登革病毒為人類重要的致病原，藉由宿主因子參與病毒的複製。透過抑制病毒複製可做為對抗登革病毒減少發病率與死亡率的策略之一，但是目前疫苗或是可以對抗登革病毒的製劑都還只限於動物實驗或是臨床試驗階段。藉由大規模篩檢細胞轉錄因子的研究證實在登革病毒感染單核吞噬細胞時會活化細胞內轉錄因子NFAT。研究發現登革病毒會透過傳統路徑係經由脾臟酪胺酸酶 (Syk)/磷脂質脂解酶 (PLC)/三磷酸肌醇 (IP3)/鈣離子/鈣調磷酸酶 (calcineurin) 調控NFATc1，並且也會透過非正規路徑係經蛋白質激酶A (PKA) 活化磷脂酰肌醇3-激酶 (PI3K) 進而抑制肝醣合成酶激酶3 GSK-3) 而維持NFATc1的核內活化態。我們也發現到病毒的外套膜蛋白 (envelope protein) 結合宿主C型凝集素受器 (CLEC5A) 活化脾臟酪胺酸酶訊號而調控NFATc1。重要的是調節NFATc1在細胞內的表現量可以影響登革病毒的複製。NFATc1的活化並不會影響病毒進入細胞，但是卻會影響乙型干擾素的反應進而幫助病毒的複製。另外，抑制NFATc1的路徑並不會影響到宿主細胞因感染病毒進而活化相關轉錄因子干擾素調控因子3 (IRF3)。相對的，使用聚肌胞苷酸 (poly(I:C)) 刺激單核吞噬細胞並不會活化NFATc1，但是過度活化NFATc1可以減少聚肌胞苷酸誘導的乙型干擾素反應。本論文的結果證實了NFATc1新穎的角色係在登革病毒感染單核吞噬細胞中NFATc1可影響乙型干擾素的反應進而助益於登革病毒的複製。

Dengue virus (DENV), an important human pathogen, may utilize host factors to facilitate viral replication. Inhibiting viral replication is one of strategies to reduce morbidity and mortality associated with DENV infection; however, no vaccine or anti-DENV drugs are available clinically. By screening a panel of transcriptional factors, we found nuclear factor of activated T-cells (NFATc1) was unusually activated by DENV infection in mononuclear phagocytes. DENV triggered NFATc1 activation canonically in spleen tyrosine kinase/phospholipase C/inositol-1,4,5-triphosphate/calcium/calcineurin-regulated pathway as well as synergistically by protein kinase A/phosphatidylinositide 3-kinase/glycogen synthase kinase-3-regualted manner. The envelope protein of DENV determined NFATc1 activation through C-type lectin domain family 5 member A/spleen tyrosine kinase signaling. Manipulating NFATc1 caused effects on DENV replication. NFATc1 activation was unable to affect DENV entry but regulated DENV-induced IFN-β response to facilitate DENV replication. Infection of DENV did not cause interference on interferon regulatory transcription factor (IRF) 3 activation. In contrast with DENV, treatment of polyinosinic-polycytidylic acid (poly(I:C)) did not cause NFATc1 activation but NFATc1 overexpression reduced poly(I:C)-induced IFN-β response. These results demonstrate a novel and the pathogenic role of NFATc1, which facilitates DENV replication by altering IFN-β response in mononuclear phagocytes.

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