Early in vivo expressed antigens and their role in virulence, immune response, and vaccines for coccidioidomycosis

早期体内表达的抗原及其在球孢子菌病毒力、免疫反应和疫苗中的作用

• 批准号: 10689668
• 负责人: Bridget Marie Barker
• 金额: $ 45.29万
• 依托单位: NORTHERN ARIZONA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-24 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10689668
• 关键词: Address; Animal Model; Animal Testing; Animals; Antibody titer measurement; Antigens; Arizona; Attenuated Vaccines; Basic Science; Biological Models; Biometry; Breeding; C57BL/6 Mouse; CD8-Positive T-Lymphocytes; CRISPR/Cas technology; Clinic; Coccidioides; Coccidioides immitis; Coccidioides posadasii; Coccidioidomycosis; Collaborations; Communities; DNA; Data; Development; Diagnostic; Diagnostic tests; Disease; Disease Progression; Disease model; Dose; Early identification; Epitopes; Future; Gene Deletion; Goals; Human; Immune; Immune response; Immunity; Immunization; Immunize; Immunology; Inbred BALB C Mice; Incidence; Individual; Infection; Institution; Invertebrates; Investigation; Knock-out; Location; Lung; Macaca; Macaca nemestrina; Modeling; Morphology; Moths; Mus; Nucleic Acid Vaccines; Nucleic Acids; Pathology; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phase; Population; Predisposition; Preventive vaccine; Primates; Productivity; Proteins; RNA; Rapid screening; Research; Research Project Grants; Resources; Role; Serum; Source; Specimen; Speed; T-Cell Depletion; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Epitopes; Technology; Testing; Therapeutic Agents; Tissue Sample; Tissues; Translational Repression; Universities; Vaccinated; Vaccines; Virulence; Virulence Factors; Waxes; Work; candidate identification; chronic infection; cohort; comparative; cost effective; desert fever; dosage; experience; experimental study; improved; in vivo; knowledge translation; mortality; mouse model; nonhuman primate; novel; novel therapeutics; novel vaccines; programs; response; risk mitigation; screening; tool; vaccine development; vaccine evaluation; vaccine trial

Project Summary/Abstract (Animal Core) Coccidioides immitis and C. posadasii cause coccidioidomycosis (Valley Fever - VF), which is of great concern due to recent rapid increases in US disease incidence. The overall goal of our program (VIRV-CCRC) is to in- vestigate proteins that are highly expressed early in the VF infection cycle, when the fungal arthroconidia are developing into spherules and endospores forming. Our hypothesis in Research Project 1 (RP1) is that pro- teins expressed at this critical stage are key to disease progression and potential represent virulence factors. The Animal Core (AnC) will be instrumental in addressing this hypothesis by providing new animal models for virulence testing. In Aim 1, the Galleria (wax worm) invertebrate model that we have shown supports arthro- conidia development into mature spherules represents a good test of virulence factors key to this step. It is also economical and will reduce the number of mice needed for research. Nevertheless, the mouse model pro- vides data that Galleria cannot and the AnC will provide it to confirm Galleria virulence data. In aim 2, mouse challenge experiments will be conducted at the ABSL3 facility at Northern Arizona University. Identification of early infection virulence factors will be used guide the identification of T cell epitopes in a T cell receptor analy- sis in RP2. T cell recognition of Coccidioides epitopes is a key step in the immune response, which we will lev- eraged into novel VF diagnostic tests. Both virulence factor and T cell receptor results will guide the prioritiza- tion of advanced nucleic acid (RNA and DNA) vaccine development. RP3 will use the mouse model and a non- human primate model to develop and test new vaccines. In aim 3, we will develop a new pig-tailed macaque (NHP) model. Our focus on this model is due to their established VF susceptibility and the availability of natu- rally infected colony animals from the Arizona Breed Colony (WaNPRC). The AZ macaque disease incidence is similar to the Arizona human population and represents a valuable source of pathology data, serum, PBMC, and other tissues. The Fuller lab (RP3) has already successfully used pig-tailed macaques in vaccination stud- ies, achieving high antibody titers and protective immunity to other diseases. The AnC will coordinate the vac- cine work through the naturally infected NHP population in Arizona, the Seattle WaNPRC facility for NHP im- munization studies, and at Tulane National Primate Research Center for Coccidioides challenge studies in NHP. In summary, the AnC will develop, provide, and support three complementary animal models: Galleria, mouse, and NHP. Each has its distinct advantages that support the individual and overall research goals of the VIRV-CCRC. The AnC is a coordinated effort across three institutions and four locations that leverages institu- tional strengths to maximize productive of the whole VIRV-CCRC. As the VIRV-CCRC develops these animal model resources, we will encourage collaboration with other CCRC and broadly with the Valley Fever research community. High quality animal models and their tissue specimens will alleviate some of the research barriers to developing better therapeutic agents, diagnostic tests, and preventive vaccines.

项目总结/摘要（动物核心） 粗球孢子菌（Coccidioides immitis）和C. posadasii引起球孢子菌病（山谷热-VF），这是非常关注的 由于最近美国疾病发病率的迅速增加。我们的计划（VIRV-CCRC）的总体目标是- 在VF感染周期早期高度表达的vestigate蛋白，此时真菌节分生孢子 发育成小球体，形成内生孢子。我们在研究项目1（RP1）中的假设是，亲- 在这个关键阶段表达的蛋白是疾病进展的关键，并可能代表毒力因子。 动物核心（AnC）将通过提供新的动物模型来解决这一假设 毒力测试在目标1中，我们已经证明的Galleria（蜡虫）无脊椎动物模型支持关节炎， 分生孢子发育成成熟小球代表了对该步骤关键的毒力因子的良好测试。是 也很经济，并且将减少研究所需的小鼠数量。然而，小鼠模型亲- 提供Galleria无法提供的数据，AnC将提供该数据以确认Galleria毒力数据。在aim 2中，鼠标 挑战实验将在北方亚利桑那大学的ABSL 3设施进行。鉴定 早期感染毒力因子将用于指导T细胞受体分析中T细胞表位的鉴定， 在RP 2中。球孢子菌抗原表位的T细胞识别是免疫应答的关键步骤，我们将从 用于新型VF诊断测试。毒力因子和T细胞受体的结果将指导优先考虑- 先进的核酸（RNA和DNA）疫苗的发展。RP3将使用小鼠模型和非 人类灵长类动物模型来开发和测试新疫苗。在目标3中，我们将培育一种新的猪尾猕猴 (NHP)模型我们对这个模型的关注是由于他们已经建立了VF易感性和天然药物的可用性。 来自亚利桑那繁殖群（WaNPRC）的集会感染的群体动物。AZ猕猴疾病发病率 与亚利桑那州人群相似，代表了病理学数据、血清、PBMC， 和其他组织。富勒实验室（RP3）已经成功地将猪尾猕猴用于疫苗接种研究， 即，实现高抗体滴度和对其他疾病的保护性免疫。非国大会协调撤离 通过亚利桑那州自然感染NHP人群的电影工作，西雅图WaNPRC的NHP im设施， 免疫研究，并在杜兰国家灵长类动物研究中心的球孢子菌挑战研究， NHP。总之，AnC将开发，提供和支持三种互补的动物模型：Galleria， 小鼠和NHP。每一个都有其独特的优势，支持个人和整体的研究目标， VIRV-CCRC。AnC是三个机构和四个地点的协调努力，利用了信息技术， 以最大限度地提高整个VIRV-CCRC的生产力。随着VIRV-CCRC开发这些动物 模型资源，我们将鼓励与其他CCRC和广泛的山谷热研究合作 社区高质量的动物模型及其组织标本将缓解一些研究障碍 开发更好的治疗剂，诊断测试和预防疫苗。