Self-assembled flagella protein nanofibers induce enhanced mucosal immunity
Self-assembled flagella protein nanofibers induce enhanced mucosal immunity
复制标题
自组装鞭毛蛋白纳米纤维诱导增强的粘膜免疫。
DOI：
10.1016/j.biomaterials.2022.121733
复制
发表时间：
2022-09-01
期刊：
影响因子：
14
通讯作者：
Mao, Chuanbin
中科院分区：
文献类型：
--
作者：
Fu, Duo;Wang, Mengjia;Mao, Chuanbin
纳米纤维是在粘膜界面接种疫苗的潜在疫苗或佐剂。然而，它们的长度如何影响粘膜免疫尚不清楚。以长度可调鞭毛（由鞭毛蛋白自组装而成）为模型蛋白纳米纤维，研究了其与粘膜界面相互作用诱导长度依赖性免疫反应的机制。简单地说，通过调整鞭毛蛋白组装，制备了长度可控的蛋白质纳米纤维。由于细胞摄取、溶酶体损伤和线粒体活性氧的产生，较短的纳米纤维表现出更明显的toll样受体5 （TLR5）和炎症小体活化，并伴有焦亡。因此，在基于卵清蛋白的鼻内疫苗接种中，较短的纳米纤维提高了粘膜分泌物中的IgA水平，并提高了血清IgG水平。这些粘膜和系统抗体反应与纳米纤维的粘液穿透能力相关。在TC-1宫颈癌模型中，鼻内注射短纳米纤维佐剂疫苗（人乳头瘤病毒16型肽）可显著引发细胞毒性T淋巴细胞反应，强烈抑制肿瘤生长并提高生存率。这项工作表明，纳米纤维的长度依赖性免疫反应可以被阐明，用于设计用于传染病和癌症的纳米纤维疫苗和佐剂。
Nanofibers are potential vaccines or adjuvants for vaccination at the mucosal interface. However, how their lengths affect the mucosal immunity is not well understood. Using length-tunable flagella (self-assembled from a protein termed flagellin) as model protein nanofibers, we studied the mechanisms of their interaction with mucosal interface to induce immune responses length-dependently. Briefly, through tuning flagellin assembly, length-controlled protein nanofibers were prepared. The shorter nanofibers exhibited more pronounced toll-like receptor 5 (TLR5) and inflammasomes activation accompanied by pyroptosis, as a result of cellular uptake, lysosomal damage, and mitochondrial reactive oxygen species generation. Accordingly, the shorter nanofibers elevated the IgA level in mucosal secretions and enhanced the serum IgG level in ovalbumin-based intranasal vaccinations. These mucosal and systematic antibody responses were correlated with the mucus penetration capacity of the nanofibers. Intranasal administration of vaccines (human papillomavirus type 16 peptides) adjuvanted with shorter nanofibers significantly elicited cytotoxic T lymphocyte responses, strongly inhibiting tumor growth and improving survival rates in a TC-1 cervical cancer model. This work suggests that length -dependent immune responses of nanofibers can be elucidated for designing nanofibrous vaccines and adju-vants for both infectious diseases and cancer.