Impact of the menstrual cycle on granulysin-mediated immunity in the human cervicovaginal tract
月经周期对人宫颈阴道颗粒溶素介导的免疫的影响
基本信息
- 批准号:10616798
- 负责人:
- 金额:$ 17.65万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-05-03 至 2025-04-30
- 项目状态:未结题
- 来源:
- 关键词:AlamarBlueBacteriaBiological AssayBiological Response ModifiersBiopsyBlocking AntibodiesCD4 Positive T LymphocytesCell CountCell SurvivalCellsCervicalChemicalsChlamydia InfectionsChlamydia trachomatisClinical ResearchClinical Trials DesignColumnar EpitheliumContraceptive AgentsCytolysisDetectionEffector CellEndocervixEnzyme-Linked Immunosorbent AssayEpithelial CellsFemaleFlow CytometryGranzymeGrowth FactorHemorrhageHomeHomologous GeneHormonalHormonesHumanImmuneImmune responseImmunityIn VitroIncidenceInfectionInfection ControlInfertilityInflammationInterferon Type IIKnowledgeListeria monocytogenesLuteal PhaseLuteinizing HormoneLymphocyteMeasuresMediatingMembraneMenstrual cycleMenstruationMeta-AnalysisMicrobeModelingMusNanotubesNatural Killer CellsOvulationPaperParasitesParticipantPatientsPelvic Inflammatory DiseasePeriodicityPhasePhenotypePlayPredispositionPrevalenceProcessProgesteroneProtein IsoformsProteinsPublic HealthReproductive HealthResistance developmentRoleSeminalSerumSexually Transmitted DiseasesSourceT-LymphocyteTestingTherapeuticToxoplasma gondiiTransgenic MiceTrypanosoma cruziVaginaVisitWild Type MouseWomanWomen&aposs Healthantimicrobialburden of illnesscervicovaginalchemokinecohortexperimental studygranulysinimprovedinhibitormicrobialnovelpathogenpathogenic bacteriapathogenic microbeperforinproliferative phase Menstrual cyclepublic health relevancereproductive tracttimelinetranslational potentialurinary
项目摘要
PROJECT SUMMARY/ABSTRACT
Granulysin (GNLY) is an understudied human protein necessary for cell-mediated killing of microbes, including
intracellular bacteria. We observed that GNLY is abundant in cervicovaginal tract (CVT) secretions during the
follicular phase of the menstrual cycle, but nearly absent from the luteal phase. GNLY may play a major role in
CVT immunity by killing intracellular pathogens prior to infected cell lysis (thus limiting inflammation) or even
without damaging the infected cell. Thus, the change in GNLY over the menstrual cycle may have important
consequences for women’s health, particularly susceptibility to sexually transmitted infections (STIs).
The bacterial pathogen Chlamydia trachomatis (Ct) has a large disease burden, with more than 125 million
annual infections worldwide and about 10% of untreated infections progressing to pelvic inflammatory disease,
a major cause of infertility. Because Ct is an intracellular bacterial pathogen, we hypothesize that GNLY-
expressing immune cells contribute to control of Ct in humans. There is suggestive evidence that Ct-
specific T cells may express GNLY, but GNLY has not been studied in the context of Ct. The lack of studies
may be in part due to complete control of infection by IFN-γ-producing CD4 T cells in mice. However, mice
lack a GNLY homologue, making inference from mouse studies about the role of GNLY in human Ct
infection impossible. In fact, human GNLY-transgenic mice control infection with other bacteria better than
wild-type mice that lack GNLY. Additionally, Ct infection is more commonly detected late in the menstrual
cycle, when GNLY disappears from CVT secretions.
In Aim 1, we will determine how GNLY shifts so dramatically across the menstrual cycle. We will follow
women from the follicular to the luteal phase. We will assess GNLY expression in cells from endocervical
cytobrushes and cervical and vaginal biopsies at one visit per phase, with detailed cell phenotyping. We will
assess GNLY levels in daily, self-collected secretions.
In Aim 2, we will investigate GNLY’s contributions to anti-Ct immunity and increased control of CT in the
follicular phase. We will perform in vitro experiments using Ct alone and Ct-infected cells; purified GNLY,
granzymes, and perforin; and GNLY-expressing cells.
These studies will contribute to our understanding of women’s reproductive health and STI susceptibility by
elucidating mechanisms of CVT immunity during the menstrual cycle. This knowledge is important for
designing clinical trials (such as of hormonal, especially intravaginal, contraceptives) and Ct therapeutics.
项目概要/摘要
颗粒溶素 (GNLY) 是一种尚未充分研究的人类蛋白质,对于细胞介导的微生物杀伤是必需的,包括
细胞内细菌。我们观察到 GNLY 在宫颈阴道道 (CVT) 分泌物中含量丰富
月经周期的卵泡期,但黄体期几乎不存在。 GNLY 可能发挥重要作用
CVT 免疫通过在受感染的细胞裂解之前杀死细胞内病原体(从而限制炎症)甚至
而不损坏受感染的细胞。因此,月经周期中 GNLY 的变化可能具有重要意义。
对女性健康的影响,特别是对性传播感染(STI)的易感性。
细菌病原体沙眼衣原体 (Ct) 具有巨大的疾病负担,超过 1.25 亿人
全球每年都会发生感染,约 10% 的未经治疗的感染会进展为盆腔炎,
不孕不育的一个重要原因。由于 Ct 是一种细胞内细菌病原体,我们假设 GNLY-
表达免疫细胞有助于控制人类的 Ct。有暗示性证据表明 Ct-
特定的 T 细胞可能表达 GNLY,但 GNLY 尚未在 Ct 背景下进行研究。缺乏研究
部分原因可能是由于小鼠体内产生 IFN-γ 的 CD4 T 细胞完全控制了感染。然而,老鼠
缺乏 GNLY 同源物,从小鼠研究中推断 GNLY 在人类 Ct 中的作用
感染不可能。事实上,人类 GNLY 转基因小鼠比其他小鼠更好地控制其他细菌的感染。
缺乏 GNLY 的野生型小鼠。此外,Ct 感染更常见于月经后期
循环,当 GNLY 从 CVT 分泌物中消失时。
在目标 1 中,我们将确定 GNLY 如何在整个月经周期中发生如此巨大的变化。我们将跟随
女性从卵泡期到黄体期。我们将评估宫颈管细胞中 GNLY 的表达
每阶段一次进行细胞刷以及宫颈和阴道活检,并进行详细的细胞表型分析。我们将
评估每日自行收集的分泌物中的 GNLY 水平。
在目标 2 中,我们将研究 GNLY 对抗 Ct 免疫和增强 CT 控制的贡献
卵泡期。我们将使用单独的Ct和感染Ct的细胞进行体外实验;纯化的GNLY,
颗粒酶和穿孔素;和 GNLY 表达细胞。
这些研究将有助于我们了解女性生殖健康和性传播感染的易感性
阐明月经周期期间 CVT 免疫机制。这些知识对于
设计临床试验(例如激素,尤其是阴道内避孕药)和 Ct 疗法。
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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Florian Hladik其他文献
Florian Hladik的其他文献
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{{ truncateString('Florian Hladik', 18)}}的其他基金
The push and pull of inflammation on HIV susceptibility: impact of host variation in CD101 and AXL
炎症对 HIV 易感性的推拉:CD101 和 AXL 宿主变异的影响
- 批准号:
10546199 - 财政年份:2022
- 资助金额:
$ 17.65万 - 项目类别:
Impact of the menstrual cycle on granulysin-mediated immunity in the human cervicovaginal tract
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10450305 - 财政年份:2022
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