's efficacy

机译：ESAT-6的新型脂肽可诱导强大的针对结核分枝杆菌的保护性免疫：免疫途径和TLR激动剂会严重影响疫苗的功效

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Mycobacterium tuberculosis (Mtb), the bacterial cause of tuberculosis, is a leading infectious agent worldwide. The development of a new vaccine against Mtb is essential to control global spread of tuberculosis, since the current vaccine BCG is not very effective and antibiotic resistance is a serious, burgeoning problem. ESAT-6 is a secreted protein of Mtb, which is absent in BCG but has been implicated in inducing protective immunity against Mtb. Peptide based subunit vaccines are attractive due to their safety and high specificity in eliciting immune responses, but small synthetic peptides are usually not very immunogenic. We have designed a novel subunit vaccine for Mtb by using simple lipid (palmitic acid) modified derivatives of peptides from ESAT-6 protein corresponding to dominant human T cell epitopes and examined their ability to stimulate protective immunity against Mtb by intranasal and subcutaneous immunization in mice. We also investigated how individual TLR agonists as adjuvants (PolyI:C, MPL and GDQ) contribute to enhancing the induced immune responses and resulting protective efficacy of our vaccine. We observed that single C-terminal palmitoyl-lysine modified lipopeptides derived from ESAT-6 induce significant cellular immune responses on their own upon mucosal and subcutaneous immunizations. Intriguingly, a combination of immunogenic lipopeptides of ESAT-6 antigen exhibited local (pulmonary) and systemic immune responses along with efficient protective efficacy when administered intranasally or subcutaneously. Surprisingly, combination of ESAT-6 derived lipopeptides with a TLR-4 agonist (MPL) enhanced protection, whereas TLR-3 (Poly I:C) and TLR-7/8 agonists (gardiquimod, GDQ) led to reduced protection associated with specific local and systemic immune modulation. Our studies demonstrate the potential of ESAT-6 derived lipopeptides as a promising vaccine candidate against Mtb, and emphasize that selection of adjuvant is critical for the success of vaccines. These findings demonstrate the promise of synthetic lipopeptides as the basis of a subunit vaccine for TB. (C) 2016 Elsevier Ltd. All rights reserved.
机译：结核分枝杆菌是结核的细菌病原，是全球领先的传染病原体。由于目前的BCG疫苗不是很有效，而且抗生素耐药性是一个严重的新兴问题，因此开发一种新的抗Mtb疫苗对于控制结核在全球的传播至关重要。 ESAT-6是一种Mtb的分泌蛋白，它在BCG中不存在，但与诱导针对Mtb的保护性免疫有关。基于肽的亚单位疫苗由于其引发免疫应答的安全性和高特异性而具有吸引力，但是合成的小肽通常免疫原性不高。我们已经设计了一种新的Mtb亚单位疫苗，方法是使用ESAT-6蛋白的简单脂质（棕榈酸）修饰的肽衍生物（对应于人类主要T细胞表位），并研究它们通过小鼠鼻内和皮下免疫刺激针对Mtb的保护性免疫的能力。我们还研究了单独的TLR激动剂作为佐剂（PolyI：C，MPL和GDQ）如何有助于增强诱导的免疫反应和疫苗的保护功效。我们观察到，源自ESAT-6的单个C末端棕榈酰基-赖氨酸修饰的脂肽在粘膜和皮下免疫后会自行诱导明显的细胞免疫反应。有趣的是，鼻内或皮下给药时，ESAT-6抗原的免疫原性脂肽的组合表现出局部（肺）和全身免疫反应以及有效的保护功效。出乎意料的是，ESAT-6衍生的脂肽与TLR-4激动剂（MPL）的组合可增强保护作用，而TLR-3（Poly I：C）和TLR-7 / 8激动剂（gardiquimod，GDQ）导致与特异性相关的保护作用降低局部和全身免疫调节。我们的研究证明了ESAT-6衍生的脂肽作为抗Mtb的有前途的候选疫苗的潜力，并强调佐剂的选择对于疫苗的成功至关重要。这些发现证明了合成脂肽有望成为结核病亚单位疫苗的基础。 （C）2016 Elsevier Ltd.保留所有权利。

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