Incorporation of a bi-functional protein FimH enhances the immunoprotection of chitosan-pVP1 vaccine against coxsackievirus B3-induced myocarditis
Incorporation of a bi-functional protein FimH enhances the immunoprotection of chitosan-pVP1 vaccine against coxsackievirus B3-induced myocarditis
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双功能蛋白 FimH 的掺入增强了壳聚糖-pVP1 疫苗对柯萨奇病毒 B3 诱导的心肌炎的免疫保护作用
DOI：
10.1016/j.antiviral.2017.01.020
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发表时间：
2017-04-01
影响因子：
7.6
通讯作者：
Xiong, Sidong
中科院分区：
文献类型：
--
作者：
Fan, Xiangmei;Yue, Yan;Xiong, Sidong
病毒性心肌炎是一种常见的临床心血管疾病，主要由柯萨奇B3病毒（CVB3）引发，且无有效的治疗措施。诱导有效的黏膜免疫应答对抵抗CVB3引发的心肌炎至关重要。FimH是一种源自大肠杆菌（E. coli）的蛋白质，具有靶向M细胞的特性，并作为一种Toll样受体4（TLR4）激动剂发挥作用。在本研究中，我们将重组FimH蛋白引入我们先前开发的CVB3黏膜疫苗壳聚糖（CS） - pVP1中，旨在激发更有效的黏膜免疫应答以及对CVB3引发的心肌炎的免疫保护作用。与CS - pVP1疫苗相比，FimH - CS - pVP1免疫显著提高了CVB3特异性保护性分泌型IgA（sIgA）的水平和中和效价，增加了产生CVB3特异性IgA的B细胞的频率，并增强了肠系膜淋巴结（MLNs）中的黏膜T细胞免疫应答，尽管未能显著增强CVB3特异性的全身免疫应答。一致地，FimH - CS - pVP1组显示出对CVB3引发的心肌炎更强的免疫保护作用，这体现在心肌损伤有限、病毒载量降低以及存活率提高等指标上。进一步研究表明，这种增强的免疫保护作用不仅归因于其靶向M细胞的特性，该特性导致黏膜抗原VP1表达增强，还与FimH的黏膜佐剂效应有关，这种佐剂效应促进了生发中心（GCs）的形成、IgA诱导因子的产生以及抗原呈递细胞（APCs）的成熟。综上所述，我们在此开发了一种双功能黏膜疫苗FimH - CS - pVP1，它同时具有靶向M细胞的特性和黏膜佐剂能力，并且我们表明FimH - CS - pVP1能够比CS - pVP1更有效地诱导更高水平的CVB3特异性保护性黏膜免疫应答，并对CVB3引发的心肌炎提供更好的预防效果。（C）2017爱思唯尔有限公司。保留所有权利。
Viral myocarditis is a common clinical cardiovascular disease mainly induced by coxsackievirus B3 (CVB3) with no effective therapeutic measures. Induction of efficient mucosa] immune responses is very critical against CVB3-induced myocarditis. FimH is an Escherichia coli (E. coli)-derived protein, which possesses an M cell-targeting property and functions as a TLR4 agonist. In this study, we introduced the recombinant FimH protein, into our previously developed CVB3 mucosal vaccine chitosan (CS)-pVP1, aiming to provoke more efficient mucosal immune responses and immunoprotection against CVB3-induced myocarditis. Compared with the CS-pVP1 vaccine, immunization with FimH-CS-pVP1 remarkably increased the levels and neutralizing titers of CVB3-specific protective secretory IgA (sIgA), enhanced the frequency of CVB3-specific IgA-producing B cells and amplified mucosal T-cell immune responses in mesenteric lymph nodes (MLNs), although failing to significantly amplify CVB3-specific systemic immune responses. Consistently, FimH-CS-pVP1 group showed the enhanced immunoprotection against CVB3-induced myocarditis, evidenced by the indices of limited myocardial injury, reduced viral loads and enhanced survival rate. Further study showed that this enhanced immunoprotection was not only ascribed to its M cell-targeting property, which led to the enhanced mucosal antigen VP1 expression, but also associated with the mucosal adjuvant effect of FimH, which facilitated the formation of germinal centers (GCs), production of IgA-inducing factors and maturation of antigen-presenting cells (APCs). Taken together, here we developed a bi-functional mucosal vaccine FimH-CS-pVP1, which simultaneously possessed the M cell-targeting property and mucosal adjuvant ability, and we showed that FimH-CS-pVP1 could efficiently induce the higher levels of CVB3-specific protective mucosal immune responses and provide better prophylactic effects against CVB3-induced myocarditis than CS-pVP1. (C) 2017 Elsevier B.V. All rights reserved.