Arpron Leesombun1,2, Masatomi Iijima3, Kousuke Umeda1, Daisuke Kondoh4, Baldorj Pagmadulam1, Ahmed M Abdou1,5, Yutaka Suzuki6, Shun-Ichi Ohba3, Kunio Isshiki7, Tomoyuki Kimura7, Yumiko Kubota7, Ryuichi Sawa7, Coh-Ichi Nihei7, Yoshifumi Nishikawa1. 1. National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Inada-cho, Obihiro, Hokkaido, Japan. 2. Department of Pre-clinic and Applied Animal Science, Faculty of Veterinary Science, Mahidol University, Salaya, Phutthamonthon Nakhonpathom, Thailand. 3. Institute of Microbial Chemistry, Shizuoka, Japan. 4. Department of Basic Veterinary Medicine, Obihiro University of Agriculture and Veterinary Medicine, Inada-cho, Obihiro, Hokkaido, Japan. 5. Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, South Valley University, Qena City, Egypt. 6. Graduate School of Frontier Science, University of Tokyo, Kashiwa, Chiba, Japan. 7. Institute of Microbial Chemistry, Shinagawa, Tokyo, Japan.
Abstract
BACKGROUND: Toxoplasmosis, a parasitic disease caused by Toxoplasma gondii, is an important cause of miscarriage or adverse fetal effects, including neurological and ocular manifestations in humans. Current anti-Toxoplasma drugs have limited efficacy against toxoplasmosis and also have severe side effects. Therefore, novel efficacious drugs are urgently needed. Here, we identified metacytofilin (MCF) from a fungal Metarhizium species as a potential anti-Toxoplasma compound. METHODS: Anti-Toxoplasma activities of MCF and its derivatives were evaluated in vitro and in vivo using nonpregnant and pregnant mice. To understand the mode of action of MCF, the RNA expression of host and parasite genes was investigated by RNAseq. RESULTS: In vitro, MCF inhibited the viability of intracellular and extracellular T. gondii. Administering MCF intraperitoneally or orally to mice after infection with T. gondii tachyzoites increased mouse survival compared with the untreated animals. Remarkably, oral administration of MCF to pregnant mice prevented vertical transmission of the parasite. Interestingly, RNA sequencing of T. gondii-infected cells treated with MCF showed that MCF inhibited DNA replication and enhanced RNA degradation in the parasites. CONCLUSIONS: With its potent anti-T. gondii activity, MCF is a strong candidate for future drug development against toxoplasmosis.
BACKGROUND:Toxoplasmosis, a parasitic disease caused by Toxoplasma gondii, is an important cause of miscarriage or adverse fetal effects, including neurological and ocular manifestations in humans. Current anti-Toxoplasma drugs have limited efficacy against toxoplasmosis and also have severe side effects. Therefore, novel efficacious drugs are urgently needed. Here, we identified metacytofilin (MCF) from a fungal Metarhizium species as a potential anti-Toxoplasma compound. METHODS: Anti-Toxoplasma activities of MCF and its derivatives were evaluated in vitro and in vivo using nonpregnant and pregnant mice. To understand the mode of action of MCF, the RNA expression of host and parasite genes was investigated by RNAseq. RESULTS: In vitro, MCF inhibited the viability of intracellular and extracellular T. gondii. Administering MCF intraperitoneally or orally to mice after infection with T. gondii tachyzoites increased mouse survival compared with the untreated animals. Remarkably, oral administration of MCF to pregnant mice prevented vertical transmission of the parasite. Interestingly, RNA sequencing of T. gondii-infected cells treated with MCF showed that MCF inhibited DNA replication and enhanced RNA degradation in the parasites. CONCLUSIONS: With its potent anti-T. gondii activity, MCF is a strong candidate for future drug development against toxoplasmosis.