A Multivalent Lyme Disease Vaccine Targeting Tick-Host-Pathogen Interactions

描述（由申请人提供）：本提案旨在开发一种针对莱姆病的新型疫苗——通过靶向对伯氏疏螺旋体从蜱虫传播到哺乳动物宿主至关重要的肩胛伊蚊蛋白。早期的工作已经确定了四种蜱虫蛋白，Salp15、TRE31、tHRF和TSLPI，它们促进了螺旋体传播的不同步骤，对这些蛋白的免疫分别部分地损害了螺旋体向小鼠宿主的传播。同时靶向这些蛋白质可能会破坏传播的多个步骤，并有效地阻止传播。针对这一预防莱姆病的新策略，我们将评估疫苗靶向的效果：A.将与伯氏疏螺旋体相互作用的蜱虫蛋白TRE31和Salp15组合，分别破坏促进螺旋体从肠道排出的相互作用和确保螺旋体在宿主中存活的相互作用；B.疏螺旋体辅助唾液蛋白、蜱虫唾液凝集素途径抑制剂（TSLPI）和蜱虫组胺释放因子（tHRF）的组合，它们与螺旋体没有物理关联，但在传播和蜱虫膨胀过程中分别对提高螺旋体在宿主体内的存活起着重要作用；C.疏螺旋体相互作用（Salp15和TRE31）和疏螺旋体辅助（TSLPI和tHRF）蜱虫蛋白的组合，有效阻止螺旋体到达蜱虫叮咬部位并存活。这种系统的方法迄今尚未被探索，原则上也可以适用于阻止其他节肢动物传播的病原体。这种多管齐下的脱轨方法的成功将为在II期工作中制定基于蜱抗原肽的多价莱姆病疫苗提供基础。

DESCRIPTION (provided by applicant): This proposal seeks to develop a novel vaccine against Lyme disease -- by targeting Ixodes scapularis proteins critical for Borrelia burgdorferi transmission from the tick to mammalian host. Earlier work has identified four tick proteins, Salp15, TRE31, tHRF and TSLPI, that facilitate different steps of spirochete transmission and immunity against these proteins individually provided partial impairment of spirochete transmission to the murine host. Simultaneously targeting these proteins might compromise multiple steps of transmission and effectively thwart transmission. Towards this new strategy to prevent Lyme disease, we will assess the efficacy of vaccine targeting: A. A combination of Borrelia-interacting tick proteins, TRE31, and Salp15, to impair interactions that facilitate spirochete egress from the gut and interactions that ensure spirochete survival in the host respectively; B. A combination of Borrelia-assisting salivary proteins, Tick Salivary Lectin Pathway Inhibitor (TSLPI) and tick histamine release factor (tHRF), that do not physically associate with the spirochete, but play a significant role in enhancing spirochete survival in the host during transmission and in tick engorgement respectively; and C. A combination of Borrelia-interacting (Salp15 and TRE31) and Borrelia-assisting (TSLPI and tHRF) tick proteins to effectively thwart spirochete arrival and survival at the tick bite-site. Such a systematic approach has hitherto not been explored and could in principle also be applicable to thwart other arthropod- borne pathogens. The success of this multipronged derailment approach will provide the basis for the formulation of a multivalent tick antigenic peptide-based vaccine against Lyme disease in Phase II efforts.