Host-Microbiota Interactions and Chlamydia Trachomatis Infection Outcomes

宿主-微生物群相互作用和沙眼衣原体感染结果

• 批准号: 10449336
• 负责人: LARRY J FORNEY
• 金额: $ 19.69万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-12 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10449336
• 关键词: 3-Dimensional; Anaerobic Bacteria; Animal Model; Animals; Atopobium vaginae; Bacterial Vaginosis; Biological; Biological Factors; Biological Models; Cell Culture Techniques; Cell model; Cell physiology; Cells; Chlamydia; Chlamydia Infections; Chlamydia trachomatis; Data; Development; Disease Progression; Environment; Epithelial; Epithelial Cells; Ethics; Future; Gardnerella vaginalis; Genetic Transcription; Goals; Histologic; Histology; Homeostasis; Human; Immune response; Immunologics; Incidence; Indigenous; Infection; Intervention; Knowledge; Lactobacillus; Methodology; Microscopic; Mission; Modeling; Mucous Membrane; Outcome; Pathogenesis; Pattern; Personal Satisfaction; Preclinical Testing; Predisposition; Preventive; Preventive measure; Prevotella; Public Health; Research; Resistance; Risk; Role; Severity of illness; Sexually Transmitted Agents; Sexually Transmitted Diseases; Structure; Syndrome; Testing; Therapeutic; United States National Institutes of Health; Woman; cervicovaginal; comparative; epidemiologic data; high risk; host microbiota; improved; in vivo; innovation; microbial composition; microbiota; microorganism; novel; pathogen; pre-clinical; prevent; reproductive tract; restoration; tool; transcriptome sequencing; vaginal microbiota

PROJECT SUMMARY The risk of sexually transmitted infection (STI) in humans depends on multiple biological factors, among which the occurrence of a cervicovaginal microbiota that is `permissive' to STI stands out. The microbial composition of a STI-permissive microbiota is similar to that observed in association with the syndrome of bacterial vaginosis, a condition that is generally defined by a high pH (>4.5), the absence of Lactobacillus spp. and an array of strict and facultative anaerobes such as Gardnerella vaginalis, Atopobium vaginae, Megasphaera spp., and Prevotella spp. In contrast, a typical `non-permissive' microbiota is dominated by one of several species of Lactobacillus, a unique feature of the human cervicovaginal microbiota. The mechanism(s) by which a non-permissive cervicovaginal microbiota provides protection against STIs remains poorly understood, as no animal or cell culture model system developed to date satisfactorily reproduces the cervicovaginal mucosa in its natural environment as a target for experimental infection. As a consequence, our knowledge of the pathogenesis of STIs is incomplete, particularly as it pertains to the critical role of the human cervicovaginal microbiota. We have established extensive preliminary data that support the scientific premise of this project and states that a non- permissive indigenous microbiota interacts with the cervicovaginal epithelium to establish a homeostatic state that blocks STI and/or reduces disease severity. Conversely, a permissive microbiota disrupts host cell homeostasis, thereby allowing STI to progress. Advanced 3D organotypic models of the cervicovaginal mucosa that eliminate the inherent ethical and biological limitations of existing models will be used to test this hypothesis, using the most prevalent agent of STIs worldwide, Chlamydia trachomatis. We aim to develop a better understanding of the host-microbiota interactions and how they modulate the fate of C. trachomatis infection. In this project, 3D organotypic models colonized with different types of reconstructed microbiota will be exploited to ask specific questions about how different types of microbiota (permissive and non-permissive) modulate epithelial cell functioning (Aim 1) in relationship to their susceptibility/resistance to chlamydial infection (Aim 2). We will also assess the preclinical potential of the model for testing preventive (Aim 2) and therapeutic (Aim 3) interventions against STIs. For these studies, we will leverage the full force of state-of-the-art microscopic and RNA-sequencing methodologies to identify and characterize microbiota specific alterations of structural and host epithelial homeostasis and expand our understanding of the triangular relationship between the host, the microbiota and C. trachomatis.

项目概要 人类感染性传播感染（STI）的风险取决于多种生物学因素，其中 “允许”性传播感染的子宫颈阴道微生物群的出现尤为突出。微生物组成 允许性传播感染的微生物群与细菌性阴道病综合征相关的微生物群相似， 这种情况通常由高 pH 值 (>4.5)、缺乏乳杆菌属来定义。和一系列严格的 以及兼性厌氧菌，例如阴道加德纳菌、阴道阿托波菌、巨球菌属和普雷沃菌 种。相比之下，典型的“不允许的”微生物群由几种乳酸菌中的一种占主导地位，这是一种 人类宫颈阴道微生物群的独特特征。非许可的机制 子宫颈阴道微生物群对性传播感染的保护作用仍知之甚少，因为没有动物或细胞 迄今为止开发的培养模型系统令人满意地再现了宫颈阴道粘膜的自然状态 环境作为实验感染的目标。因此，我们对疾病发病机制的了解 性传播感染是不完整的，特别是因为它涉及人类宫颈阴道微生物群的关键作用。我们有 建立了广泛的初步数据来支持该项目的科学前提，并指出非 允许的本土微生物群与宫颈阴道上皮相互作用以建立稳态 阻止性传播感染和/或降低疾病严重程度。相反，允许的微生物群会破坏宿主细胞 体内平衡，从而使性传播感染得以进展。先进的宫颈阴道粘膜 3D 器官模型 消除现有模型固有的伦理和生物学限制将用于检验这一假设， 使用世界上最流行的性传播感染病原体——沙眼衣原体。我们的目标是发展更好的 了解宿主与微生物群的相互作用以及它们如何调节沙眼衣原体感染的命运。在 该项目将利用不同类型的重建微生物群定植的 3D 器官模型 询问有关不同类型的微生物群（允许的和非允许的）如何调节的具体问题 上皮细胞功能（目标 1）与其对衣原体感染的易感性/抵抗力（目标 2）的关系。 我们还将评估该模型用于测试预防性（目标 2）和治疗性（目标 3）的临床前潜力 针对性传播感染的干预措施。对于这些研究，我们将充分利用最先进的微观和 用于识别和表征微生物群结构和宿主特异性改变的 RNA 测序方法 上皮稳态并扩大我们对宿主、细胞之间三角关系的理解 微生物群和沙眼衣原体。