R01AI168306

Genital Immune, Mucosal, and Viral Effects of Female Genital Schistosomiasis in Tanzania - 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. This results in symptoms including genital discharge, bleeding, pain, and infertility. Despite praziquantel therapy effectively killing parasite worms and resolving most tissue pathology in the bladder, chronic genital tract damage and symptoms persist in approximately 70% of women.

In contrast to the bladder, parasite eggs remain trapped in genital tissue post-treatment. Autopsy studies have shown that these eggs induce a mucosal immune response characterized by granuloma formation and fibrosis. Female genital schistosomiasis 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, decrease anti-viral immune cells, cause breakdowns in the epithelial barrier, and increase recurrences of HSV-2. This results 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 treatment.
2) Determine the molecular mechanisms linked to breakdown of genital epithelial integrity in women with S. haematobium infection.
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. Furthermore, it advances novel studies of parasites and viruses to expand our understanding of interactions between helminths, mucosal immunity, and viral infections.

Weill Medical College Of Cornell University

TO ASSIST PUBLIC AND PRIVATE NONPROFIT INSTITUTIONS AND INDIVIDUALS TO ESTABLISH, EXPAND AND IMPROVE BIOMEDICAL RESEARCH AND RESEARCH TRAINING IN INFECTIOUS DISEASES AND RELATED AREAS; TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS. TO ASSIST PUBLIC, PRIVATE AND COMMERCIAL INSTITUTIONS TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS, TO PROVIDE RESEARCH SERVICES AS REQUIRED BY THE AGENCY FOR PROGRAMS IN INFECTIOUS DISEASES, AND CONTROLLING DISEASE CAUSED BY INFECTIOUS OR PARASITIC AGENTS, ALLERGIC AND IMMUNOLOGIC DISEASES AND RELATED AREAS. PROJECTS RANGE FROM STUDIES OF MICROBIAL PHYSIOLOGY AND ANTIGENIC STRUCTURE TO COLLABORATIVE TRIALS OF EXPERIMENTAL DRUGS AND VACCINES, MECHANISMS OF RESISTANCE TO ANTIBIOTICS AS WELL AS RESEARCH DEALING WITH EPIDEMIOLOGICAL OBSERVATIONS IN HOSPITALIZED PATIENTS OR COMMUNITY POPULATIONS AND PROGRESS IN ALLERGIC AND IMMUNOLOGIC DISEASES. BECAUSE OF THIS DUAL FOCUS, THE PROGRAM ENCOMPASSES BOTH BASIC RESEARCH AND CLINICAL RESEARCH. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM EXPANDS AND IMPROVES PRIVATE SECTOR PARTICIPATION IN BIOMEDICAL RESEARCH. THE SBIR PROGRAM INTENDS TO INCREASE AND FACILITATE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT; TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT; AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM STIMULATES AND FOSTERS SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS; TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS; TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT; AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. RESEARCH CAREER DEVELOPMENT AWARDS SUPPORT THE DEVELOPMENT OF SCIENTISTS DURING THE FORMATIVE STAGES OF THEIR CAREERS. INDIVIDUAL NATIONAL RESEARCH SERVICE AWARDS (NRSAS) ARE MADE DIRECTLY TO APPROVE APPLICANTS FOR RESEARCH TRAINING IN SPECIFIED BIOMEDICAL SHORTAGE AREAS. IN ADDITION, INSTITUTIONAL NATIONAL RESEARCH SERVICE AWARDS ARE MADE TO ENABLE INSTITUTIONS TO SELECT AND MAKE AWARDS TO INDIVIDUALS TO RECEIVE TRAINING UNDER THE AEGIS OF THEIR INSTITUTIONAL PROGRAM.

93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

New York, New York 100654805 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 385% from $637,595 to $3,090,162.