Schistosomiasis is a neglected tropical disease caused by parasitic flatworms, called schistosomes, that affects hundreds of millions of the world?s poorest people. The pathology of this disease stems from the fact that schistosomes can lay hundreds-to-thousands of eggs per day while living in the blood vessels of their human hosts. Therefore, understanding the mechanisms that control schistosome egg production could present new opportunities to both limit the spread of the disease and abrogate the pathology caused by the parasite. Interestingly, female schistosomes only become sexually mature when they are in constant physical contact with a male worm. Indeed, females grown in the absence of male worms produce no eggs and cause no serious adverse consequences in their hosts. Although the requirement of male worms for female sexual development was described almost 100 years ago, there are few insights into how this process is regulated on a molecular level. A major impediment for addressing this issue is that current culture conditions do not support schistosome sexual development in vitro. To address this issue we have developed a novel media formulation that supports male-induced female sexual development and long-term egg production in vitro. Capitalizing on this medium, we have made two important observations. First, we find that gene expression changes in females immediately upon pairing with a male worm do not occur in the reproductive organs, but rather in the parasite?s somatic tissues including neurons and muscle cells. Second, we identified a transcription factor highly expressed in the nervous system and muscle cells that is essential for female sexual development after pairing with a male worm. Based on these data, we hypothesize that somatic non-reproductive cell types in the female worm are responsible for perceiving the presence of the male worm and in turn regulating the development of the reproductive organs. Defining the cell types directly responsible for perceiving the presence of the male worm could provide important clues about the nature of the male-derived signal that controls female sexual development. Therefore, we will test our central hypothesis in two specific aims.
In Specific Aim 1 we will describe the cellular and molecular response of the reproductive and somatic tissues of the female worm to pairing with a male worm using basic developmental biology approaches and single cell RNA sequencing.
Specific Aim 2 will utilize RNA interference and single cell RNA sequencing to discover genes and somatic cell types that are essential for controlling female maturation and determine how these genes act in concert to coordinate the female response to pairing with a male. We expect these studies to define the signaling events that stimulate female maturation and hope they will suggest new therapeutic targets against schistosomes.
These studies are pertinent to public health since they aim to understand the mechanisms that control reproduction of the human pathogen Schistosoma mansoni. Completion of the proposed research could aid in the discovery of new drugs to combat disease caused by this important human parasite.
