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

描述（由申请人提供）：尽管公共卫生努力和有效的抗生素治疗，在美国和西欧的青少年/年轻人中，沙眼衣原体感染的患病率为2-15%。人们普遍认为，有必要开发衣原体疫苗，以减少其流行。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志物，以便筛选候选疫苗。目前还没有可行的衣原体保护性免疫生物标志物。Johnson实验室已经确定了第二种CD4 T细胞介导的机制，足以清除依赖于Plac8的生殖道衣原体。布伦汉姆实验室已经证明，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Th1反应。从不同角度研究保护性免疫的两个实验室已形成保护性免疫的工作模式，这对疫苗开发具有重大潜在影响。在已发表和未发表数据的支持下，他们假设保护性沙眼衣原体疫苗的基础将是产生多功能CD4Plac8抗衣原体反应，并且多功能CD4Plac8 T细胞反应将作为保护性免疫和疫苗功效的可行生物标志物。为了验证这一假设并研究潜在的免疫生物学，他们提出了以下具体目标：具体目标#1-研究plac8依赖性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发表的保护性小鼠PmpG疫苗和现有的敲除小鼠。特定目的#2-研究与plac8依赖性免疫相关的效应机制。这一目标将利用约翰逊实验室发表的衣原体特异性Plac8pos和Plac8neg CD4 T细胞克隆，以及Plac8敲除生殖道上皮细胞系。具体目标#3-调查在没有或存在衣原体感染的小鼠和人类中多功能CD4Plac8 T细胞的频率和分布。这是一项新颖的转化研究。

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 Supported by published and unpublished data they postulate that the foundation of a protective C. trachomatis vaccine will be generation of a multifunctional CD4Plac8 anti-Chlamydia response, and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.