JQ-1 ameliorates schistosomiasis liver granuloma in mice by suppressing male and female reproductive systems and egg development of Schistosoma japonicum

Abstract

AbstractSchistosomiasis is a serious and widespread parasitic disease caused by infection with Schistosoma japonicum. Because the parasite’s eggs are primarily responsible for schistosomiasis dissemination and pathogenesis, inhibiting egg production is a potential approach to control the spread and severity of the disease. The bromodomain and extra-terminal (BET) proteins represent promising targets for the development of epigenetic drugs against Schistosoma. JQ-1 is a selective inhibitor of the BET protein family. In the present study, JQ-1 was applied S. japonicum in vitro. By using laser confocal scanning microscopy and EdU incorporation assays, we showed that application of JQ-1 to worms in vitro affected egg laying and the development of both the male and female reproductive systems. JQ-1 also inhibited the expression of the reproductive-related genes SjPlk1 and SjNanos1 in S. japonicum. Mice infected with S. japonicum were treated with JQ-1 during egg granuloma formation. JQ-1 treatment significantly reduced the size of the liver granulomas and levels of serum alanine aminotransferase and aspartate aminotransferase in mice and suppressed both egg laying and the development of male and female S. japonicum reproductive systems in vivo. Moreover, the mRNA expression levels of some proinflammatory cytokines were decreased in the parasites. Our findings suggest that JQ-1 treatment attenuates S. japonicum egg– induced hepatic granuloma due at least in part to suppressing the development of the reproductive system and egg production of S. japonicum. These findings further suggest that JQ-1 or other BET inhibitors warrant additional study as a new approach for the treatment or prevention of schistosomiasis.Author summaryAmong neglected tropical diseases, schistosomiasis is a serious disease caused by infection with the parasite Schistosomiasis japonicum. Treatment of schistosomiasis is currently almost exclusively with praziquantel, which kills mainly adult parasites, with minimal effectiveness against immature schistosomes and eggs. However, the parasite’s eggs are primarily responsible for schistosomiasis dissemination and pathology. In addition, overuse of praziquantel in epidemic areas has led to drug resistance and a reduced cure rate. Thus, new parasite targets for the development of novel therapeutics are crucial. Here, we evaluated the potential of JQ-1, a bromodomain and extra-terminal protein inhibitor, to suppress the production of S. japonicum eggs. Application of JQ-1 to S. japonicum in vitro decreased the number of mature germ cells, the rates of oviposition, and the number of eggs produced in each male-female pairing. JQ-1 treatment of mice infected with S. japonicum ameliorated hepatic granuloma and decreased serum liver enzymes, suggesting improved liver function. These results indicate that JQ-1 inhibits reproductive development and egg production in S. japonicum, providing supporting evidence that JQ-1 warrants additional study for use as a novel approach in the prevention or treatment of schistosomiasis.