Cellular mechanisms by which Neisseria gonorrhoeae infects the female reproductive tract

淋病奈瑟菌感染女性生殖道的细胞机制

• 批准号: 10434772
• 负责人: WENXIA SONG
• 金额: $ 56.53万
• 依托单位: UNIV OF MARYLAND, COLLEGE PARK
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-05 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10434772
• 关键词: Actins; Address; Binding; Binding Proteins; Biological Models; Cell Culture Techniques; Cells; Cervical; Cervix Uteri; Clinical; Columnar Cell; Cytoskeleton; Drug Design; Ectopic Pregnancy; Endocervix; Environment; Epidermal Growth Factor Receptor; Epithelial; Epithelial Attachment; Epithelial Cells; Event; Exocervix; Female; Goals; Gonorrhea; Heparan Sulfate Proteoglycan; Human; Infection; Infertility; Intercellular Junctions; Intervention; Life; Link; Mediating; Modeling; Mucous Membrane; Multi-Drug Resistance; Nature; Neisseria gonorrhoeae; Outcome; Pelvic Infection; Pelvic Inflammatory Disease; Penetration; Phase; Physiological; Pilum; Predisposition; Prevention; Process; Property; Protein Isoforms; Proteins; Public Health; Regulation; Role; STI prevention; Sexual Transmission; Sexually Transmitted Diseases; Signal Transduction; Site; Squamous Epithelium; Surface; Symptoms; Testing; Therapeutic; Time; Tissue Model; Tissues; Variant; Woman; Women' s Health; base; design; emerging antibiotic resistance; in vivo; innovation; pathogen; protein expression; reproductive tract; tissue culture

Project Summary Sexually transmitted infections (STIs) are a major public health challenge and a serious women's health issue, as women can suffer severe complications from these infections: pelvic inflammatory disease (PID), infertility, and predisposition to life-threatening ectopic pregnancy. However, the majority of these infections in the female reproductive tract (FRT) are asymptomatic. How infection in the FRT causes such a wide range of clinical outcomes in the absence of symptoms remains unknown. The primary obstacle to understanding STIs of the FRT is the lack of a model that reasonably mimics all aspects of human infection. The cervix is the initiation site for STIs in the FRT. The cervical mucosa is not uniform, composed of multilayered non-polarized squamous epithelial cells at the ectocervix, a single layer of polarized columnar cells at the endocervix, and the progressively changing epithelia in the transformation zone. While tissue culture models have contributed significantly to explaining specific host-pathogen interactions, how STI pathogens deal with different epithelia for infection is unclear, as no cell culture model can mimic the varying mucosal surfaces of the human cervix. To overcome these obstacles, we are developing a new infection model using human cervical tissue explants to address our long-term goal: to delineate the mechanisms by which STI pathogens infect the FRT. To pursue this goal, this proposal focuses on the cellular mechanism by which Neisseria gonorrhoeae (GC) modulates the infection process in the human cervix. GC causes gonorrhea that is the second most common STI and a public health crisis worldwide due to the upsurge of multi-drug resistant GC. The surface molecules of GC undergo phase variation, which has been implicated in its broad infection outcomes. We hypothesize that the expression of pili and distinct variants of opacity associated proteins (Opa) allows for changes in GC infectivity, while the properties of epithelial cells of the human cervix determine which regions are vulnerable to GC infections. To test the hypothesis, we will use our human cervical tissue model and isogenic strains of GC that express invariable Opas and pili to define the cellular mechanism by which pili and Opa phase variation and the distinct properties of cervical epithelial cells regulate GC infection in the FRT. Our cervical explant model breaks a major barrier of the field, making it possible for the first time to examine cellular events occurring during GC infection to their in vivo targeted epithelial cells under a physiologically relevant environment. These studies will reveal new mechanisms that can finally explain how GC manipulate signaling and cytoskeleton based on their surface molecules and the type of epithelial cells with which they interact to switch the cervical infection between colonizing and penetrating nature. The new tissue model and infection mechanisms established by this project may fundamentally change our way to pursue the understanding of STIs and open new avenues for interventive drug designs for the prevention of STIs.

项目摘要 性传播感染(STI)是一项重大的公共卫生挑战和严重的妇女健康问题， 因为女性可能会遭受这些感染的严重并发症：盆腔炎(PID)、不孕不育、 以及易患危及生命的宫外孕。然而，这些感染大多发生在女性 生殖道(FRT)无症状。FRT中的感染是如何导致如此广泛的临床 在没有症状的情况下，结果仍然未知。理解性传播感染的主要障碍 FRT是缺乏一个合理模拟人类感染所有方面的模型。宫颈是起始点 FRT中性传播感染的地点。宫颈粘膜不均匀，由多层非极化组成 宫颈外的鳞状上皮细胞，内宫颈的单层极化的柱状细胞，以及 转化带内有渐进性变化的上皮细胞。虽然组织培养模型做出了贡献 对解释特定的宿主-病原体相互作用具有重要意义，STI病原体如何处理不同的上皮 对于感染的影响尚不清楚，因为没有细胞培养模型可以模拟人类宫颈不同的粘膜表面。 为了克服这些障碍，我们正在开发一种使用人类宫颈组织外植体的新感染模型。 为了解决我们的长期目标：描绘STI病原体感染FRT的机制。 为了实现这一目标，这项建议集中在淋球菌(GC)的细胞机制上。 调节人类宫颈的感染过程。GC引起的淋病是第二常见的疾病 由于多药耐药GC的激增，STI和全球公共卫生危机。表面分子 的GC经历了阶段变化，这与其广泛的感染结果有关。我们假设 菌毛和不透明相关蛋白(OpA)的不同变体的表达允许变化 在GC感染性方面，而人类宫颈上皮细胞的特性决定了哪些区域 容易受到GC感染。为了验证这一假设，我们将使用我们的人类宫颈组织模型和 表达不变的opas和菌毛的GC等基因菌株，以定义菌毛和菌毛的细胞机制 OPA时相变化和宫颈上皮细胞的独特特性调节着FRT中的GC感染。 我们的宫颈外植体模型打破了该领域的一大障碍，使其首次有可能 检查GC感染体内靶向上皮细胞期间发生的细胞事件 生理上相关的环境。这些研究将揭示新的机制，最终可以解释 GC根据它们的表面分子和上皮细胞的类型来操纵信号和细胞骨架 它们相互作用，使宫颈感染在侵袭性和穿透性之间切换。新的组织 这个项目建立的模型和感染机制可能会从根本上改变我们追求 了解性传播感染，为防止性传播感染的干预药物设计开辟新途径。