A bacterial flagellin, Vibrio vulnificus FlaB, has a strong mucosal adjuvant activity to induce protective immunity
A bacterial flagellin, Vibrio vulnificus FlaB, has a strong mucosal adjuvant activity to induce protective immunity
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DOI：
10.1128/iai.74.1.694-702.2006
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发表时间：
2006-01-01
影响因子：
3.1
通讯作者：
Rhee, JH
中科院分区：
文献类型：
--
作者：
Lee, SE;Kim, SY;Rhee, JH
鞭毛蛋白是宿主细胞toll样受体5 （TLR5）的配体，是多种移动细菌鞭毛丝的结构成分。各种病原体相关的分子模式刺激TLR导致先天和随后的适应性免疫反应的激活。因此，TLR配体被认为是疫苗开发中有吸引力的佐剂候选体。在这项研究中，我们展示了创伤弧菌大鞭毛蛋白（FlaB）的高效粘膜佐剂活性。通过鼻内免疫小鼠模型，我们观察到鞭毛蛋白与破伤风类毒素（TT）共同给药可显著增强粘膜和全身腔室的TT特异性免疫球蛋白A （IgA）反应以及全身腔室的IgG反应。用TT + FlaB免疫的小鼠完全免受200倍最小致死剂量破伤风毒素的全身攻击。放射标记的FlaB进入鼻腔，容易到达颈部淋巴结和体循环。FlaB直接与培养的上皮细胞上表达的TLR5结合，从而诱导nf - κ B和白细胞介素-8活化。经鼻给药的FlaB与CD11c共定位，在假定的树突状细胞中作为斑块，并导致颈淋巴结中表达tlr5的细胞数量增加。提示鞭毛蛋白可作为一种有效的粘膜佐剂，通过激活TLR5诱导保护性免疫应答。
Flagellin, the structural component of flagellar filament in various locomotive bacteria, is the ligand for Toll-like receptor 5 (TLR5) of host cells. TLR stimulation by various pathogen-associated molecular patterns leads to activation of innate and subsequent adaptive immune responses. Therefore, TLR ligands are considered attractive adjuvant candidates in vaccine development. In this study, we show the highly potent mucosal adjuvant activity of a Vibrio vulnificus major flagellin (FlaB). Using an intranasal immunization mouse model, we observed that coadministration of the flagellin with tetanus toxoid (TT) induced significantly enhanced TT-specific immunoglobulin A (IgA) responses in both mucosal and systemic compartments and IgG responses in the systemic compartment. The mice immunized with TT plus FlaB were completely protected from systemic challenge with a 200x minimum lethal dose of tetanus toxin. Radiolabeled FlaB administered into the nasal cavity readily reached the cervical lymph nodes and systemic circulation. FlaB bound directly to human TLR5 expressed on cultured epithelial cells and consequently induced NF-kappa B and interleukin-8 activation. Intranasally administered FlaB colocalized with CD11c as patches in putative dendritic cells and caused an increase in the number of TLR5-expressing cells in cervical lymph nodes. These results indicate that flagellin would serve as an efficacious mucosal adjuvant inducing protective immune responses through TLR5 activation.