Vaccines Against Ehrlichia and Anaplasma Species Infections

项目概要： 由无形体科病原体引起的立克次体疾病，包括该属的成员 埃利希体和无形体在过去三十年中已成为日益严重的公共卫生问题，并且 它是美国和世界许多地区人类蜱传感染的主要原因。的 疾病包括由恰菲埃利希体引起的人类单核细胞和粒细胞埃利希体病和 尤文埃利希体和无形体引起的人粒细胞无形体病 嗜吞噬细胞感染。犬艾美耳球虫最初被描述为一种犬类病原体，也会引起人类感染。 最近，另一种蜱传病原体，埃利希体亚种。 eauclairensis，也被报道为引起 人身上的疾病。这些病原体已经进化出逃避宿主免疫并导致持续性感染的策略。 感染。持续感染的人难以诊断并对血液和器官构成风险 收件人。通过我们最近建立的诱变实验，我们创建了恰菲埃里希菌突变体 其中包含导致功能基因破坏的插入。 ECH_0660 基因中的插入突变 导致病原体从两种脊椎动物宿主中快速清除。用这种减毒突变体进行疫苗接种 诱导强烈的宿主反应并完全抵抗血流感染和蜱传播 野生型 E. cahffeensis 的挑战。我们的进一步研究表明 ECH_0660 同源物很好 在不同埃利希体/无形体物种之间保守。我们广泛的研究共同形成了强大的 拟议项目的基础和前提。在这个提案中，我们将测试衰减的假设 通过查菲埃里希菌 ECH_0660 基因及其在其他相关基因中的同源物的功能缺陷 立克次体将产生安全有效的疫苗，足以预防野生型感染 血流或蜱传播；蜱传立克次体引起的两种可能的方式 人感染。我们提出以下三个具体目标：1）评估免疫力的持续时间 ECH_0660基因突变减毒活疫苗（MLAV）针对野生型感染挑战提供 通过血流和蜱虫传播。 2) 评估 MLAV 对遗传独特病毒的保护作用 查菲埃里希菌菌株。 3) 评估相关埃里希体和无形体中的ECH_0660基因同源突变体 物种作为减毒活疫苗的功效，可提供针对病原体感染的保护 进入血液并通过蜱传播。这些目标代表了实质性进展的逻辑延伸 我们通过持续的研究得出了结论。此外，我们还制定了严格的实验计划来执行 项目目标对于推进疫苗开发以预防由以下疾病引起的疾病至关重要 几种重要的蜱传播埃里希体和无形体病原体。我们有高水平的 专业知识和必要的资源，以确保成功执行拟议的项目目标。

PROJECT SUMMARY: Rickettsial diseases caused by pathogens of the Anaplasmataceae family, including members of the genera Ehrlichia and Anaplasma, have become a growing public health concern over the past three decades and are a leading cause of tick-borne infections in humans throughout the USA and many parts of the world. The diseases include the human monocytic and granulocytic ehrlichiosis caused by Ehrlichia chaffeensis and Ehrlichia ewingii respectively, and the human granulocytic anaplasmosis resulting from Anaplasma phagocytophilum infections. E. canis, first described as a canine pathogen, also causes infections in people. Recently, another tick-borne pathogen, Ehrlichia muris subsp. eauclairensis, is also reported as causing disease in people. These pathogens have evolved strategies to evade host immunity and cause persistent infections. People with persistent infections are difficult to diagnose and pose risk to blood and organ recipients. Through our recently established mutagenesis experiments, we created E. chaffeensis mutants that contained insertions causing functional gene disruptions. An insertion mutation in the ECH_0660 gene resulted in the pathogen's rapid clearance from two vertebrate hosts. Vaccination with this attenuated mutant induced a strong host response and offered complete against blood stream infection and tick transmission challenges with wild-type E. cahffeensis. Our further studies suggest that the ECH_0660 homologs are well conserved among different Ehrlichia/Anaplasma species. Together, our extensive research forms the strong foundation and premise for the proposed project. In this proposal, we will test the hypothesis that attenuation through a functional deficiency in the E. chaffeensis ECH_0660 gene and its homologs in other related rickettsials will result in safe and efficacious vaccines that are sufficient to prevent wild type infection into the blood stream or from tick transmission; the two possible means by which tick-borne rickettsials cause infections in people. We propose the following three specific aims: 1) Evaluate the duration of immunity offered by the ECH_0660 gene mutant live attenuated vaccine (MLAV) against wild type infection challenge through blood stream and tick-transmission. 2) Evaluate the protection of the MLAV against genetically distinct E. chaffeensis strains. 3) Evaluate ECH_0660 gene homolog mutants in related Ehrlichia and Anaplasma species for their efficacy as live attenuated vaccines in conferring protection against the pathogens' infection into blood stream and by tick-transmission. The goals represent a logical extension of the substantial progress we have made from our ongoing research. Further, we have included a rigorous experimental plan to execute the project goals, which are critical in advancing the development of vaccines to prevent diseases caused by several important tick-transmitted Ehrlichia and Anaplasma species pathogens. We have the high-level expertise and the necessary resources to ensure the successful execution of the proposed project goals.