Vaccines Against Ehrlichia and Anaplasma Species Infections

埃里希体和无形体物种感染疫苗

• 批准号: 10812917
• 负责人: ROMAN R. GANTA
• 金额: $ 59.88万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10812917
• 关键词: Adaptive Immune System; Address; Advanced Development; Anaplasma; Anaplasma phagocytophilum; Anaplasmataceae; Anaplasmosis; Attenuated; Attenuated Vaccines; Bacteriophages; Blood; Canis familiaris; Code; Data; Development; Diagnosis; Disease; Ehrlichia; Ehrlichia canis; Ehrlichia chaffeensis; Ehrlichia ewingii; Ehrlichiosis; Ensure; Epitopes; Family; Family member; Foundations; Gene Mutation; Genes; Goals; Health; Homologous Gene; Human; Immune response; Immunity; Immunologic Memory; Infection; Insertion Mutation; Intervention; Membrane Proteins; Methods; Modeling; Mutagenesis; Mutation; Organ; Pathogenesis; Patients; Persons; Physiological; Positioning Attribute; Proteins; Proteome; Public Health; Publishing; RNA; Reporting; Research; Resources; Rickettsia; Rickettsia Infections; Risk; Route; Sepsis; Stream; Structure; System; Testing; Tick-Borne Diseases; Tick-Borne Infections; Ticks; Vaccination; Vaccines; Variant; Vertebrates; Work; antiporter; attenuation; chronic infection; deep sequencing; effective intervention; experimental study; gene function; granulocyte; innovation; member; microbial; monocyte; mutant; pathogen; prevent; tick transmission; tick-borne; tick-borne pathogen; tool; transcriptome; vaccine development

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.

项目概要： 由无形体科病原体引起的立克次体病，包括 埃里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， 是美国和世界许多地区人类蜱传感染的主要原因。的 疾病包括由查菲埃里希体引起的人单核细胞和粒细胞埃里希体病， 埃氏埃立克体和人粒细胞无形体病 嗜吞噬细胞菌感染E.犬瘟热最初被描述为犬病原体，也会引起人感染。 最近，另一种蜱传病原体，小鼠埃立克体亚种。eauclairensis，也被报道为引起 人的疾病。这些病原体已经进化出逃避宿主免疫的策略， 感染.持续感染的人很难诊断，并对血液和器官构成风险 受惠人士通过我们最近建立的诱变实验，我们创建了E。查菲突变体 含有导致功能性基因破坏的插入物。ECH_0660基因中的插入突变 导致病原体从两种脊椎动物宿主身上迅速清除。接种这种减毒突变体 诱导了强烈的宿主反应，并提供了完全的抗血流感染和蜱传播 野生型E. cahffeensis。我们进一步的研究表明，ECH_0660同系物是良好的， 在不同埃里希体/无形体属物种中保守。我们广泛的研究共同形成了强大的 项目建设的基础和前提。在这个建议中，我们将测试衰减的假设， 通过E. chaffeensis ECH_0660基因及其在其他相关基因中的同源物 立克次氏体将产生安全和有效的疫苗，足以防止野生型感染进入 血液或蜱传播;蜱传立克次体引起的两种可能的方式 人的感染。我们提出以下三个具体目标：1）评估免疫持续时间 ECH_0660基因突变减毒活疫苗（MLAV）提供的抗野生型感染攻毒 通过血液和蜱虫传播。2)评估MLAV对遗传上不同的 E. chaffeensis菌株。3)评价相关埃里希体和无形体中的ECH_0660基因同源突变体 种作为减毒活疫苗在提供针对病原体感染的保护方面的功效 进入血液和通过蜱虫传播。这些目标代表了实质性进展的逻辑延伸， 从我们正在进行的研究中得出的结论。此外，我们还制定了严格的实验计划， 该项目的目标，这是至关重要的，在推进疫苗的发展，以防止疾病引起的 几种重要的蜱传埃立克体和无形体属病原体。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。