登革病毒感染是病媒蚊傳播的病毒感染中最盛行的疾病，雖然目前已有一種經食品藥物管理局核准的登革疫苗，但其疫苗效力及安全性仍有爭議而且臨床上也還沒有有效的抗病毒藥物，這些需求都有待進一步研究解決。對於藥物開發部分，目前主要針對宿主調控或是病毒因子發展不同策略。由於登革病毒感染其疾病嚴重程度和血液中的促發炎性細胞激素(巨噬細胞移動抑制因子)有關，而且巨噬細胞移動抑制因子能夠促進細胞自噬，而過去研究顯示登革病毒複製需要誘導細胞的細胞自噬，因此我們假設抑制巨噬細胞移動抑制因子所誘導的自噬作用能干擾登革病毒複製。我們首先顯示登革病毒感染能誘導巨噬細胞移動抑制因子從人類肝癌細胞中釋放以及促使自噬產生。另外以shRNA抑制細胞內生性巨噬細胞移動抑制因子表現或是藉由巨噬細胞移動抑制因子抑制劑阻絕其活性皆能降低登革病毒複製以及細胞自噬的形成。我們也進一步以抗生素(美諾四環素, minocycline)老藥新用在體外以及體內試驗，發現它能藉由阻斷登革病毒誘導的巨噬細胞移動抑制因子釋放以及細胞自噬而降低登革病毒感染。另一方面，登革病毒非結構性蛋白1被發現在登革病人血清中是一個會造成血漿滲漏以及凝血病變的重要病毒毒素。針對登革病毒非結構性蛋白1，我們找到一株非結構性蛋白1翅膀區域專一的單株抗體33D2能識別所有四型登革病毒非結構性蛋白1並且不會交叉辨識到人類宿主蛋白。我們根據單株抗體33D2的抗原決定位移除了在翅膀區域紊亂環上的交叉反應胺基酸，並且以此修飾後的非結構性蛋白1翅膀區域胜肽免疫小鼠。我們發現這些對抗修飾後非結構性蛋白1翅膀區域的抗體，以及單株抗體33D2在體內以及體外試驗中都能減緩登革病毒感染以及非結構性蛋白1造成的血管通透性增加。此外，以修飾後的非結構性蛋白1翅膀區域胜肽主動免疫以及被動給予小鼠單株抗體33D2皆能減輕登革病毒造成的凝血病變、出血以及死亡率。總結，這些結果指出巨噬細胞移動抑制因子以及非結構性蛋白1都能作為有潛力的治療性標靶，並且以非結構性蛋白1為基礎的疫苗很可能可以成為有效的次代登革疫苗

Dengue virus (DENV) infection is the most prevalent mosquito-borne viral infection. Although there is a Food and Drug Administration (FDA)-approved dengue vaccine, the efficacy and safety of the vaccine are still arguable. In addition, there is still no effective anti-viral drug. Therefore, the development of effective drugs and vaccines against DENV infection is of great importance. Different strategies targeting either host regulation or viral factors have been investigated for therapeutic potential against DENV. Macrophage migration inhibitory factor (MIF), a proinflammatory cytokine, was increased in sera from DENV patients which correlated with disease severity. Previous studies have shown that autophagy is required for DENV replication. Since MIF is able to induce autophagy, we hypothesized that inhibition of MIF-induced autophagy can limit DENV replication. We first showed that DENV infection induced MIF secretion and autophagic flux in human hepatoma cell line (HuH-7 cells). Suppression of endogenous MIF by short hairpin RNA or inhibition of MIF activity by MIF inhibitors can attenuate DENV infection and autophagy. Furthermore, minocycline, a tetracycline derivative antibiotic, could attenuate DENV infection by blocking DENV-induced MIF secretion and autophagy both in vitro and in vivo. On the other hand, DENV nonstructural protein 1 (NS1) which can be found in sera of DENV patients, is believed to act as a critical viral toxin contributing to vascular leakage and coagulopathy. Based on DENV NS1 structural analysis, we identified a NS1 wing domain (WD)-specific monoclonal antibody (mAb) 33D2 which can recognize all four serotypes of DENV NS1. According to the epitope recognized by mAb 33D2, we designed a synthetic peptide which represents the modified NS1-WD disordered loop to immunize mice. We found that antibodies (Abs) against modified NS1-WD and mAb 33D2 can attenuate DENV infection as well as NS1-induced endothelial permeability both in vitro and in vivo. In addition, both active immunization with modified NS1-WD peptide and passive transfer of mAb 33D2 into mice can alleviate DENV-induced coagulopathy, hemorrhage and mortality. Taken together, these results indicate that both MIF and NS1 are potential therapeutic targets against DENV infection and that NS1-based vaccine development may be an alternative approach towards a next generation dengue vaccine.

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