Schistosoma immune evasion of NETosis is reversed by aryl hydantoin Ro 13-3978

Schistosomiasis remains a major global health burden, with praziquantel as the only available treatment despite limitations such as reduced efficacy against juvenile stages. Aryl hydantoins such as Ro 13-3978 (AR02) and its derivative AR102, exhibit potent in vivo activity against all major human schistosome species, yet lack direct in vitro efficacy, suggesting a host-directed mechanism. Here, we identify neutrophils as critical mediators of aryl hydantoin activity. In a murine model of Schistosoma mansoni infection, neutrophil depletion or enzymatic degradation of extracellular DNA significantly impaired drug efficacy. Using human neutrophil co-cultures, we show that schistosomes suppress extracellular trap formation (NETosis), but aryl hydantoins restore this response without directly inducing NETs. Proteomics revealed compound-dependent modulation of neutrophil activation pathways, including chromatin remodeling and degranulation, specifically in the presence of parasite-derived products. Compound effects were limited to PMA-induced NETosis, implicating a pathway downstream of ROS production. While the precise molecular target remains elusive, our findings provide key mechanistic insight into a unique host-directed anthelmintic strategy, highlighting a neutrophil-dependent mode of action that restores NETosis suppressed by schistosomes -offering a promising pathway for immunomodulatory anti-parasitic therapies.