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

研究沙眼衣原体是否可以增加生殖道感染期间 HPV 的传染性

基本信息

批准号：
10648156
负责人：
WILBERT A DERBIGNY
金额：
$ 20.89万
依托单位：
MARIAN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-10 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10648156
关键词：
Acceleration Agreement Animal Model Apoptosis Autoimmunity Basal Cell Biological Biological Assay Biological Markers Biological Models Cancer Etiology Cancerous Cell Survival Cells Cervical Cervical Squamous Cell Carcinoma Cessation of life Chlamydia Chlamydia Infections Chlamydia muridarum Chlamydia trachomatis Chromatin DNA Damage DNA Repair Pathway Data Developing Countries Development Enzyme-Linked Immunosorbent Assay Epidemiology Epigenetic Process Epithelial Cell Proliferation Epithelial Cells Epithelium Exposure to Future Goals HPV E7 Heterochromatin Hormonal Human Human Papillomavirus Human papilloma virus infection Immune response Impairment In Vitro Infection Inflammation Mediators Inflammatory Intercellular Junctions Invaded Investigation Link MEKs Malignant Female Reproductive System Neoplasm Malignant Neoplasms Malignant neoplasm of cervix uteri Mammalian Oviducts Meta-Analysis Mus Neoplasm Metastasis Neoplasms Oncogenic Outcome Papillomavirus Papillomavirus Infections Papillomavirus Transforming Protein E6 Pathogenesis Pathology Pathway interactions Patients Permeability Play Predisposition Proteins Reporting Reproductive Health Risk Role Sexual Transmission Sexually Transmitted Diseases Signal Pathway Signal Transduction Squamous cell carcinoma Stratum Basale TLR3 gene Testing Therapeutic Intervention Tissues Woman Women&apos s Health cell transformation cervical carcinogenesis co-infection cofactor efficacy evaluation epidemiologic data in vivo innovation insight keratinocyte lifetime risk monolayer mouse model novel pathogen premalignant prevent reproductive tract response senescence sensor targeted treatment transcriptome transcriptomics tumor tumorigenesis unvaccinated vaginal microbiota

项目摘要

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.

项目概要尽管未接种疫苗的人一生中感染人乳头瘤病毒 (HPV) 的风险估计高达 75% 女性患宫颈癌的实际风险仅为 0.68%，这表明仅接触 HPV 就可以预防宫颈癌。不足以发展为宫颈癌，并且 HPV 感染可能需要存在生物或细胞诱导的“辅助因子”有助于引发肿瘤发生，是最常见的细菌性传播病原体。因为沙眼衣原体 (Ct) 感染也对妇女的生殖健康构成重大威胁，流行病学报告表明，与妇科癌症的发生越来越相关 Ct 和 HPV 相对常见，对流行病学数据的荟萃分析和对假定的早期调查。 Ct 在妇科癌症中的作用表明，细胞免疫反应对衣原体感染是一种潜在的协同作用。我们和其他人已经证明，可以增强宿主对 HPV 诱发的宫颈癌的易感性。对衣原体感染的免疫反应会导致生殖道病变，我们最近的报告显示 TLR3 人类输卵管上皮 (hOE) 细胞的缺陷会改变对 Ct 感染的免疫反应，导致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，并且 TLR3 缺陷导致单层通透性增加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，我们还提供了 TLR3 在维持上皮屏障完整性方面发挥作用的证据因此，我们认为衣原体感染会破坏上皮屏障。功能（部分由 TLR3 调节），并且屏障破坏将允许更好地访问底层基础细胞层，从而可以增加 HPV 的感染性。在本提案中，我们将检验 Ct 可以发挥作用的假设。作为 HPV 感染诱发宫颈癌的辅助因素，通过： (1) 检查是否有衣原体感染或分泌衣原体感染的产物可以增强 HPV 对其靶细胞的附着和进入，(2) 确定是否 TLR3 信号传导调节 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将使小鼠更容易受到随后的乳头瘤病毒感染。该假设将揭示对 Ct-HPV 合并感染、TLR3 在改变合并感染结果中的作用的新见解，以及暗示 TLR3 作为治疗干预的潜在靶标，以预防 HPV 感染者中 Ct 触发的肿瘤发生患者。