根據次世代定序分析，我們發現了登革病毒的感染降低了Mitochondria ATP F1-F0 synthase β subunit (ATP5B)的表現。而miRNA array分析結果顯示miR-101的表現被登革病毒降低。首先，ATP5B基因靜默或其小分子抑制劑oligomycin A也能夠抑制登革病毒之複製。利用細胞層面的實驗我們觀察到miR-101抑制ATP5B的表現可有效抑制登革病毒的複製。且我們發現miR-101提升了AMP-activated protein kinase (AMPK)的活性並且進一步的對AKT-NF-κB-CREB調控之cyclooxygenase-2 (COX-2)基因表現產生負調控。相反的過度表現外源性之COX-2將會降低miR-101造成之ATP5B基因靜默所產生的抗登革病毒之效果。值得注意的是，攜帶有miR-101之腺病毒能夠有效的保護ICR未離乳小鼠不受到登革病毒感染所產生之生命威脅。登革病毒感染及其病毒蛋白質會影響粒線體功能，進而導致粒線體氧化壓力產生，而粒線體氧化壓力被證實會誘導heme oxygenase-1 (HO-1)表現。於本論文中我們發現HO-1表現量於登革病毒感染早期提升而於感染晚期被抑制。若是在感染晚期誘導或外源性表現HO-1則可有效抑制登革病毒複製。此外，HO-1的抗病毒效果會受到其小分子抑制劑tin protoporphyrin (SnPP)的削弱。在HO-1的代謝產物中，膽綠素透過對於登革病毒蛋白酶的非競爭型的抑制效果(抑制常數為8.55 ± 0.38 μM)來達到抑制登革病毒的效果。如預期的，我們觀察到利用cobalt protoporphyrin (CoPP)誘導HO-1或是過度表現外源性之HO-1能夠回復受到登革病毒所抑制之抗病毒干擾素反應並且抑制登革病毒複製，顯示誘導HO-1表現是一個有潛力的抗登革病毒策略。基於上述之發現，我們篩選了許多天然物並且發現andrographolide以及celastrol可以顯著的延後由登革病毒造成的小鼠疾病或是死亡的發生，並且有效的降低了小鼠腦中之登革病毒複製量。在登革病毒造成之出血研究中，很有趣的我們發現提升HO-1可以保持登革感染之EA.hy926細胞單層膜的完整性以及降低登革病毒所造成之胞移作用。且其也具有保護AG129小鼠免於登革病毒造成之出血現象。本研究清楚的指出以ATP5B/COX-2以及HO-1當作標靶將可能是一個有潛力之對抗登革病毒感染或是登革相關疾病之策略。

According to next-generation sequencing (NGS) analysis, we found that the expression of Mitochondria ATP F1-F0 synthase β subunit (ATP5B) was up-regulated by dengue virus (DENV) infection. In the microRNA (miRNA) array analysis the expression of miR-101 was down-regulated by DENV infection. Firstly, we found that ATP5B gene silencing or specific inhibitor oligomycin A treatment resulted in suppression of DENV replication. Due to down-regulation of ATP5B expression by miR-101, we observed that miR-101 also can inhibit DENV replication through increase of AMP-activated protein kinase (AMPK) activity, leading to down-regulation of the AKT-NF-κB-CREB axis-mediated cyclooxygenase-2 (COX-2) expression. Notably, exogenous expression of COX-2 attenuated the antiviral effect of miR-101. Using an ICR suckling mouse model, we demonstrated that adenovirus carrying miR-101 can protect the mice from the strike of life-threatening DENV infection. DENV infection and viral proteins cause activation of mitochondrial electron transport chain, leading to generation of mitochondrial reactive oxygen species (ROS) which has been reported to be associated with heme oxygenase-1 (HO-1) induction. In the present study, we observed that HO-1 expression levels were up-regulated at early phase of DENV infection, but down-regulated at late phase of DENV infection. When HO-1 was induced or exogenously overexpressed at late phase of DENV infection, DENV replication was effectively inhibited. The antiviral effect of HO-1 was attenuated by its inhibitor tin protoporphyrin (SnPP). Among HO-1 metabolites, biliverdin, but not carbon monoxide and ferrous ions, non-competitively inhibited DENV protease, with an inhibition constant (Ki) of 8.55 ± 0.38 μM. DENV protease has been reported to block cellular antiviral interferon responses. As expected, HO-1 induction by cobalt protoporphyrin (CoPP) or exogenous overexpression of HO-1 could rescue DENV-suppressed antiviral interferon responses against DENV replication, indicating that HO-1 induction is a potential strategy to inhibit DENV replication. Based on these findings, we identified two natural products, andrographolide and celastrol, with high HO-1 inductive activity exhibited a significant delay in the onset of disease, mortality, and virus load in the infected mice’s brains of the DENV-infected ICR suckling mouse. In the DENV-caused hemorrhagic study, it is interesting to found that the HO-1 induction can maintain the integrity of DENV-infected EA.hy926 cell monolayer and decrease DENV-induced transcytosis in the EA.hy926 cells. The HO-1 induction also showed the protective effect against DENV-induced plasma leakage in the DENV-infected AG129 mouse. In conclusion, targeting ATP5B/COX-2 and HO-1 signaling pathways is a promising strategy against DENV infection and DENV-induced hemorrhage.

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