Genital Immune, Mucosal, and Viral Effects of Female Genital Schistosomiasis in Tanzania

坦桑尼亚女性生殖器血吸虫病的生殖器免疫、粘膜和病毒影响

• 批准号: 10597102
• 负责人: Jennifer Alzos Downs
• 金额: $ 60.86万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-25 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10597102
• 关键词: Address; Affect; Africa; Aftercare; Age; Animals; Autopsy; Bladder; Brush Cell; CD14 gene; CD3 Antigens; CD8B1 gene; Case Series; Cells; Cervical; Chronic; Collecting Cell; Cytometry; Cytotoxic T-Lymphocytes; Data; Depressed mood; Disease; Enrollment; Epithelial Cells; Epithelium; Excretory function; Female genitalia; Fibroblasts; Fibrosis; Flare; Fostering; Frequencies; Functional disorder; Gene Expression; Genes; Genital; Genitalia; Genitourinary system; Goals; Granuloma; Health; Health Priorities; Helminths; Hemorrhage; Herpesviridae Infections; Hour; Human; Human Herpesvirus 2; Immune; Immune response; Immunity; Impaired healing; Impairment; Infection; Infertility; Intervention; Knowledge; Link; Macrophage; Magnetism; Matrix Metalloproteinases; Mission; Molecular; Morbidity - disease rate; Mucosal Immune Responses; Mucosal Immunity; Mucous Membrane; Mus; National Institute of Allergy and Infectious Disease; Pain; Parasites; Pathology; Pathway interactions; Peptide Hydrolases; Pharmacotherapy; Pilot Projects; Praziquantel; Predisposition; Proteins; Public Health; RNA purification; Recurrence; Reproductive Health; Research; Schistosoma; Schistosoma haematobium; Schistosomiasis; Signal Pathway; Swab; Symptoms; Tanzania; Testing; Tight Junctions; Tissues; United States National Institutes of Health; Urine; Vagina; Viral; Virus; Virus Diseases; Virus Shedding; Virus-like particle; Widespread Disease; Woman; Work; World Health Organization; cell type; chronic pain; cohort; cytokine; cytotoxic; drug standard; egg; eosinophil; experience; follow-up; genital herpes; girls; healing; immune function; immunoreaction; immunoregulation; improved; innovation; latent virus activation; metagenomic sequencing; migration; neglected tropical diseases; neovascularization; new therapeutic target; novel; novel therapeutic intervention; persistent symptom; prevent; reactivation from latency; reproductive tract; seropositive; superinfection; transcriptome; transcriptome sequencing; treatment strategy; trend; venule; virome

Project Summary/Abstract Female genital schistosomiasis (FGS), caused by the parasitic worm Schistosoma haematobium, affects 40 million girls and women in Africa. Parasite eggs migrate through mucosal tissue, inducing a host immune reaction that leads to erosions and mucosal breaches of the female genital tract with symptoms including genital discharge, bleeding, pain, and infertility. Chronic genital tract damage and symptoms persist after praziquantel therapy in ~70% of women, even though praziquantel effectively kills parasite worms, reduces excretion of eggs in urine, and resolves most tissue pathology in the bladder. In contrast, parasite eggs remain trapped in genital tissue post-treatment where, from autopsy studies, they are known to induce a mucosal immune response characterized by granuloma formation and fibrosis. FGS is a neglected tropical disease and there are important knowledge gaps in our understanding of its cellular and molecular pathophysiology. We do not know the profiles or functions of immune cells that respond to S. haematobium eggs in genital tissue, the effects of FGS on the epithelial cell barrier, and if FGS-related cellular and molecular changes increase susceptibility to viral genital tract infections. The rationale for this proposal is that addressing these knowledge gaps could lead to targeted immunomodulatory, tissue reparative, or viral suppressive interventions to restore damaged genital mucosa. Based on our preliminary data, our central hypothesis is that S. haematobium eggs in the genital mucosa modulate cervical immunity and decrease anti-viral immune cells, cause breakdowns in the epithelial barrier, and increase recurrences of HSV-2, resulting in the morbidity and persistent symptoms of FGS even after praziquantel therapy. To test this hypothesis, we will study 90 women with S. haematobium infection and 90 controls without. Women with S. haematobium will receive praziquantel treatment at baseline and during 12 months of follow up if persistent or recurrent S. haematobium is detected. We will pursue three specific aims: 1) Define the genital mucosal immune cell composition in S. haematobium infection, before and after praziquantel; 2) Determine the molecular mechanisms linked to breakdown of genital epithelial integrity in women with S. haematobium infection; and 3) Quantify the effect of S. haematobium infection on the frequency, intensity, and duration of genital HSV-2 reactivation. In the first aim, we will collect cervical cells by brush and characterize cells by flow and mass cytometry. In the second aim, we will isolate epithelial cells collected by cervical brush and perform RNA-Seq to elucidate genes and pathways specific to epithelial integrity. In the third aim, we will quantify HSV-2 viral shedding over one month in women from the cohort who are HSV-2 seropositive (n=90). In an exploratory analysis, we will also examine the vaginal virome by metagenomic sequencing. The proposed research is significant because it may identify new therapeutic targets for millions of girls and women with FGS. Further, it advances novel studies of parasites and viruses to expand our understanding of interactions between helminths, mucosal immunity, and viral infections.

项目摘要/摘要 由寄生虫血吸虫引起的女性生殖器血吸虫病(FGS)影响40 非洲有数百万女孩和妇女。寄生虫卵通过粘膜组织迁移，诱导宿主免疫 导致女性生殖道侵蚀和粘膜破裂的反应，症状包括 生殖器分泌物、出血、疼痛和不孕不育。慢性生殖道损害和症状持续存在后 大约70%的女性接受吡喹酮治疗，尽管吡喹酮有效地杀死了寄生虫，但减少了 排出尿液中的卵子，并解决膀胱中的大部分组织病理。相比之下，寄生虫卵仍然存在 被困在治疗后的生殖器组织中，根据尸检研究，它们被认为可以诱导粘膜 以肉芽肿形成和纤维化为特征的免疫反应。FGS是一种被忽视的热带疾病， 在我们对其细胞和分子病理生理学的了解方面，存在着重要的知识空白。我们有 不知道生殖器组织中对血瘤沙门氏菌卵做出反应的免疫细胞的概况或功能， FGS对上皮细胞屏障的影响，以及FGS相关的细胞和分子变化是否增加 对病毒性生殖道感染的易感性。这项提议的基本原理是，解决这些知识 差距可能导致有针对性的免疫调节、组织修复或病毒抑制干预以恢复 生殖器粘膜受损。根据我们的初步数据，我们的中心假设是血瘤沙门氏菌卵 在生殖器粘膜中调节宫颈免疫并减少抗病毒免疫细胞，导致 上皮屏障，并增加HSV-2的复发，导致 即使在吡喹酮治疗后FGS也是如此。为了验证这一假设，我们将研究90名患有嗜血杆菌的女性。 感染组和对照组各90例。患有嗜血杆菌的妇女将在基线水平上接受吡喹酮治疗 在12个月的随访期间，如果检测到持续或复发的血吸虫。我们将追求三个目标 具体目标：1)明确血瘤链霉菌感染前和感染后生殖器粘膜免疫细胞的组成 吡喹酮治疗后；2)确定与生殖器上皮完整性破坏有关的分子机制 以及3)量化血瘤链霉菌感染对妇女的影响。 生殖器HSV-2重新激活的频率、强度和持续时间。在第一个目标中，我们将通过以下方式收集宫颈细胞 用流式细胞仪和质量细胞仪对细胞进行刷检和鉴定。在第二个目标中，我们将分离上皮细胞 用宫颈刷子收集并进行RNA-Seq以阐明上皮细胞特有的基因和通路 正直。在第三个目标中，我们将量化队列中女性一个月内HSV-2病毒的脱落情况 HSV-2血清阳性(n=90)。在探索性分析中，我们还将通过 元基因组测序。这项拟议的研究意义重大，因为它可能会发现新的治疗方法 数百万患有FGS的女孩和妇女的目标。此外，它还推动了对寄生虫和病毒的新研究 扩大我们对蠕虫、粘膜免疫和病毒感染之间相互作用的理解。