The bladder is frequently involved in urogenital schistosomiasis, primarily infection by Schistosoma haematobium worms. Urogenital schistosomiasis is the most common form of schistosomiasis worldwide and is estimated to affect at least 112 million people. Another 436 million individuals are at risk of infection. We and others have shown that deposition of S. haematobium eggs in the bladder induces type 2 inflammation-mediated, bladder-specific sequelae such as hematuria, urinary frequency, urothelial hyperplasia, and bladder carcinogenesis. Treatment with praziquantel can reverse early, mild bladder pathology in approximately 75% of patients, but fails to cure advanced pathology. There is a critical need to better understand the earliest host responses to egg deposition in order to identify new approaches to prevent progression to advanced bladder pathology. However, it is difficult to study early schistosomal bladder pathology in humans, since the onset of egg deposition in the bladder is uncertain in most affected individuals, and it is unethical to perform medically unnecessary bladder biopsies in these individuals to obtain tissue. Natural infection of mice with S. haematobium cercariae, the infective larval stage for humans, does not result in bladder involvement. Thus, natural infection of mice is a poor model for schistosomal bladder pathogenesis. Nevertheless, failing to advance our understanding of schistosomal bladder pathology will perpetuate the 150,000 annual deaths caused by obstructive renal failure secondary to schistosomal bladder fibrosis. To address this knowledge gap, we developed the first tractable mouse model of urogenital schistosomiasis. In this model, mice undergo laparotomy, the bladder is exteriorized, and then S. haematobium eggs are injected into the bladder wall. S. haematobium egg injection triggers hematuria, urinary frequency, urothelial hyperplasia, and granulomatous fibrosis, akin to human urogenital schistosomiasis. However, this model is limited by its dependence on laparotomy, which results in non- specific local and systemic inflammation. Thus, the current mouse model of urogenital schistosomiasis may not optimally reflect human disease due to confounding, non-specific immune effects of laparotomy. Other workers have refined the bladder wall injection technique by using ultrasound to guide percutaneous injection of tumor cells into the bladder wall, which avoids a laparotomy. The goal of this application is to develop a next generation model of schistosomal bladder pathogenesis through use of ultrasound-guided, percutaneous injection of the mouse bladder wall with S. haematobium eggs. Once our project is completed, we will have more precise knowledge regarding early bladder changes induced by S. haematobium eggs, unhindered by any confounding immune effects of laparotomy. Completion of this project will improve animal welfare and have a positive impact on urogenital schistosomiasis research by helping to find novel therapeutic targets to prevent early schistosomal bladder pathology from advancing to irreversible disease.
The bladder is frequently involved in urogenital schistosomiasis, primarily infection by Schistosoma haematobium worms, but schistosomal bladder pathogenesis is understudied due to a historical lack of a good animal model. To address this need we developed the first tractable mouse model of urogenital schistosomiasis, wherein mice undergo laparotomy, the bladder is exteriorized, and then S. haematobium eggs are injected into the bladder wall, and results in schistosomal bladder pathogenesis very similar to human disease. To bypass laparotomy-induced non-specific inflammation and thereby further improve our mouse model, we propose to develop a next generation mouse model of urogenital schistosomiasis via ultrasound- guided, percutaneous injection of the bladder wall.
