為了發展以調控先天免疫作為對抗病毒的策略，我們選擇廣泛分布在細胞中的粒線體抗病毒蛋白（MAVS）作為標的建立抗病毒藥物篩選系統，想藉由此系統篩選出可影響MAVS所調控的干擾素誘發訊號之標的基因及藥物。首先，我們建立了誘導型myc-MAVS基因表現系統，並挑選出兩株myc-MAVS表現時間有所差異細胞株（A549+on/myc-MAVS#10, #19），其可經由doxycycline（Dox）誘導表現出具功能性的myc-MAVS蛋白質，並引起下游的干擾素誘發訊號（IFN-induction signal）、並造成細胞死亡。藉由實驗結果我們發現在A549+on/myc-MAVS#10中調降 autophagy related 5（ATG5）基因表現，或加入chloroquine（CQ）可增強經Dox誘導後MAVS所調控的干擾素誘發訊號。CQ還可增強A549+on/myc-MAVS#10經Dox誘導後-干擾素的mRNA表現量與分泌量。而A549+on/myc-MAVS#19分別以辛德畢斯病毒（sindbis virus； SINV）、水泡性口炎病毒（vesicular stomatitis virus； VSV）及登革病毒（DENV）感染後加入藥物處理，發現同時經Dox及CQ處理之細胞皆有最佳抗病毒效果。這代表CQ為具有潛力之增強先天免疫對抗病毒的藥物。綜合以上結果顯示，表現shATG5及chloroquine（CQ）可分別作為藥物/基因篩選系統中的對照組。藉由未來持續建構高通量抗病毒藥物/基因篩選系統，我們期望能篩選出增強先天免疫力的廣效性抗病毒藥物。

Virus infection is a thorny problem in clinic because of limited therapeutics for each pathogenic virus. The mitochondrial antiviral signaling (MAVS) is a cellular adaptor protein that mediates interferon (IFN) induction and death signals in response to the infection of various viruses. To manipulate MAVS-triggered antiviral signaling, we established a stable cell line A549+on/myc-MAVS, in which myc-MAVS is ectopically expressed in the presence of doxycycline (Dox). As expected, two clones of the A549+on/myc-MAVS cells, which expressed myc-MAVS and triggered IFN-induction and cell death signals with different kinetics, were selected in this study. We found that silencing autophagy related 5 (ATG5) gene expression or administration of chloroquine (CQ) could facilitate myc-MAVS-triggered antiviral signaling in A549+on/myc-MAVS. Moreover, the levels of intracellular IFN mRNA and secreted IFN proteins were further enhanced by CQ in A549+on/myc-MAVS cells with Dox treatment. The conditioned culture media derived from A549+on/myc-MAVS with both CQ and Dox treatment showed the highest antiviral activity among the others. Importantly, this CQ-enhanced MAVS signaling functionally suppressed the replication of various viruses, including dengue, sindbis, and vesicular stomatitis virus, although the exact mechanism remain to be determined. Therefore shATG5 expression and CQ treatment could serve as the control gene and chemical respectively in a MAVS-targeted antiviral drug/gene screen system. Based on the broad-spectrum antiviral activity of the IFN system, we expect this new screening system could rapidly provide antiviral candidates against variety of pathogenic viruses in the future.

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