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

• 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
• 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' 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

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.

项目摘要 尽管人类乳头瘤病毒（HPV）感染的寿命估计风险可能高达75％ 妇女，患宫颈癌的实际风险仅为0.68％。这表明仅接触HPV是 不足以发展宫颈癌，HPV感染可能需要生物学或 细胞诱导的“副因素”有助于引发肿瘤发生。作为最常见的细菌性传播病原体和 因为这也对妇女的复制健康构成了重大威胁，所以衣原体沙眼（CT）感染是 随着流行病学报告表明，与妇科癌症发展有关 CT和HPV相对常见。流行病学数据的荟萃分析和对推定的早期研究 CT在妇科癌中的作用已实施了对衣原体感染的细胞免疫反应 可以增强宿主对HPV诱导宫颈癌的敏感性的因素。我们和其他人表明 对衣原体感染的免疫反应导致生殖道病理学，我们的最新报告表明TLR3 人卵形上皮（HOE）细胞缺乏改变对CT感染的免疫反应，从而增加 衣原体复制。我们最近还报道说，衣原体感染诱导了细胞因子的合成 破坏生殖道组织中的细胞细胞连接，TLR3缺乏导致单层渗透率增加 衣原体感染。我们的数据支持其他研究，表明衣原体感染会破坏受保护的上皮 屏障功能，我们还提供了证据，表明TLR3在维持上皮屏障功能的完整性中起作用 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 函数（由TLR3进行部分调节），屏障破坏将使访问基础的基本基本 细胞层，从而增加HPV的感染。在此提案中，我们将测试CT可以服务的假设 作为HPV感染引起的宫颈癌的共同因素：（1）检查衣原体感染还是分泌 衣原体感染的产物可以增强HPV进入其靶细胞的附着和进入，（2）确定是否是否 TLR3信号传导调节CT对增加HPV感染的影响，以及（3）确定生殖道是否存在 衣原体感染将使小鼠更容易受到随后的乳头瘤病毒感染的影响。确认我们 假设将揭示对CT-HPV共感染的新见解，TLR3在改变共同感染和结局中的作用以及 隐式TLR3是治疗干预措施的潜在靶标，以防止CT触发的HPV感染中的肿瘤发生 患者。