Vaccines Against Ehrlichia and Anaplasma Species Infections

埃里希体和无形体物种感染疫苗

• 批准号: 10399534
• 负责人: ROMAN R. GANTA
• 金额: $ 62.25万
• 依托单位: KANSAS STATE UNIVERSITY
• 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 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10399534
• 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.

项目摘要： 由Anaplastaceae家族的病原体引起的立克疾病，包括属的成员 在过去的三十年中 在美国和世界许多地区，人类和世界许多地区感染tick传播的主要原因。这 疾病包括人类的单核细胞和粒细胞性卵形病，由埃希氏菌和肉芽生菌引起 ehrlichia ewingii分别和人类粒细胞质膜病由adaplasma产生 吞噬细胞感染。 E. Canis首先被描述为犬病病原体，也引起人们的感染。 最近，另一种tick传播的病原体Ehrlichia Muris subsp。 eauclairensis也据报道引起 人的疾病。这些病原体已经发展了逃避宿主免疫力并导致持久性的策略 感染。持续感染的人很难诊断并构成血液和器官的风险 收件人。通过我们最近建立的诱变实验，我们创建了Chaffeensis突变体 其中包含引起功能基因破坏的插入。 ECH_0660基因中的插入突变 从两个脊椎动物宿主那里得出了病原体的快速清除。使用该衰减突变体的疫苗接种 引起了强烈的宿主反应，并针对血流感染和tick传播提供了完整 野生型E. Cahffeensis面临的挑战。我们的进一步研究表明，ECH_0660同源物很好 在不同的ehrlichia/anaplasma物种中保守。我们广泛的研究共同构成了强大的研究 拟议项目的基础和前提。在此提案中，我们将检验衰减的假设 通过E. chaffeensis ech_0660基因的功能缺陷及其其他相关的同源物 立克人士将导致安全有效的疫苗，足以防止野生型感染 血流或滴答传播；两种可能的手段是tick传播的立克造成的 人们感染。我们提出以下三个特定目的：1）评估免疫持续时间 ECH_0660基因突变体活疫苗（MLAV）针对野生型感染挑战提供 通过血流和tick传递。 2）评估MLAV对遗传上不同的保护 E. chaffeensis菌株。 3）评估相关Ehrlichia和Anaplasma中的ECH_0660基因同源突变体 物种作为对病原体感染的保护的活疫苗的效力 进入血液和tick传输。目标代表了实质进步的逻辑扩展 我们从正在进行的研究中做出了。此外，我们还包括一个严格的实验计划来执行 项目目标对于推进疫苗的开发至关重要，以防止由 几种重要的tick虫传播的ehrlichia和Anaplasma物种病原体。我们有高级 专业知识和必要的资源，以确保成功执行拟议的项目目标。