CPAF induced CD4+ T cell mediated immunity against Chlamydia

项目摘要 目前还没有针对沙眼衣原体的许可疫苗， 细菌性性传播疾病未经治疗的生殖器衣原体 感染引起严重后遗症如盆腔炎、异位妊娠 怀孕和不孕一种衣原体分泌的蛋白质，命名为CPAF （衣原体蛋白酶/蛋白酶体样活性因子），负责降解 宿主MHC转录因子RFX 5和USF 1。抑制CPAF活性将 因此是一种可行的疫苗接种策略，用于阻断衣原体逃避免疫应答， 识别.我们现在已经提供了直接证据来证明 使用重组（r）CPAF和IL-12的鼻内（i. n.）递送 系统鼻内接种rCPAF和IL-12诱导了稳健的抗原特异性免疫应答。 IFN-γ产生，显著减少阴道内（i.vag.） 衣原体挑战，并显着加快感染的解决相比， 模拟免疫（PBS）小鼠。重要的是，rCPAF+IL-12疫苗接种的小鼠表现出 保护免受衣原体感染的病理后果，包括 输卵管系膜炎症、输卵管积水和输卵管扩张。的 rCPAF+IL-12介导的衣原体感染的消退和针对衣原体感染的保护 炎症病理高度依赖于内源性IFN-γ的产生， 抗原特异性CD 4 + T细胞的作用。根据我们的大量证据，我们 假设“CPAF疫苗接种促进生育力的保持， 生殖器衣原体感染后细菌增强的炎症病理学 通过分泌抗原特异性IFN-γ的CD 4+在上生殖道内清除 在局部吞噬细胞的参与下的T细胞”。我们将检验这一假设 （1）检查i.n.的直接效果。CPAF疫苗接种对保持生育力的作用 生殖道衣原体感染后;（2）确定减少与 在衣原体微生物和抗原特异性CD 4 + T细胞浸润内， CPAF疫苗接种引起的上生殖道感染;（3）通过 产生IFN-γ的CPAF特异性CD 4 + T细胞增强细菌清除， 预防与衣原体感染相关的泌尿生殖道病理的发展。

Project Summary There currently is no licensed vaccine against Chlamydia trachomatis, the leading cause of bacterial sexually transmitted disease worldwide. Untreated genital chlamydial infection cause serious sequelae such as pelvic inflammatory disease, ectopic pregnancy, and infertility. A Chlamydia-secreted protein, designated as CPAF (chlamydial protease/proteasome-like activity factor), is responsible for degradation of the host MHC transcription factors RFX5 and USF1. Inhibiting CPAF activity will therefore be a feasible vaccination strategy for blocking chlamydial evasion of immune recognition. We have now provided direct evidence to demonstrate the effectiveness of such an approach using recombinant (r)CPAF and IL-12 in an intranasal (i.n.) delivery system. Intranasal vaccination with rCPAF and IL-12 induced robust antigen-specific IFN-¿ production, significantly reduced bacterial shedding upon intravaginal (i.vag.) chlamydial challenge and significantly accelerated the resolution of infection compared to mock-immunized (PBS) mice. Importantly, rCPAF+IL-12 vaccinated mice exhibited protection against pathological consequences of chlamydial infection, including mesosalpingeal inflammation and development of hydrosalpinx and oviduct dilation. The rCPAF+IL-12-mediated resolution of chlamydial infection and protection against inflammatory pathology was highly dependent on endogenous IFN-¿ production and the action of antigen-specific CD4+ T cells. Based on our notable body of evidence, we hypothesize that "CPAF vaccination promotes preservation of fertility and reduces inflammatory pathology after genital Chlamydia infection by enhancing bacterial clearance within the upper genital tract via antigen-specific IFN-¿ secreting CD4+ T-cells with the participation of local phagocytic cells". We will test this hypothesis by; (1) Examining the direct effect of i.n. CPAF vaccination on the preservation of fertility after genital chlamydial challenge; (2) Determine the relationship between the reduction in chlamydial organisms and the infiltration of antigen-specific CD4+ T cells within the upper genital tract induced by CPAF vaccination; (3) Investigating the mechanism(s) by which IFN-¿ producing CPAF specific CD4+ T cells enhance bacterial clearance and prevent the development of urogenital pathology associated with chlamydial infection.