微小核糖核酸155藉由誘導第一型血紅素氧化酶調節抗病毒干擾素反應抑制登革熱病毒複製

登革熱病毒（DENV）是一種新興的蚊媒病毒，是一種嚴重的全球性健康問題，由於在熱帶和亞熱帶地區引起登革熱，登革出血熱或登革熱休克綜合症而導致嚴重的發病率和死亡率。臨床上，沒有有效可以抗DENV藥物和疫苗。過去的研究報導說microRNAs（miRNA）是一種非編碼小RNA，可以直接改變病毒的生命週期和病毒與宿主之間的相互作用。因此，miRNA被認為是控制病毒感染有希望的小分子。在本研究中，我們觀察到miR-155在DENV感染時下調。相比之下，miR-155的外源性過表達似乎限制了體外病毒複製，這表明低水平的miR-155可能有利於DENV複製。進一步體內分析，過表達的miR-155可以保護ICR乳鼠免於危及生命的DENV感染並減少DENV繁殖。進一步的研究表明，miR-155的抗DENV活性是由於透過指標HO-1抑製劑Bach1誘導血紅素加氧酶-1（HO-1）信號傳導途徑，其中HO-1抑製劑SnMP的治療減弱miR-155的抗DENV活性。此外，HO-1介導的抗病毒干擾素反應，包括干擾素誘導的蛋白激酶R（PKR），2'-5'-寡聚腺苷酸合成酶1（OAS1），OAS2和OAS3表達，顯示出對DENV複製的關鍵作用miR-155過表達的存在。總的來說，我們的研究結果提供了一種新的有前景的策略，通過調控miR-155表達來抑制DENV感染。

關鍵字

第一型血紅素氧化酶微小核糖核酸；登革熱病毒

並列摘要

Dengue virus (DENV), an emerging mosquito-borne virus, infection is a severe global health problem with substantial morbidity and mortality due to causing dengue fever, dengue hemorrhagic fever or dengue shock syndrome in tropical and sub-tropical areas. Clinically, there is no effective drug and vaccine against DENV. Past studies have reported that microRNAs (miRNAs), the small noncoding RNAs, could directly alter virus life cycle and virus-host interactions. Thus, miRNAs are considered as promising molecules controlling virus infection. In the present study, we observed that the expression of miR-155 was down-regulated upon DENV infection. By contrast, exogenous overexpression of miR-155 limited viral replication in vitro, suggesting that the reduction of miR-155 expression may be beneficial for DENV replication. Further in vivo analysis, the overexpressed miR-155 could protect ICR suckling mice from life-threatening DENV infection and reduce DENV propagation. Further investigation revealed that anti-DENV activity of miR-155 was due to induction of heme oxygenase-1 (HO-1) signaling pathway by targeting Bach1, a transcriptional suppressor of HO-1. In constrast, the treatment of HO-1 inhibitor SnMP attenuated the anti-DENV activity of miR-155. Moreover, miR-155-mediated HO-1 induction resulted in production of interferon and several interferon-mediated antiviral genes, including the double-stranded RNA-activated protein kinase R (PKR), 2′-5′-oligoadenylate synthetase 1 (OAS1), OAS2, and OAS3. Collectively, our results provide a new promising strategy to block DENV infection by modulation of miR-155 expression.