A spatial transcriptional analsysis of Chlamydia-mediated upper genital tract pathology

衣原体介导的上生殖道病理学的空间转录分析

• 批准号: 10573583
• 负责人: Raphael H Valdivia
• 金额: $ 24.15万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-10 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10573583
• 关键词: Acute; Animal Model; Architecture; Bacteria; Catalogs; Cells; Chlamydia; Chlamydia Infections; Chlamydia muridarum; Chlamydia trachomatis; Chronic; Cicatrix; Data Set; Epithelium; Event; Female; Fibrosis; Freezing; Gene Expression; Gene Expression Profiling; Genetic Transcription; Genomics; Goals; Hormones; Human; Immune; Immunologics; Infection; Infertility; Inflammatory; Integration Host Factors; Longitudinal Studies; Mammalian Oviducts; Mediating; Molecular; Monitor; Mus; Organ; Pathologic; Pathology; Pelvic Inflammatory Disease; Phenotype; Plasmids; Play; Pregnancy; Process; Reproductive Health; Resolution; Resources; Role; Sexual Transmission; Spatial Distribution; System; Technology; Tissues; Vagina; Virulence; Virulence Factors; Woman; acute infection; cell type; chronic infection; immune cell infiltrate; insight; mouse model; mutant; pathogen; pathogenic bacteria; repaired; reproductive tract; response; single-cell RNA sequencing; tissue repair; transcriptomics

Chlamydia trachomatis is the most common sexually transmitted bacterial pathogen. C. trachomatis infections can ascend to the female upper genital tract (UGT) leading to acute and chronic infections than cause pelvic inflammatory disease and fallopian tube scarring. These inflammatory pathologies have a large negative impact on women’s reproductive health. We know remarkably little as to the cellular and molecular processes underlying acute and chronic infections of the UGT, and how they promote permanent tissue damage even long after the pathogen has been cleared. Similarly, what role Chlamydia virulence factors play in this process is largely unknown. In this application we propose to apply emerging transcriptional profiling technologies to catalogue the cellular and gene expression events from initial infection, to resolution, to fibrotic damage post bacterial clearance at single cell resolution in the female UGT following a challenge with Chlamydia muridarum, a mouse adapted Chlamydia sp. In addition, to understand the mechanisms underlying the emergence of fibrosis and how long-lasting tissue damage that can lead to infertility, we will compare cellular responses in the UGT and their corresponding single-cell gene expression profiles upon challenges with Chlamydia mutants that cause altered pathologies. These longitudinal studies will define the types of cells that drive Chlamydia-dependent inflammatory damage and provide new insight as to how the spatial distribution of these cells correlate with pathogen clearance and pathology. Furthermore, the proposed studies will provide a unique resource for the characterization of inflammatory processes and fibrotic damage in an organ of significant importance for reproductive health.

沙眼衣原体是最常见的性传播细菌病原体。C.沙眼衣原体感染 可上行至女性上生殖道（UGT）导致急性和慢性感染，引起盆腔炎 炎症性疾病和输卵管瘢痕形成。这些炎症性病理具有很大的负面影响， 影响妇女生殖健康。我们对细胞和分子过程知之甚少 潜在的急性和慢性UGT感染，以及它们如何促进永久性组织损伤， 在病原体被清除后很久。同样，衣原体毒力因子在这一过程中发挥了什么作用 基本上是未知的。在本申请中，我们提出将新兴的转录谱分析技术应用于 对从最初感染到消退再到纤维化损伤后的细胞和基因表达事件进行编目 衣原体攻毒后雌性UGT中单细胞分辨率下的细菌清除率 此外，为了了解衣原体感染的机制， 纤维化的出现和如何持久的组织损伤，可导致不孕，我们将比较细胞 UGT中的应答及其相应的单细胞基因表达谱， 衣原体突变体导致病理改变。这些纵向研究将确定细胞的类型， 驱动衣原体依赖性炎症损伤，并提供新的见解，如何空间分布， 这些细胞与病原体清除和病理学相关。此外，拟议的研究将提供 独特的资源表征炎症过程和纤维化损伤的器官， 对生殖健康非常重要。