Doctor of Philosophy (PhD)
Immunology, Pathology & Infectious Disease
Paul H. Davis
Schistosoma mansoni, schistosomiasis, parasitic diseases
Schistosomiasis is a significant human disease caused by the helminth parasite Schistosoma mansoni. Praziquantel remains the only clinically used treatment, yet it is rapidly metabolized and only effective against the adult stage worm infection. Ro 13-3978 (AR02) is a potent antischistosomal compound with activity against multiple S. mansoni life stages; however, it manifests anti-androgenic activity. Additionally, the mechanism of action for worm clearance remains unknown. The structure of Ro 13-3979 was used to generate optimized derivatives, including AR102, that show increased potency towards worms, reduced off-target anti-androgen effects, and extended half-life thereby increasing the feasibility for a single-dose curative treatment. Animal knockout experiments and worm ex vivo assays suggest AR102 and analogs may be host-modulating with no direct lethal activity against worms. In this work, innate immune cells are identified as participating in worm clearance. With scRNA sequencing, we identify transcriptional changes in AR102-treated enriched splenocytes that include hallmarks of neutrophilic differentiation indicating a neutrophil or leukocyte mobilization phenotype may be present. Moreover, flow cytometry analysis of mouse blood neutrophils similarly detect population changes, including increased CD63+ neutrophils. Further, a neutrophil elastase-specific inhibitor (BAY85) significantly reverses AR02-mediated WBR in vivo, suggesting neutrophils are necessary for aryl hydantoin-mediated worm burden reduction. Additionally, expanded studies on adults Schistosoma mansoni identify a consistent transcriptional phenotype with the aryl hydantoins but with low magnitude of transcriptional changes relative to praziquantel and mefloquine controls. Moreover, an ex vivo study noted that aryl hydantoins reduce worm viability with the addition of diluted whole blood. Overall, these findings suggest the mode of action may include effects on both the host and worms, similar to praziquantel. However, the identification of a molecular target will likely be necessary to identify the target(s) of the antischistosomal aryl hydantoins.
Schulze, Thomas, "Towards a Mode of Action for the Anti-Schistosomal Aryl Hydantoins" (2023). Theses & Dissertations. 785.
Available for download on Wednesday, December 03, 2025