Vaccination against Zika virus infection using mosquito NeSt1 protein

节肢动物传播的病毒(虫媒病毒)对人类和动物的健康构成严重威胁 全世界。它们是通过食血节肢动物传播的，其中蚊子是 主要的发射机。埃及伊蚊是埃及伊蚊的主要传播媒介。 几种广泛传播的虫媒病毒，如寨卡病毒、登革热病毒或西尼罗河病毒。蚊子传播 这些病原体是通过在探测过程中将感染病毒的唾液接种到宿主皮肤中来实现的 喂食。这种唾液含有一百多种独特的蛋白质，这些蛋白质有不同的 功能，包括促进血液喂养。已知这些蛋白质中的一些可以增强 寨卡病毒和其他虫媒病毒通过调节免疫反应的传染性和致病机制，以及 开发针对它们的阻断疗法可能是减少 在宿主中的传染性和致病力。此外，重点关注蚊子蛋白作为疫苗 靶标可以克服使用病毒抗原作为疫苗靶标的相关问题， 由于它们具有很高的可变性。 在这项计划中，我们将开发一种新型的寨卡病毒传播阻断疫苗(ZIKV) 通过靶向埃及伊蚊细菌反应蛋白1(AgBR1)和埃及伊蚊中性粒细胞 刺激因子1(NeSt1)唾液腺蛋白。使用酵母表面显示屏，我们 鉴定了一组埃及伊蚊唾液蛋白，这些蛋白能与被反复叮咬的小鼠的血清发生反应 埃及伊蚊。用抗血清被动免疫其中两种蛋白质， AgBR1和NeSt1，使蚊虫感染ZIKV的小鼠的存活率显著增加 咬一口。同时用两种抗血清进行被动免疫显示出协同作用，导致 个体化治疗的存活率高于预期。 基于这些结果，在这项建议中，我们打算仔细检查以下物质的保护作用 阻断蚊虫AgBR1和NeSt1蛋白预防严重蚊媒ZIKV 小鼠的感染。我们将开发一种策略，主动免疫小鼠对抗这两种蛋白质 开发一种用于人类的疫苗。这种方法的成功还提供了 开发针对其他黄病毒和其他节肢动物的疫苗的功能范例- 传播的具有医学重要性的病原体。

Arthropod-borne viruses (arboviruses) present a substantial threat to human and animal health worldwide. They are transmitted by hematophagous arthropods, in which mosquitoes are one of the main transmitters. The mosquito specie, Aedes aegypti, is the primary mosquito vector of several widely spread arboviruses as zika, dengue or West Nile viruses. Mosquitoes transmit these pathogens by inoculating virus-infected saliva into host skin during probing and feeding. This saliva contains over one hundred unique proteins and these proteins have diverse functions, including facilitating blood feed. Some of these proteins are known to enhance infectivity and pathogenesis in Zika and other arboviruses by modulating immune responses, and the development of blocking therapies against them could be a good approach to reduce infectivity and pathogenesis in the host. In addition, focusing on mosquito proteins as vaccine targets can overcome the problems associated with the use of viral antigens as a vaccine targets, due to their high variability. In this proposal, we will develop a novel transmission-blocking vaccine against Zika virus (ZIKV) by targeting A. aegypti bacteria responsive protein 1 (AgBR1) and A. aegypti neutrophil stimulating factor 1 (NeSt1) salivary gland protein. Using a yeast surface display screen, we identified a set of A. aegypti salivary proteins that react with sera from mice repeatedly bitten by A. aegypti mosquitoes. Passive immunization with antiserum against two of these proteins, AgBR1 and NeSt1, resulted in significantly more survival in mice infected with ZIKV by mosquito bite. Simultaneous passive immunization with both antisera demonstrated a synergy resulting in higher survival than expected from the individual treatments. Based on these results, in this proposal we intend to carefully examine the protective effects of blocking the mosquito AgBR1 and NeSt1 proteins in preventing severe mosquito-borne ZIKV infection in mice. We will develop a strategy for actively immunizing mice against both proteins towards the development of a vaccine for use in humans. The success of this approach also offers a functional paradigm for developing vaccines against other flaviviruses and other arthropod- borne pathogens of medical importance.