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

点击翻译按钮获取中文摘要

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.