Arthropod vector-based vaccines for leishmaniasis

描述（由申请人提供）：疾病吸血节肢动物载体的唾液含有具有强效药理或免疫抑制作用的分子。这些分子帮助病媒获得血食，这些分子也无意中增强了这些病媒传播的病原体的传染性（节肢动物在皮肤中探测血食，并可以通过唾液将病原体运送到皮肤中）。沙蝇（利什曼病的媒介）的唾液可显著加剧小鼠对利什曼原虫的感染，并可决定利什曼原虫是否能够成功地在宿主中建立感染。这些观察结果表明，通过对媒介唾液中允许病原体在宿主中建立感染的分子进行疫苗接种，有可能为人类接种预防媒介传播疾病的疫苗。现在已经清楚沙蝇唾液中的maxadilan （MAX）具有双重功能：它是一种有效的血管舒张剂，也是一种免疫反应调节剂。它通过与垂体腺苷酸环化酶激活多肽（PACAP）受体相互作用介导这些作用，并影响巨噬细胞的各种功能。MAX替代全唾液，与全唾液一样加重利什曼原虫感染。我们还用MAX生产了一种基于蛋白质的疫苗，并表明它可以在小鼠中诱导对利什曼原虫加全唾液的攻击产生深刻的保护作用。

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.