AUTHOR=Zhang Jili , Si Hongfei , Li Bing , Zhou Xuzheng , Zhang Jiyu 

TITLE=Myrislignan Exhibits Activities Against Toxoplasma gondii RH Strain by Triggering Mitochondrial Dysfunction

JOURNAL=Frontiers in Microbiology

VOLUME=10

YEAR=2019

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2019.02152

DOI=10.3389/fmicb.2019.02152

ISSN=1664-302X

ABSTRACT=<p><italic>Toxoplasma gondii</italic> is a widespread obligatory parasitic protozoon that infects nearly all warm-blooded animals and causes toxoplasmosis. However, the current treatments for toxoplasmosis are limited by severe side effects. Myrislignan is a natural product from <italic>Myristica fragrans</italic> Houtt with wide pharmacological activities. In the current study, we tested the anti-<italic>T. gondii</italic> activity of myrislignan both <italic>in vitro</italic> and <italic>in vivo</italic> and explored its potential mechanism of action. The cytotoxicity of myrislignan in African green monkey kidney (Vero) cells was assessed using Cell Counting Kit-8 (CCK-8) assays. The <italic>in vitro</italic> effects of myrislignan on <italic>T. gondii</italic> were determined by quantitative PCR and Giemsa staining. An <italic>in vivo</italic> murine model of <italic>T. gondii</italic> infection was used to determine the efficacy of myrislignan. The changes in tachyzoites after myrislignan exposure were examined by electron microscopy. The impact of myrislignan on mitochondrial function in tachyzoites was assessed by MitoTracker Red CMXRos staining and an ATP detection kit. <italic>In vitro</italic>, myrislignan inhibited <italic>T. gondii</italic> tachyzoite proliferation with a 50% effective concentration of 32.41 μg/ml, and reduced the invasion of cells by tachyzoites (14.63 and 1.92% invasion rates for control and 70 μg/ml myrislignan, respectively). Importantly, myrislignan had no significant cytotoxicity against Vero cells at concentrations less than 132 μg/ml. In addition, surface shrinkage and mitochondrial damage were observed in tachyzoites after myrislignan exposure. The reduced Δ<italic>Ψm</italic> and ATP levels in tachyzoites treated with myrislignan further confirmed mitochondrial damage. In the <italic>in vivo</italic> murine model, myrislignan treatment significantly reduced the parasite burden in tissues compared to no treatment. In conclusion, myrislignan had potent anti-<italic>T. gondii</italic> activities both <italic>in vitro</italic> and <italic>in vivo,</italic> and these activities might involve the interruption of mitochondrial function. These data suggest that myrislignan might be a useful compound for the treatment of toxoplasmosis.</p>