Synthetic Toll like receptor-4 (TLR-4) agonist peptides as a novel class of adjuvants.
Synthetic Toll like receptor-4 (TLR-4) agonist peptides as a novel class of adjuvants.
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DOI：
10.1371/journal.pone.0030839
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Tiwari RK
中科院分区：
文献类型：
--
作者：
Shanmugam A;Rajoria S;George AL;Mittelman A;Suriano R;Tiwari RK
佐剂通过引发局部炎症来充当先天免疫反应的催化剂，而炎症通过抗原和 Toll 样受体 (TLR) 蛋白之间的相互作用而减轻。目前，大多数疫苗都是用铝佐剂配制的，铝佐剂会产生各种副作用。为了开发一类新的佐剂，TLR 蛋白的激动剂（例如细菌产物）将是自然的候选者。脂多糖 (LPS) 是革兰氏阴性菌细胞壁的主要结构成分，通过与 TLR-4 相互作用诱导脓毒性休克中观察到的全身炎症。使用 LPS 或 TLR-4 激动剂的合成肽模拟 TLR-4 和 LPS 之间的相互作用，可以潜在地调节细胞信号转导途径，从而实现与佐剂产生的类似的局部炎症反应。我们报告了使用噬菌体展示组合肽技术分离的几种肽的鉴定和活性，其功能模仿 LPS。 LPS-TLR-4 相互作用的活性通过 HEK-BLUE™-4 细胞（一种仅表达 TLR-4 的细胞培养模型）和鼠巨噬细胞系 RAW264.7 中的 NF-κB 核易位分析进行评估。此外，LPS 肽模拟物能够诱导 RAW264.7 细胞分泌炎症细胞因子。最后，对接种疫苗的 BALB/c 小鼠血清进行 ELISA 分析，结果表明 LPS 肽模拟物可充当功能性佐剂。我们的数据证明了通过与 TLR-4 相互作用来模拟 LPS 的合成肽的鉴定。这种 LPS 模拟表位-TLR-4 相互作用将允许开发和使用这些肽作为一类新的佐剂，即 TLR-4 激动剂。
Adjuvants serve as catalysts of the innate immune response by initiating a localized site of inflammation that is mitigated by the interactions between antigens and toll like receptor (TLR) proteins. Currently, the majority of vaccines are formulated with aluminum based adjuvants, which are associated with various side effects. In an effort to develop a new class of adjuvants, agonists of TLR proteins, such as bacterial products, would be natural candidates. Lipopolysaccharide (LPS), a major structural component of gram negative bacteria cell walls, induces the systemic inflammation observed in septic shock by interacting with TLR-4. The use of synthetic peptides of LPS or TLR-4 agonists, which mimic the interaction between TLR-4 and LPS, can potentially regulate cellular signal transduction pathways such that a localized inflammatory response is achieved similar to that generated by adjuvants. We report the identification and activity of several peptides isolated using phage display combinatorial peptide technology, which functionally mimicked LPS. The activity of the LPS-TLR-4 interaction was assessed by NF-κB nuclear translocation analyses in HEK-BLUE™-4 cells, a cell culture model that expresses only TLR-4, and the murine macrophage cell line, RAW264.7. Furthermore, the LPS peptide mimics were capable of inducing inflammatory cytokine secretion from RAW264.7 cells. Lastly, ELISA analysis of serum from vaccinated BALB/c mice revealed that the LPS peptide mimics act as a functional adjuvant. Our data demonstrate the identification of synthetic peptides that mimic LPS by interacting with TLR-4. This LPS mimotope-TLR-4 interaction will allow for the development and use of these peptides as a new class of adjuvants, namely TLR-4 agonists.
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影响因子：
8
作者：
Leung, J. Y. K.;Chapman, J. A.;Chuah, M. I.
通讯作者：
Chuah, M. I.
影响因子：
5.5
作者：
Huleatt, James W.;Jacobs, Andrea R.;Powell, T. J.
通讯作者：
Powell, T. J.
影响因子：
64.5
作者：
HASHIMOTO, C;HUDSON, KL;ANDERSON, KV
通讯作者：
ANDERSON, KV
影响因子：
1.6
作者：
Beveridge, TJ
通讯作者：
Beveridge, TJ
DOI：
10.4049/jimmunol.0902024
发表时间：
2010-05-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Ellett JD;Atkinson C;Evans ZP;Amani Z;Balish E;Schmidt MG;van Rooijen N;Schnellmann RG;Chavin KD
通讯作者：
Chavin KD