Vector-targeting CLP-vaccines against tick-transmitted infections

许多由细菌、病毒和原虫引起的人类重大传染病都是通过节肢动物传播的。这包括蜱传播的螺旋体伯氏疏螺旋体（Bb），莱姆病的病原体。蜱的唾液中含有多种免疫抑制因子，这些因子对于成功地喂养蜱是必不可少的，但也被蜱传病原体利用来增强自身的传播。其中一个因素是最近表征的Ixodes（I.）肩胛骨唾液蛋白Salp 15，其通过通常抑制宿主的辅助细胞活性以及另外通过特异性结合Bb外表面蛋白OspC来增强Bb的传播，从而在细菌进入哺乳动物宿主时为细菌提供伪装衣。本项目的目的是诱导针对Salp 15的中和抗体应答，并分析其阻断小鼠中Bb传播和随后感染的潜力。为了克服Salp 15的免疫抑制活性，我们建议使用B型肝炎病毒衣壳样颗粒（CLP）作为一种有效的免疫增强蛋白抗原呈递系统。由于Salp 15的结构是未知的，我们将利用这种CLP系统的新版本，该系统允许全长蛋白质作为免疫原在很大程度上独立于其天然结构的表面展示。结合三个实验室的互补专业知识，将产生各自的Salp 15-CLP，表征并用于免疫小鼠。特异性抗体的保护潜力将在建立的Bb感染小鼠模型中确定。这项工作应该开辟新的途径，以防止Bbinfection，但除此之外，应该提供信息的适用性，抗载体疫苗作为一种新的战略，以控制节肢动物传播的病原体一般。

Many severe infectious diseases of humans caused by bacteria, viruses and protozoa are transmittedby arthropod vectors. This includes the tick-transmitted spirochete Borrelia burgdorferi (Bb), thecausative agent of Lyme disease. Tick saliva contains a cocktail of immunosuppressive factors thatare essential for successful tick feeding but which are also exploited by tick-borne pathogens toenhance their own transmission. One such factor is the recently characterized Ixodes (I.) scapularistick saliva protein Salp15, which potentiates transmission of Bb by generally inhibiting the hosts’ Thelper cell activity and, in addition, by specifically binding to the Bb outer surface protein OspC,providing a camouflage coat for the bacteria when they enter the mammalian host. The aim of thisproject is to induce neutralizing antibody responses to Salp15 and to analyze their potential to blockBb transmission and subsequent infection in mice. To overcome the immunosuppressive activity ofSalp15, we propose to use hepatitis B virus capsid-like particles (CLPs) as a potent immuneenhancingprotein antigen presentation system. Because the structure of Salp15 is unknown, we willtake advantage of a novel version of this CLP system that allows for the surface display of full-lengthproteins as immunogens largely independent of their native structure. Joining the complementaryexpertises of three laboratories, the respective Salp15-CLPs will be generated, characterized, andused to immunize mice. The protective potential of the specific antibodies will be determined inestablished mouse models of Bb infection. This work should open new avenues to protect against Bbinfection but beyond should provide information on the applicability of anti-vector vaccines as a novelstrategy to control arthropode-borne pathogens in general.