Host-Microbiota Interactions and STI Outcomes

宿主-微生物群相互作用和性传播感染结果

• 批准号: 10596513
• 负责人: Jacques Ravel
• 金额: $ 13.66万
• 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: 2021-04-20 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10596513
• 关键词: 3-Dimensional; Anaerobic Bacteria; Animals; Atopobium vaginae; Bacterial Vaginosis; Biological; Biological Factors; Biological Models; Biomimetics; Cell Culture Techniques; Cell physiology; Cells; Chlamydia Infections; Chlamydia trachomatis; Complex; Data; Disease Progression; Environment; Epithelial Cells; Epithelium; Ethics; Gardnerella vaginalis; Genetic Transcription; Goals; Histologic; Histology; Homeostasis; Human; Immune response; Immunity; Immunologics; Indigenous; Infection; Intervention; Knowledge; Knowledge acquisition; Lactobacillus; Metagenomics; Methodology; Modeling; Mucous Membrane; Mucous body substance; Outcome; Pathogenesis; Pattern; Preclinical Testing; Predisposition; Preventive; Prevotella; Process; Property; Research; Resistance; Risk; Role; Seminal fluid; Series; Severity of illness; Sexually Transmitted Agents; Sexually Transmitted Diseases; Structure; Syndrome; Testing; Therapeutic; Woman; cervicovaginal; comparative; host microbiota; immune function; in vivo; innovation; metabolomics; metatranscriptomics; microbial composition; microbiome; microbiota; microorganism; permissiveness; pre-clinical assessment; prevent; programs; 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 Project 1 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. Innovative and advanced 3D biomimetic 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. Project 1 aims to develop a better understand of the host-microbiota interactions and how they modulate the fate of C. trachomatis infection. In this project, the biomimetic models 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). Project 1 will also assess the preclinical potential of the model for testing preventive (Aim 2) and therapeutic (Aim 3) interventions against STIs. For these studies, Project 1 will leverage the full force of an array of state-of-the-art omics methodologies, including metatranscriptomics and RNA-sequencing to identify and characterize alterations of microbiota and host cellular homeostasis, metagenomics and metataxonomics to define the composition of carefully reconstructed microbiota or from human donors on the biomimetic models, and glycomics to analyze mucus structural features.

项目摘要 人类中性传播感染（STI）的风险取决于多种生物学因素，其中 STI“允许”的宫颈阴道微生物群的发生。微生物组成 Sti-permissive微生物群类似于与阴道综合征相关的菌群， 通常由高pH（> 4.5）定义的条件，缺乏乳酸杆菌属。和一系列严格 和兼性厌氧菌，例如gardnerella daginalis，Atopobium Vaginae，Megasphaera spp。和Prevotella spp。相比之下，典型的“非疗法”微生物群以几种乳杆菌之一的形式占主导 人宫颈阴道微生物群的独特特征。非允许的机制 子宫颈阴道微生物群提供了针对性传播感染的保护，因为没有动物或细胞， 迄今为止开发的文化模型系统令人满意地再现了宫颈阴道粘膜的自然粘膜 环境作为实验感染的靶标。结果，我们对 性传播感染是不完整的，特别是与人宫颈阴道菌群的关键作用有关。我们有 建立了广泛的初步数据，支持项目1的科学前提，并指出非 - 允许的土著菌群与子宫颈上皮相互作用以建立稳态状态 这会阻止性传播感染和/或降低疾病的严重程度。相反，宽松的微生物群破坏了宿主细胞 稳态，从而允许STI进步。创新和先进的3D仿生模型 消除现有模型的继承道德和生物学局限性的子宫颈阴道粘膜将是 用于检验该假设，使用全球性传播疾病的最普遍的药物，即沙眼衣原体。项目 1旨在更好地了解宿主 - 微生物群的相互作用以及它们如何调节C的命运。 气管体感染。在这个项目中，将探索仿生模型，以询问有关如何 不同类型的微生物群（允许和非验证）调节上皮细胞功能（AIM 1） 与他们对衣原体感染的敏感性/抵抗关系的关系（AIM 2）。项目1还将评估 测试预防性（AIM 2）和治疗（AIM 3）的临床前潜能 性传播疾病。对于这些研究，项目1将利用一系列最先进的Omics方法的全部力量， 包括metatranscriptomics和RNA的顺序，以识别和表征微生物群的改变和 宿主的细胞稳态，宏基因组学和metataxonomics，以定义仔细的组成 重建的微生物群或仿生模型中的人类供体，以及分析粘液的糖果学 结构特征。