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

项目摘要 尽管未接种疫苗的人乳头瘤病毒(HPV)感染的估计终身风险可能高达75% 女性患宫颈癌的实际风险只有~0.68%。这表明，仅接触HPV就是 不足以发展为宫颈癌，HPV感染可能需要存在生物学或 细胞诱导的“辅因子”有助于触发肿瘤的发生。作为最常见的细菌性传播病原体， 由于沙眼衣原体也是对妇女生殖健康的重大威胁，沙眼衣原体(CT)感染 越来越多的人与妇科癌症的发展联系在一起，因为流行病学报告表明，与 CT和HPV相对常见。流行病学数据的Meta分析和对推定病例的早期调查 CT在妇科肿瘤中的作用可能与衣原体感染相关的细胞免疫反应有关。 可以增加宿主对HPV诱导的宫颈癌的易感性的因素。我们和其他人已经证明 对衣原体感染的免疫反应导致生殖道病理，我们最新的报告表明TLR3 人类输卵管上皮(HOE)细胞缺陷改变了对CT感染的免疫反应，导致 衣原体复制。我们最近也报道了衣原体感染诱导细胞因子的合成， 破坏生殖道组织细胞-细胞连接，TLR3缺乏导致单层通透性增加 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具有保护作用的上皮细胞 我们还提供了TLR3在维持上皮屏障完整性方面的作用的证据 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(部分受TLR3调节)，屏障破坏将允许更好地进入基础基础 因此可以增加HPV的感染力。在这个提案中，我们将测试我们的假设，即CT可以服务于 作为HPV感染诱发宫颈癌的辅助因素：(1)检测衣原体感染或分泌物 衣原体感染产物可增强HPV对靶细胞的附着和进入，(2)确定是否 TLR3信号调节Ct对增加HPV感染性的影响，以及(3)确定生殖道 衣原体感染将使小鼠更容易受到随后的乳头瘤病毒感染。确认我们的 假说将揭示对CT-HPV合并感染、TLR3在改变合并感染结果中的作用的新见解，以及 将TLR3作为治疗干预的潜在靶点以预防HPV感染中CT触发的肿瘤发生 病人。

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.