Investigating whether chlamydia trachomatis can increase the infectivity of HPV during genital tract infections

项目摘要 虽然在未接种疫苗的人群中，人乳头瘤病毒（HPV）感染的估计终生风险可高达75%， 女性患宫颈癌的实际风险仅为~ 0.68%。这表明单独暴露于HPV是 HPV感染可能需要存在生物学或免疫学上的缺陷， 细胞诱导的“辅因子”，以帮助触发肿瘤发生。作为最常见的细菌性性传播病原体， 因为它也是对妇女生殖健康的重大威胁，沙眼衣原体（Ct）感染是 越来越多地与妇科癌症的发展有关，因为流行病学报告表明， CT和HPV是比较常见的。流行病学数据的荟萃分析和对推定疾病的早期调查 Ct在妇科癌症中的作用暗示了对衣原体感染的细胞免疫应答是一种潜在的协同作用， 这是一个可以增强宿主对HPV诱导的宫颈癌易感性的因素。我们和其他人已经表明， 对衣原体感染的免疫应答导致生殖道病理学，我们最近的报道表明TLR 3 人输卵管上皮（hOE）细胞的缺陷改变了对Ct感染的免疫应答，导致增加的 衣原体复制我们最近还报道衣原体感染诱导细胞因子的合成， 破坏生殖道组织中的细胞-细胞连接，TLR 3缺乏导致在生殖道组织中单层通透性增加， 衣原体感染。我们的数据支持其他研究表明衣原体感染可以破坏保护性上皮细胞， 屏障功能，我们还提出了TLR 3在维持上皮屏障完整性方面发挥作用的证据 在生殖道衣原体感染期间。因此，我们假设衣原体感染破坏了上皮屏障， 功能（其部分由TLR 3调节），并且屏障破坏将允许更好地进入底层基底膜。 细胞层，从而可以增加HPV的感染性。在这个提议中，我们将测试我们的假设，Ct可以服务于 作为HPV感染诱导的宫颈癌的辅助因子：（1）检查衣原体感染或分泌 衣原体感染的产物可以增强HPV附着和进入其靶细胞，（2）确定是否 TLR 3信号调节Ct对增加HPV感染性的影响，以及（3）确定生殖道是否 衣原体感染会使小鼠更容易受到随后的乳头瘤病毒感染。确认我们的 这一假设将揭示对Ct-HPV合并感染的新见解，TLR 3在改变合并感染结果中的作用， 提示TLR 3是预防HPV感染者中Ct触发肿瘤发生治疗性干预的潜在靶点 患者

Project Summary Although the estimated lifetime risk of human papillomavirus (HPV) infection can be as high as 75% in unvaccinated women, the actual risk of developing cervical cancer is only ~0.68%. This indicates that exposure to HPV alone is insufficient for the development of cervical cancer and that HPV infections likely require the presence of a biological or cellular induced “co-factor” to help trigger oncogenesis. As the most common bacterial sexually transmitted pathogen and because it too is a significant threat to the reproductive health of women, Chlamydia trachomatis (Ct) infections are increasingly being linked to gynecological cancer development as epidemiological reports indicate that co-infections with Ct and HPV are relatively common. Meta-analyses of the epidemiological data and the early investigations into the putative role of Ct in gynecological cancers have implicated the cellular immune response to chlamydial infection as a potential co- factor that can enhance the host’s susceptibility to HPV-induced cervical cancers. We and others have shown that the immune response to Chlamydia infection results in genital tract pathology and our most recent report shows that TLR3 deficiency in HUMAN oviduct epithelial (hOE) cells alters the immune response to Ct infection, resulting in increased chlamydial replication. We also recently reported that Chlamydia infection induces the syntheses of cellular factors that disrupt cell-cell junctions in genital tract tissue and that TLR3 deficiency leads to increased monolayer permeability during Chlamydia infection. Our data support other studies showing that Chlamydia infection can disrupt the protective epithelial barrier function, and we also presented evidence that TLR3 plays a role in maintaining the integrity of the epithelial barrier during genital tract Chlamydia infection. Therefore, we hypothesize that Chlamydia infection disrupts epithelial barrier function (which is in part modulated by TLR3), and the barrier disruption will allow better access to the underlying basal cell layers and thereby can increase the infectivity of HPV. In this proposal, we will test our hypothesis that Ct can serve as a co-factor in HPV-infection-induced cervical cancer by: (1) examining whether Chlamydia infection or secreted products of Chlamydia infection can enhance the attachment and entry of HPV into their target cells, (2) determining if TLR3 signaling modulates the impact that Ct has on increasing HPV infectivity, and (3) ascertaining if genital tract Chlamydia infection will make mice more susceptible to subsequent papillomavirus infections. Confirmation of our hypothesis would reveal novel insight into Ct-HPV coinfection, the role of TLR3 in altering outcomes of coinfection, and implicate TLR3 as a potential target for therapeutic interventions to prevent Ct-triggered oncogenesis in HPV-infected patients.