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疫苗，沙眼衣原体是沙眼衣原体的主要原因 细菌性传播疾病在世界范围内的传播。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 怀孕和不孕不育。衣原体分泌蛋白，命名为CPAF (衣原体蛋白水解酶/蛋白酶体样活性因子)，负责降解 宿主MHC转录因子RFX5和USF1。抑制CPAF活性将 因此是一种可行的阻断衣原体免疫逃避的疫苗接种策略 承认。我们现在已经提供了直接的证据来证明 这种方法使用重组(R)CPAF和IL-12在鼻腔(I.N.)送货 系统。RCPAF和IL-12鼻腔免疫诱导强效抗原特异性 干扰素的产生，显著减少了细菌在阴道内的脱落(i.vag.) 与沙眼衣原体攻击相比，明显加快了感染的消退 给模拟免疫(PBS)小鼠。重要的是，rCPAF+IL-12疫苗接种的小鼠表现出 预防衣原体感染的病理后果，包括 输卵管系膜炎症与输卵管积水和输卵管扩张的发展。这个 RCPAF+IL-12介导的衣原体感染的溶解和保护作用 炎症病理高度依赖于内源性干扰素的产生，而 抗原特异性的CD4+T细胞的作用。根据我们值得注意的证据，我们 假设“接种CPAF疫苗可促进生育力的保存并降低 生殖器衣原体感染后细菌增强的炎性病理 分泌CD4+的抗原特异性干扰素在上生殖道内的清除 T细胞和局部吞噬细胞的参与。我们将检验这一假说 通过；(1)考察I.N的直接影响。CPAF疫苗在保持生育能力方面的作用 生殖器衣原体感染后；(2)确定减少的关系 在衣原体生物体中和抗原特异性的CD4+T细胞在 铜绿假单胞菌疫苗致上生殖道感染；(3)S 产生CPAF的哪种干扰素特异性的CD4+T细胞增强细菌清除和 防止与衣原体感染相关的泌尿生殖系统病理的发展。

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.