Role of Plac8 in natural and vaccine-generated immunity against Chlamydia infections

Plac8 在针对衣原体感染的自然免疫和疫苗免疫中的作用

• 批准号: 9114842
• 负责人: Robert Conrad Brunham
• 金额: $ 37.36万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9114842
• 关键词: Role; Plac8; natural; vaccine; generated

DESCRIPTION (provided by applicant): Chlamydia trachomatis infections have a prevalence of 2-15% in adolescents/young adults in the USA and Western Europe in spite of public health efforts and effective antibiotic therapy. It is widely accepted that development of a Chlamydia vaccine is necessary reduce its prevalence. A critical component of vaccine development is identification of a surrogate biomarker for protective immunity to enable screening of candidate vaccines. Currently there are no practicable biomarkers for Chlamydia protective immunity. The Johnson laboratory has identified a second CD4 T cell-mediated mechanism singly-sufficient for clearing Chlamydia from the genital tract that is dependent on Plac8. The Brunham laboratory has demonstrated that vaccine-generated protective immunity against Chlamydia genital tract infections requires a multifunctional Th1 response. The two laboratories approaching protective immunity from different perspectives have converged on working model for protective immunity that has major potential implications for vaccine development. Supported by published and unpublished data they postulate that the foundation of a protective C. trachomatis vaccine will be generation of a multifunctional CD4Plac8 anti-Chlamydia response, and that multifunctional CD4Plac8 T cell responses will serve as practicable biomarkers for protective immunity and vaccine efficacy. To test that hypothesis and investigate the underlying immunobiology they propose the following specific aims: Specific aim #1- to investigate the role of the Plac8-dependent clearance mechanism in vaccine-generated protective immunity. This aim will utilize the Brunham laboratory's published protective murine PmpG vaccine, and existing knockout mice. Specific aim #2- to investigate the effector mechanism associated with Plac8-dependent immunity. This aim will utilize the Johnson lab's published Chlamydia-specific Plac8pos and Plac8neg CD4 T cell clones, and Plac8 knockout reproductive tract epithelial lines. Specific aim #3- to investigate the frequency and distribution of multifunctional CD4Plac8 T cells in mice and humans, in the absence and presence of Chlamydia infections. This is novel translational research.

描述(申请人提供)：尽管美国和西欧做出了公共卫生努力和有效的抗生素治疗，但沙眼衣原体感染在美国和西欧的青少年/年轻人中的流行率为2-15%。人们普遍认为，开发衣原体疫苗是必要的，以降低其流行率。疫苗开发的一个关键组成部分是确定保护性免疫的替代生物标记物，以便能够筛选候选疫苗。目前尚无可行的衣原体保护性免疫生物标志物。约翰逊实验室已经确定了第二种单独的CD4T细胞介导的机制--足以清除依赖PLAC8的生殖道衣原体。布鲁纳姆实验室已经证明，疫苗产生的针对衣原体生殖道感染的保护性免疫需要多功能的Th1反应。从不同角度研究保护性免疫的两个实验室在保护性免疫的工作模式上达成了一致，这对疫苗开发具有重大的潜在影响。在已发表和未发表的数据的支持下，他们假设保护性沙眼衣原体疫苗的基础将是产生多功能的CD4Plac8抗衣原体反应，多功能的CD4Plac8T细胞反应将作为保护性免疫和疫苗效力的实用生物标志物。为了验证这一假设并调查潜在的免疫生物学，他们提出了以下特定目标：特定目标#1--调查PLAC8依赖清除机制在疫苗产生的保护性免疫中的作用。这一目标将利用布鲁纳姆实验室公布的保护性小鼠PmpG疫苗和现有的基因敲除小鼠。具体目标2--研究PLAC8依赖免疫的效应机制。这一目标将利用约翰逊实验室发表的针对衣原体的Plac8pos和Plac8neg CD4T细胞克隆，以及PLAC8基因敲除的生殖道上皮系。具体目标#3-研究在没有和存在衣原体感染的情况下，多功能CD4Plac8T细胞在小鼠和人类中的频率和分布。这是一项新颖的翻译研究。