Anemoside B4 inhibits enterovirus 71 propagation in mice through upregulating 14-3-3 expression and type Ⅰ interferon responses  

作　　者：Nai-xin Kang Yue Zou Qing-hua Liang Yan-er Wang Yan-li Liu Guo-qiang Xu Han-dong Fan Qiong-ming Xu Shi-lin Yang Di Yu 

机构地区：[1]College of Pharmaceutical Science,Soochow University,Suzhou,215123,China [2]State Key Laboratory of Bioactive Substance and Function of Natural Medicines,Institute of Materia Medica,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing,100050,China [3]Institute of Aging Research,School of Medicine,Hangzhou Normal University,Hangzhou,310036,China [4]Department of Immunology,Genetics and Pathology,Science for Life Laboratory,Uppsala University,Uppsala,Sweden

出　　处：《Acta Pharmacologica Sinica》2022年第4期977-991,共15页中国药理学报（英文版）

基　　金：This work was jointly supported by the National Natural Science Foundation of China(Nos.81903896,82073912,81273402);China Postdoctoral Science Foundation(No.2021M692359);the Open Project of State Key Laboratory of Bioactive Substance and Function of Natural Medicines of Chinese Academy of Medical Sciences and Peking Union Medical College(No.GTZK202007);Suzhou Science and Technology Plan Project(SYS2019032);Priority Academic Program Development(PAPD)of Jiangsu Higher Education Institutions.

摘　　要：Enterovirus 71 (EV71) is the major pathogens of human hand, foot, and mouth disease (HFMD). EV71 efficiently escapes innate immunity responses of the host to cause infection. At present, no effective antiviral drugs for EV71 are available. Anemoside B4 (B4) is a natural saponin isolated from the roots of Pulsatilla chinensis (Bunge) Regel. P. chinensis extracts that shows a wide variety of biological activities. In this study, we investigated the antiviral activities of B4 against EV71 both in cell culture and in suckling mice. We showed that B4 (12.5–200 μM) dose dependently increased the viability of EV71-infected RD cells with an IC50 value of 24.95 ± 0.05 μM against EV71. The antiviral activity of B4 was associated with enhanced interferon (IFN)-β response, since knockdown of IFN-β abolished its antiviral activity. We also confirmed that the enhanced IFN response was mediated via activation of retinoic acid-inducible gene I (RIG-I) like receptors (RLRs) pathway, and it was executed by upregulation of 14-3-3 protein, which disrupted the interaction between yes-associated protein (YAP) and interferon regulatory factor 3 (IRF3). By using amino acids in cell culture (SILAC)-based proteomics profiling, we identified the Hippo pathway as the top-ranking functional cluster in B4-treated EV71-infected cells. In vivo experiments were conducted in suckling mice (2-day-old) infected with EV71 and subsequently B4 (200 mg · kg−1 · d−1, i.p.) was administered for 16 days. We showed that B4 administration effectively suppressed EV71 replication and improved muscle inflammation and limb activity. Meanwhile, B4 administration regulated the expressions of HFMD biomarkers IL-10 and IFN-γ, attenuating complications of EV71 infection. Collectively, our results suggest that B4 could enhance the antiviral effect of IFN-β by orchestrating Hippo and RLRs pathway, and B4 would be a potential lead compound for developing an anti-EV71 drug.

关 键 词：human hand foot and mouth disease enterovirus 71 anemoside B4 typeⅠIFN Hippo pathway 14-3-3 protein 

分 类 号：R72[医药卫生—儿科]