Schistosomiasis ranks second (behind malaria) as the world?s most devastating parasitic disease. Despite this, treatment relies on a single drug, Praziquantel (PZQ), that has marginal efficacy. This disease is caused by Schistosoma flatworms (schistosomes) that live in the vasculature, producing eggs that spur a variety of chronic pathologies that are exacerbated by the fact that schistosomes can survive in the blood for decades. How these parasites thrive in this hostile environment remains an open question. Our group discovered that adult schistosomes possess a population of somatic stem cells, neoblasts, that are critical for tissue renewal. During our studies of these cells we made a surprising discovery: mechanical injury induces a massive increase in neoblast proliferation at the site of wounding. Because this mirrors what happens in highly regenerative free-living planarian flatworms, we reasoned that schistosomes may possess an uncharacterized regenerative capacity. Whole-body regeneration (i.e., regenerating amputated heads) is not known to occur in schistosomes; yet, classic studies suggest that treatment of adult worms with sub-lethal doses of PZQ results in extensive tissue damage that the worms can repair. Likewise, we find that sublethal concentrations of PZQ induce neoblast proliferation in adult parasites. Furthermore, rapidly growing juvenile schistosomes, which have a massive number of neoblasts, are refractory to PZQ. Thus, PZQ sensitivity and neoblast number are inversely correlated. Given these data, we hypothesize that neoblasts fuel regenerative responses in the worm and we predict these regenerative responses are critical to the parasite?s ability to respond to insults in vivo, including PZQ treatment. To test this hypothesis, we propose two specific aims.
In Specific Aim 1, we will use single cell RNA sequencing to describe the cellular lineages that operate during parasite development and determine whether these linages programs are ?reactivated? in adult worms following injury.
In Specific Aim 2, we will evaluate how well schistosomes are able to restore form and function to their tissues following injury and the extent to which tissue repair relies on neoblasts. We will additionally determine whether neoblast-driven regenerative responses are essential for juvenile and adult parasite survival following PZQ administration in vivo. Together, these studies will be the first to explore schistosome regenerative responses on a molecular level. Because we predict that neoblasts mediate tissue repair following PZQ-induced damage, these studies could also suggest that targeting neoblasts may enhance the efficacy of PZQ, thereby transforming how we treat this disease.
These studies are pertinent to public health since they aim to understand the roles for stem cells in 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.
| Wendt, George R; Collins, Julie Nr; Pei, Jimin et al. (2018) Flatworm-specific transcriptional regulators promote the specification of tegumental progenitors in Schistosoma mansoni. Elife 7: |
| Protasio, Anna V; van Dongen, Stijn; Collins, Julie et al. (2017) MiR-277/4989 regulate transcriptional landscape during juvenile to adult transition in the parasitic helminth Schistosoma mansoni. PLoS Negl Trop Dis 11:e0005559 |
| Wang, Jipeng; Collins 3rd, James J (2016) Identification of new markers for the Schistosoma mansoni vitelline lineage. Int J Parasitol 46:405-10 |
| Wendt, George R; Collins 3rd, James J (2016) Schistosomiasis as a disease of stem cells. Curr Opin Genet Dev 40:95-102 |
| Collins, Julie N R; Collins 3rd, James J (2016) Tissue Degeneration following Loss of Schistosoma mansoni cbp1 Is Associated with Increased Stem Cell Proliferation and Parasite Death In Vivo. PLoS Pathog 12:e1005963 |
