Arthropod vector-based vaccines for leishmaniasis

基于节肢动物载体的利什曼病疫苗

• 批准号: 7373564
• 负责人: RICHARD GRAEME TITUS
• 金额: $ 43万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7373564
• 关键词: Adjuvant; Affect; Agaricales; Animals; Anti-Bacterial Agents; Antibodies; Area; Arthropod Vectors; Arthropods; Bacterial Vaccines; Biological Models; Bioterrorism; Birth; Bite; Blood; Cells; Dengue; Disease; Drug Formulations; Filariasis; Genetic Polymorphism; Geographic Locations; Head; Human; Immune response; Immune system; Immunosuppression; Immunosuppressive Agents; Infection; Laboratories; Leishmania; Leishmania major; Leishmaniasis; Life; Lutzomyia genus; Malaria; Mediating; Methods; Mus; Numbers; Population; Proteins; Publications; Reporting; Research; Research Personnel; Resistance; Rift Valley fever virus; Saliva; Salivary; Salivary Glands; Salivary Proteins; Sand Flies; Science; Serum; Skin; Subunit Vaccines; System; Testing; Time; Today; Toxin; Trypanosomiasis; United States National Institutes of Health; Vaccinated; Vaccine Adjuvant; Vaccines; Vasodilator Agents; Vector-transmitted infectious disease; Virus; West Nile virus; Work; base; biodefense; disease transmission; disorder control; feeding; improved; insect maxadilan protein; interest; macrophage; mouse model; novel strategies; novel vaccines; pathogen; pituitary adenylate cyclase activating polypeptide; programs; receptor; sucking; transmission process; vaccine evaluation; vector; vector vaccine; vector-based vaccine

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.

描述（由申请人提供）：吸血节肢动物疾病媒介的唾液含有具有强效药理学或免疫抑制作用的分子。这些分子帮助载体获得血餐，并且这些分子还无意中增强了这些载体传播的病原体的感染性（节肢动物在皮肤中探测血餐，并且可以在它们的唾液中将病原体递送到皮肤）。白蛉的唾液（利什曼病的载体）显著加剧了小鼠中利什曼原虫的感染，并且可以确定利什曼原虫是否能够成功地在宿主中建立感染。这些观察结果表明，有可能通过接种针对载体唾液中允许病原体在宿主中建立感染的分子的疫苗来接种人类以对抗载体传播的疾病。目前已清楚的是，沙蝇（Lutzomyia longipalpis）唾液中的Maxadilan（MAX）具有双重功能：它是一种有效的血管扩张剂，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替代了整个唾液，并使利什曼原虫感染加重到与整个唾液相同的程度。我们还用MAX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全唾液攻击的深刻保护。 该应用将探索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和其他可能的唾液靶点的改进的沙蝇疫苗。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是否会像影响小鼠细胞那样影响人类细胞，以及人类对MAX和其他唾液分子产生免疫反应的程度。 节肢动物传播世界上一些最严重的疾病（疟疾、登革热、莱姆病、西尼罗河等），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流行的地区驻扎了越来越多的部队。目前还没有有效的方法来控制这些疾病。迫切需要新的有效方法（尤其是本文所述的新型疫苗方法）。