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:
- 金额:$ 20.89万
- 依托单位:
- 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:
- 关键词:AccelerationAgreementAnimal ModelApoptosisAutoimmunityBasal CellBiologicalBiological AssayBiological MarkersBiological ModelsCancer EtiologyCancerousCell SurvivalCellsCervicalCervical Squamous Cell CarcinomaCessation of lifeChlamydiaChlamydia InfectionsChlamydia muridarumChlamydia trachomatisChromatinDNA DamageDNA Repair PathwayDataDeveloping CountriesDevelopmentEnzyme-Linked Immunosorbent AssayEpidemiologyEpigenetic ProcessEpithelial Cell ProliferationEpithelial CellsEpitheliumExposure toFutureGoalsHPV E7HeterochromatinHormonalHumanHuman PapillomavirusHuman papilloma virus infectionImmune responseImpairmentIn VitroInfectionInflammation MediatorsInflammatoryIntercellular JunctionsInvadedInvestigationLinkMEKsMalignant Female Reproductive System NeoplasmMalignant NeoplasmsMalignant neoplasm of cervix uteriMammalian OviductsMeta-AnalysisMusNeoplasm MetastasisNeoplasmsOncogenicOutcomePapillomavirusPapillomavirus InfectionsPapillomavirus Transforming Protein E6PathogenesisPathologyPathway interactionsPatientsPermeabilityPlayPredispositionProteinsReportingReproductive HealthRiskRoleSexual TransmissionSexually Transmitted DiseasesSignal PathwaySignal TransductionSquamous cell carcinomaStratum BasaleTLR3 geneTestingTherapeutic InterventionTissuesWomanWomen&aposs Healthcell transformationcervical carcinogenesisco-infectioncofactorefficacy evaluationepidemiologic datain vivoinnovationinsightkeratinocytelifetime riskmonolayermouse modelnovelpathogenpremalignantpreventreproductive tractresponsesenescencesensortargeted treatmenttranscriptometranscriptomicstumortumorigenesisunvaccinatedvaginal 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假定的
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,我们还提供了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
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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WILBERT A DERBIGNY其他文献
WILBERT A DERBIGNY的其他文献
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{{ truncateString('WILBERT A DERBIGNY', 18)}}的其他基金
Developing a mouse model to examine the specific impact of IFNa in the pathogenesis of genital tract Chlamydia infection
开发小鼠模型来检查 IFNa 在生殖道衣原体感染发病机制中的具体影响
- 批准号:
10041346 - 财政年份:2020
- 资助金额:
$ 20.89万 - 项目类别:
The role of TLR3 signaling in Chlamydia caused urogenital pathology
TLR3信号在衣原体引起的泌尿生殖病理中的作用
- 批准号:
8761903 - 财政年份:2014
- 资助金额:
$ 20.89万 - 项目类别:
The role of TLR3 signaling in Chlamydia caused urogenital pathology
TLR3信号在衣原体引起的泌尿生殖病理中的作用
- 批准号:
8916541 - 财政年份:2014
- 资助金额:
$ 20.89万 - 项目类别:
The role of TLR3 signaling in Chlamydia caused urogenital pathology
TLR3信号在衣原体引起的泌尿生殖病理中的作用
- 批准号:
9117379 - 财政年份:2014
- 资助金额:
$ 20.89万 - 项目类别:
The role of TLR3 signaling in Chlamydia caused urogenital pathology
TLR3信号在衣原体引起的泌尿生殖病理中的作用
- 批准号:
9327861 - 财政年份:2014
- 资助金额:
$ 20.89万 - 项目类别:
Chlamydia-infected Epithelial Cell Secretion of Immunoregulatory Cytokines
衣原体感染的上皮细胞分泌免疫调节细胞因子
- 批准号:
7470141 - 财政年份:2007
- 资助金额:
$ 20.89万 - 项目类别:
Chlamydia-infected Epithelial Cell Secretion of Immunoregulatory Cytokines
衣原体感染的上皮细胞分泌免疫调节细胞因子
- 批准号:
7317231 - 财政年份:2007
- 资助金额:
$ 20.89万 - 项目类别:
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