Evaluation of CPAF Mediated Anti-Chlamydial Immunity in the Guinea Pig

描述（由申请人提供）：沙眼衣原体是世界范围内细菌性传播疾病的主要原因。未经治疗的生殖器衣原体感染会引起严重的后遗症，如盆腔炎、异位妊娠和不孕症。获得许可的疫苗被认为是限制衣原体引起的发病率的理想方法，但目前还没有。衣原体蛋白酶样活性因子（CPAF）是一种高度保守的细菌蛋白，分泌到宿主细胞质中。我们的实验室已经证明了鼻内接种重组(r) CPAF（血清型L2）对小鼠生殖器衣原体感染和病理的保护作用。这种保护是由抗原特异性CD4+ T细胞介导的，高度依赖于内源性IFN-3的诱导。考虑到(1)我们对接种rCPAF疫苗在小鼠模型中获得对生殖器衣原体感染的保护性免疫的广泛免疫学特性，以及(2)豚鼠对衣原体感染的发病机制和免疫已被证明与人类对生殖器衣原体感染的免疫非常相似，我们假设“接种rCPAF疫苗将诱导对豚鼠生殖器衣原体感染引起的炎症病理的保护性免疫”。我们建议在豚鼠包涵性结膜炎（GPIC）的病原体caviae豚鼠模型上翻译并验证rCPAF的保护作用。从这些发现中获得的结果将为设计用于人类的有效抗衣原体疫苗提供重要见解。这项研究将使Roger Rank博士（支持信）建立的生殖器衣原体感染豚鼠模型得以传播，该模型已在转译疫苗研究中得到有限的使用。此外，豚鼠基因组测序的完成将导致用于表征的免疫试剂的开发，这将进一步促进该动物模型在科学界的使用。

DESCRIPTION (provided by applicant): Chlamydia trachomatis is the leading cause of bacterial sexually transmitted disease worldwide. Untreated genital chlamydial infections cause serious sequelae such as pelvic inflammatory disease, ectopic pregnancy, and infertility. A licensed vaccine, which is considered to be the ideal way to limit Chlamydia-induced morbidity, is currently not available. Chlamydial protease- like activity factor (CPAF) is a highly conserved bacterial protein secreted into the host cytosol. Our laboratory has shown the protective efficacy of intranasal vaccination with recombinant(r) CPAF (serovar L2) against genital chlamydial infection and pathology in mice. This protection is mediated by antigen-specific CD4+ T cells and highly dependent on the induction of endogenous IFN-3. Given (1) our extensive immunological characterization of rCPAF vaccination in conferring protective immunity against genital chlamydial infection in the mouse model, and (2) that the pathogenesis and immunity to chlamydial infection in guinea pigs has been shown to be remarkably similar to chlamydial genital infection in humans, we hypothesize that "vaccination with rCPAF will induce protective immunity against inflammatory pathology induced by genital chlamydial infection in guinea pigs". We propose to translate and validate the protective efficacy of rCPAF in an alternative animal model the guinea pig with C. caviae, the causative agent of guinea pig inclusion conjunctivitis (GPIC). The results obtained from these findings will provide important insights into the design of an effective anti-chlamydial vaccine for human use. This study will enable propogation of the guinea pig model of genital chlamydial infection established by Dr. Roger Rank (letter of support), which has been put to limited use in translational vaccine studies. Moreover, the completion of the sequencing of the guinea pig genome will result in the development of immunological reagents for characterization, which will further facilitate the use of this animal model in the scientific community. PUBLIC HEALTH RELEVANCE: Chlamydia trachomatis is the leading cause of bacterial sexually transmitted disease worldwide, and lead to severe pathology in the upper genial tract including pelvic inflammatory disease, ectopic pregnancy, and infertility. Immunization with chlamydial protease-like activity factor induces robust protective immunity against chlamydial infection and reproductive pathology in mice, justifying the further validation of this protective antigen. This proposal will further examine the potential of CPAF as a vaccine candidate against genital chlamydial infection in another species, the guinea pig. .