Development of Broad-spectrum Drugs against Enteroviruses: Action Mechanism of Anthracycline Compounds as Inducers of Interferon Signaling

• Main Authors: Yu-Shan Lin, 林昱珊
• Other Authors: Szu-Hao Kung
• Format: Others
• Language: zh-TW
• Published: 2016
• Online Access: http://ndltd.ncl.edu.tw/handle/y6pr8v

碩士 === 國立陽明大學 === 醫學生物技術暨檢驗學系 === 104 === Enteroviruses (EVs) belong to enterovirus genus in the family of Picornaviridae. EVs infection causes hand, foot, and mouth disease and neurological diseases in young children. The type I interferons (IFNs) represent a major host innate immunity against invading viruses. However, enteroviruses have evolved many mechanisms to counteract type I IFN production and the IFN-induced signaling, making treatment of EV infections with IFNs unlikely. Our previous study showed that Idarubicin (IDR) inhibits EVs replication by selectively targeting the virus internal ribosomal entry site (IRES). Moreover, IDR has recently been reported to promote IFN stimulating response element (ISRE) activity at points after IFN receptor binding. However, the molecular mechanism of IDR underlying the IFN signal induction and antiviral effects remains to be explored. In this study, we showed that IDR promoted JAK-STAT pahway activation and ISGF3 translocation in HeLa cells. Knockdown of either tyrosine kinase 2 (Tyk2) or signal transducer and activator of transcription 1 (STAT1) resulted in a significant decrease of IDR-induced ISRE activity. On the other hand, knockdown of IFN-receptor gene did not affect the ISRE activity upon IDR treatment, a finding consistent with a previous report. In addition, we showed that STAT1 phosphorylation and the downstream 2'-5'-oligoadenylate synthetase 2 (OAS2) upregulation were mediated by extracellular signal-regulated kinase (ERK). Furthermore, we also found that some other anthracycline compounds induced ISRE activity in the context of infection by other serotypes of EV. In sum, we have attempted to elaborate the molecular mechanisms underlying the IFN signal-inducing activation by IDR. This finding could lead to develop a broad-spectrum anti-EV drug based on IFN signal stimulation.