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

基本信息

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
项目类别：
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

项目摘要

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造成的雌性生殖血吸虫病（FGS）影响40 非洲的百万女孩和妇女。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的侵蚀和粘膜破坏的反应，包括生殖器排出，出血，疼痛和不育。慢性生殖道损害和症状持续约有70％的女性的普拉齐素疗法，即使praziquantel有效地杀死了寄生虫，但也减少了尿液中卵的排泄，并在膀胱中解析大多数组织病理学。相比之下，寄生虫卵仍保留在治疗后被困在生殖器组织中免疫反应以肉芽肿形成和纤维化为特征。 FGS是一种被忽视的热带疾病，我们对其细胞和分子病理生理学的理解存在重要的知识差距。我们做不知道对生殖器组织中hematobium卵反应的免疫细胞的特征或功能， FGS对上皮细胞屏障的影响，以及与FGS相关的细胞和分子变化是否增加对病毒生殖道感染的敏感性。该提议的理由是解决这些知识间隙可能导致靶向免疫调节，组织修复或病毒抑制干预措施以恢复受损的生殖器粘膜。基于我们的初步数据，我们的中心假设是止血链球菌在生殖器粘膜中调节宫颈免疫并降低抗病毒免疫细胞，导致破坏上皮障碍，并增加HSV-2的复发，导致发病率和持续症状即使经过Praziquantel疗法，FG也是如此。为了检验这一假设，我们将研究90名ha骨链球菌的女性感染和90个控制。止血炎链球菌的妇女将在基线上接受praziquantel治疗如果检测到持续或经常性的肺炎链球菌，则随访12个月。我们将追求三个具体目的：1）定义止血链球菌感染中的生殖器粘膜免疫细胞组成，前后 praziquantel之后； 2）确定与生殖器上皮完整性分解有关的分子机制造血链球菌感染的妇女； 3）量化止血链球菌感染对生殖器HSV-2重新激活的频率，强度和持续时间。在第一个目标中，我们将通过通过流量和质量细胞仪来刷和表征细胞。在第二个目标中，我们将分离上皮细胞通过颈刷收集并执行RNA-Seq以阐明基因和特定于上皮的途径正直。在第三个目标中，我们将量化来自同类女性一个月以上的HSV-2病毒脱落是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。拟议的研究很重要，因为它可能识别出新的治疗性数以百万计的FGS的女孩和女性的目标。此外，它将寄生虫和病毒的新研究推向扩展我们对蠕虫，粘膜免疫和病毒感染之间相互作用的理解。