登革熱病毒感染在熱帶與亞熱帶城鄉地區導致登革熱 (dengue fever) 的流行，大部分病例為無症狀或輕症，但發展為危及生命的登革出血熱 (dengue hemorrhagic fever ) 和登革休克綜合症 (dengue shock syndrome) 的可能性讓人無法忽視防治登革熱的重要性。角質細胞佔被登革病毒感染的皮膚細胞當中的60%，並被認為會被病毒當作感染其他細胞的橋樑。脂質代謝長年來僅被認為提供細胞能量來源。然而最近的研究開始重視脂質代謝物在調節細胞內訊號傳遞和數種疾病的發病機制中的重要性。據報導，多種黃病毒複製位置發現被脂滴 (lipid droplets) 所圍繞。脂滴主要由三酸甘油脂和膽固醇酯組成，負責中性脂質儲存和調節細胞間通訊。有研究發現，脂滴的累積受病毒感染信號控制，並且與第I型干擾素反應有關。因此，我們利用角質形成細胞株 (HaCaT) 作為我們的研究模型，研究登革病毒感染對角質形成細胞中脂質代謝以及抗病毒能力的影響。首先，我們使用登革病毒感染HaCaT細胞，收集不同時間點的細胞樣本，以油紅染色來測量脂滴大小，發現登革病毒感染後第一天脂滴增加，後兩天脂滴顯著減少。其次，通過進行三酸甘油酯和膽固醇脂熒光定量來測量脂質含量變化，結果顯示登革病毒感染後第三天，三酸甘油酯和膽固醇酯的含量均與病毒含量呈顯著負相關，表示受感染的HaCaT細胞中脂質的消耗提高，可能為病毒所用。在免疫反應與脂質的關聯性方面，有研究發現游離脂肪酸不利於干擾素的表達。接著我們測定了受登革病毒感染的HaCaT細胞中的第I型干擾素分泌水平。發現我們的感染模型中隨著時間增加，脂質消耗水平增加，並且IFN-β分泌水平減少，同時外加脂肪酸使IFN-β水平減少得更多，表明HaCaT細胞在登革病毒感染中的抗病毒功能受損，且外加脂肪酸會加重此現象。進一步我們檢測了IFNB1以及下游兩種干擾素刺激基因的基因表達，發現不論有無外加脂肪酸都呈現與IFN-β分泌水平相同的趨勢，同時我們也檢測了負責負調控第I型干擾素的USP18 (ubiquitin specific peptidase 18) 的基因表達，發現USP18在登革病毒感染HaCaT細胞後上調，並且在加入脂肪酸後上調趨勢更加明顯，說明外加脂肪酸除了能幫助登革病毒複製外，還可以強化透過USP18抑制宿主抗病毒能力的功能。

Dengue virus (DENV) infection contributes to a great range of diseases from asymptomatic infections and self-limiting dengue fever to life-threatening dengue hemorrhagic fever and dengue shock syndrome. Skin cells are highly permissive to DENV, and DENV is able to infect other cell types through skin cells. Lipid metabolism has been considered a source that provides energy to cells. However, recent findings have highlighted the importance of lipid metabolites involved in the regulation of cellular responses and pathogeneses of several diseases. Moreover, lipid droplets (LDs) are reported to surround the viral replication site. LDs, composed of triglyceride (TG) and cholesterol ester (CE), are responsible for neutral lipid storage and cellular communication. Recently, the accumulation of LDs has become a hallmark of viral infections and is also associated with the type I interferon (IFN) response. However, it remains unclear whether lipid metabolism may affect the immune response in skin cells during DENV infection. We therefore utilized the keratinocyte cell line, HaCaT cell, as our research model to study the metabolic effect of DENV infection on keratinocyte function. First, we used DENV to infect the HaCaT cells, and the cell pellets were collected to measure LD sizes. Our results demonstrated that the LD sizes of DENV-infected cells decreased on days 2 and 3 post-infection. Second, we measured the lipid content by performing TG, total cholesterol, and CE fluorometric assays. The levels of TG and CE were decreased in a viral dose-dependent manner on day 3 after DENV infection, suggesting the high consumption of lipids in infected HaCaT cells. It has been shown that the induction of antiviral response affects lipid consumption. Third, we measured type I IFN concentrations in infected HaCaT cells and also examined the expression (mRNA levels) of type I IFN, interferon-stimulated genes (ISGs), and ubiquitin specific peptidase 18 (USP18) gene. Our results showed increased levels of lipid consumption and decreased levels of type I IFN secretion, type I IFN, and ISG gene expression, indicating the impaired antiviral function of HaCaT cells in late DENV infection. Lastly, our results indicate that the upregulation of USP 18 expression might control the decreased IFN levels and addition of fatty acid might enhance this phenomenon.

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