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bioRxiv · 10.1101/2023.08.11.552909

Artemisitene protected against murine schistosomiasis japonica through anti-parasite activity and immune regulation

Liu, M.-k.·Chen, X.-y.·Tang, J.·Liu, Z.-p.·Lin, G.-y.·Cai, J.-l.·Chen, Z.-m.·Yan, Y.·ji, X.·Yang, Z.-j.·Li, Z.
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Abstract

Schistosoma japonicum (Sj) infection induced liver granulomatous inflammation and fibrosis. As an active artemisinin analog, the implication of artemisitene (ATT) in schistosomiasis were unclear. Herein, we found that ATT significantly reduced the count of total adult worms and eggs, and increased the count of single males, injured the tegument in the surface of Sj adult worms & gynecophoral canal of males. The transcription of 98 genes in females and 48 genes in males were significantly changed, and these genes were closely related to cellular anatomical entity through gene ontology analysis. So, ATT might possess anti-parasite activity. Meanwhile, ATT treatment significantly lowered the level of glutamic oxaloacetic transaminase (AST) and glutamic pyruvic transaminase (ALT) in sera, the size of mesenteric lymph node, and granuloma, the collagen area and -SMA expression level in the liver. Liver transcriptome and multi-cytokines analysis indicated its immune regulation effect. Flow cytometry verified that the count of eosinophils in the liver were significantly increased, while the frequency of neutrophils, M1/M2 and Th1/Th2 index were significantly decreased. Therefore, we provided strong evidence that ATT has therapeutic potential through Sj clearance and anti-liver disease. Tegument development injury and immune regulation including type 2 immunity enhancement might be the mechanisms. Author summaryCurrently, there were still 290 million people worldwide who were infected by Schistosoma, and the treatment for schistosomiasis relies majorly on the use of a single drug-praziquantel. In this study, we described for the first time that artemisinin-derived artemisitene (ATT), chemically remarkably different from praziquantel, possessed the therapeutic effects on murine schistosomiasis japonica. ATT displayed both anti-Schistsosoma japonicum and anti-liver inflammation & liver fibrosis effect. Through RNA-seq and scanning electronic microscope of adult female & male worms from hepatoportal veins with or without ATT treatment, we found that the mechanisms of ATTs anti-parasites could be through injuring tegument development and then interrupting adult worms especially adult female worms clearance by immune cells such as eosinophils. Moreover, through RNA-seq of liver total RNA, ELISA of multi-cytokines in liver lysates and flow cytometry analysis of liver single cells, we found that the anti-liver diseases efficacy of ATT was associated with immune regulation especially type 2 immunity enhancement. Therefore, ATT possessed the therapeutic potential against schistosomiasis japonica and further researches were necessary for its future clinical use.

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Liu, M.-k., Chen, X.-y., Tang, J., Liu, Z.-p., Lin, G.-y., Cai, J.-l., Chen, Z.-m., Yan, Y., ji, X., Yang, Z.-j., Li, Z.. 2023-08-14. Artemisitene protected against murine schistosomiasis japonica through anti-parasite activity and immune regulation. https://doi.org/10.1101/2023.08.11.552909

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