College of Animal Science and Technology, Northwest A&F University, Yangling, 712100, China.
College of Animal Science and Technology, Northwest A&F University, Yangling, 712100, China.
Antiviral Res. 2022 Jul;203:105346. doi: 10.1016/j.antiviral.2022.105346. Epub 2022 May 21.
Most pathogens utilize mucosal surfaces to enter and propagate within the host. As one of the main pathogens of fatal and highly contagious diseases, rhabdoviruses are distributed widely in nature affecting both human and animals. Therefore, local mucosal immune responses, most effectively induced by mucosal vaccines, act as frontline immunity to block the pathogens at its initial replication sites. However, the underlying regulatory mechanisms of mucosal immunity triggered by mucosal vaccine remains unclear. Herein, a rhabdoviruses glycoprotein-based mucosal vaccine (G131c) was used to elucidate the regulatory mechanism of local mucosal immunity in zebrafish, a typical immunological model. Firstly, we verified the strong immunoprotection of G131c mucosal vaccine. Furthermore, the delivery kinetics of G131c was evaluated in vivo, indicating the effective uptake of vaccines by mucosal tissues through immersion vaccination. Importantly, we demonstrate immersion with G131c vaccine could activate antigen presenting cells (APCs) at the local mucosal sites, and then arose robust local mucosal and systemic immune responses. More critically, we found that G131c mediated these immune effects by interacting with Toll-like receptor 2 (TLR2) and activating downstream MAPK and NF-κB signaling pathways. Thus, our findings provide previously unappreciated evidence that rhabdovirus glycoprotein could interact with TLR2 and then activate the APCs in local mucosal sites. This study provides a comprehensive perspective on the mechanism of TLR2-mediated mucosal immunity in the early vertebrates.
大多数病原体利用黏膜表面进入并在宿主内繁殖。作为致命性和高度传染性疾病的主要病原体之一，弹状病毒广泛分布于自然界，影响人类和动物。因此，局部黏膜免疫反应，最有效地通过黏膜疫苗诱导，作为阻止病原体在初始复制部位复制的第一道防线。然而，黏膜疫苗引发的黏膜免疫的潜在调节机制尚不清楚。在此，我们使用一种基于弹状病毒糖蛋白的黏膜疫苗（G131c）来阐明斑马鱼（一种典型的免疫模型）局部黏膜免疫的调节机制。首先，我们验证了 G131c 黏膜疫苗的强大免疫保护作用。此外，我们在体内评估了 G131c 的递呈动力学，表明通过浸泡免疫，疫苗可被黏膜组织有效摄取。重要的是，我们证明 G131c 疫苗浸泡可激活局部黏膜部位的抗原呈递细胞（APC），从而引发强烈的局部黏膜和全身免疫反应。更重要的是，我们发现 G131c 通过与 Toll 样受体 2（TLR2）相互作用并激活下游 MAPK 和 NF-κB 信号通路来介导这些免疫效应。因此，我们的研究结果提供了以前未被认识到的证据，即弹状病毒糖蛋白可以与 TLR2 相互作用，然后激活局部黏膜部位的 APC。本研究为 TLR2 介导的早期脊椎动物黏膜免疫机制提供了全面的视角。
