Arthropod vector-based vaccines for leishmaniasis

描述(申请人提供)：吸血节肢动物疾病媒介的唾液中含有具有强大药理或免疫抑制作用的分子。这些分子帮助媒介获得血餐，这些分子也无意中增强了这些媒介传播的病原体的传染性(节肢动物在皮肤中探测血餐，并可以将病原体传播到它们唾液中的皮肤)。沙蝇(利什曼病的媒介)的唾液极大地加剧了小鼠对利什曼原虫的感染，并可以确定利什曼原虫是否能够成功地在宿主中建立感染。这些观察表明，通过接种针对病媒唾液中允许病原体在宿主中建立感染的分子的疫苗，可能有可能为人类接种预防媒介传播疾病的疫苗。现在已经清楚的是，沙蝇Lutzmyia long gipalpis唾液中的Maxadilan(Max)具有双重功能：它是一种强大的血管扩张剂，也是免疫反应的调节剂。它通过与垂体腺苷酸环化酶激活多肽(PACAP)受体的相互作用来介导这些效应，并影响巨噬细胞的各种功能。MAX可替代全唾液，与全唾液一样可加重利什曼原虫感染。我们还与MAX一起生产了一种基于蛋白质的疫苗，并表明它可以诱导小鼠对利什曼原虫加上全唾液的攻击产生深刻的保护。 这项应用将探索MAX对免疫系统的影响，扩展和改进我们针对MAX的疫苗配方，并生产利用MAX和可能的其他唾液靶标的改进的基于沙蝇的疫苗。此外，该应用程序将探索我们在小鼠模型中使用MAX的发现与人类模型系统的相关性，以确定MAX是否像影响老鼠细胞一样影响人类细胞，以及人类对MAX和其他唾液分子的免疫反应程度。 节肢动物传播世界上一些最严重的疾病(疟疾、登革热、莱姆河、西尼罗河和许多其他疾病)，新的节肢动物传播疾病频繁出现。此外，由于生物恐怖主义，我们在节肢动物传播疾病的地方性地区部署了越来越多的部队。目前还没有有效的方法来控制这些疾病。迫切需要新的和有效的方法(特别是像这里描述的那样的新型疫苗方法)。

DESCRIPTION (provided by applicant): The saliva of blood-sucking arthropod vectors for disease contains molecules that have either potent pharmacological or immunosuppressive effects. These molecules aid the vector in obtaining a blood meal and these molecules also inadvertently enhance the infectivity of the pathogens that these vectors transmit (arthropods probe in the skin for a blood meal and can deliver pathogens to the skin within their saliva). The saliva of the sand fly (the vector for leishmaniasis) dramatically exacerbates infection with Leishmania in mice and can determine whether Leishmania is able to successfully establish infection in the host. These observations suggested that it may be possible to vaccinate humans against vector-borne diseases by vaccinating against the molecules in vector saliva that allow the pathogen to establish infection in the host. It is now clear maxadilan (MAX) in the saliva of the sand fly Lutzomyia longipalpis has dual functions: it is a potent vasodilator and also a modulator of the immune response. It mediates these effects via interaction with the pituitary adenylate cyclase activating polypeptide (PACAP) receptor and affects various functions of macrophages. MAX substitutes for whole saliva and exacerbates infection with Leishmania to the same extent as whole saliva. We have also produced a protein-based vaccine with MAX and have shown that it can induce profound protection in mice against challenge with Leishmania plus whole saliva. This application will explore the effects of MAX on the immune system, extend and refine our vaccine formulations against MAX and produce improved sand fly-based vaccines that utilize MAX and possibly other salivary targets. In addition, the application will explore the relevance of our findings with MAX in a mouse model to human model systems to determine whether MAX affects human cells as it does mouse cells and to what extent humans mount an immune response to MAX and other salivary molecules. Arthropods transmit some of the most serious diseases in the world (malaria, dengue, Lyme, West Nile, and many many more) and new arthropod-borne diseases emerge frequently. Moreover, because of bioterrorism, we station more and more troops in areas endemic for arthropod-borne diseases. There are currently no effective ways to control these diseases. New and effective methods (especially novel vaccine approaches such as the one described here) are sorely needed.