茲卡病毒 (Zika virus) 和登革病毒 (dengue virus) 都是屬於由病媒蚊傳播的黃熱病毒。文獻指出此兩種黃熱病毒都能感染神經細胞並且都會導致患者神經系統相關的症狀。由於茲卡病毒和登革病毒在基因組成、傳播方式，以及所造成的臨床症狀上相似，所以在患者出現神經系統相關症狀初期時，在做病毒鑑別診斷時需要特別留意。值得注意的是，只有茲卡病毒感染孕婦會導致胎兒小頭畸形，因此可以得知茲卡病毒和登革病毒感染神經細胞的群體與病理機制具有差異，且茲卡病毒對於神經的傷害更為顯著，其中相關的病理機制包括神經細胞分化異常以及細胞發炎反應。神經幹細胞被認為是具有增殖，分化和釋放一些訊號因子等潛在功能來維持神經組織穩定的細胞之一。我們實驗室先前研究發現，帶有CD133+標誌的幹細胞容易受到登革病毒的感染。然而，我們對於茲卡病毒和登革病毒感染神經幹細胞的影響仍不清楚。為了研究茲卡病毒和登革病毒感染對於CD133+神經幹細胞病理機制上的差異，我們在此研究中，選用了一種都能被茲卡病毒和登革病毒感染，並且富含了CD133的神經母細胞瘤細胞株，SK-N-SH細胞。首先，從SK-N-SH 細胞中分選出純度高的CD133+細胞並分別讓其感染茲卡病毒或登革病毒。接著利用RNA 測序分析感染細胞中的基因轉錄譜，發現茲卡病毒感染在 CD133+細胞中誘導出比登革病毒及對照組別更多的差異基因表現，以及透過 TNF-α訊息傳遞路徑的發炎反應是茲卡病毒感染CD133＋細胞上調基因中參與最多的訊息傳遞路經。為了進一步驗證茲卡病毒感染CD133+ 細胞後能誘導出強烈的TNF-α訊息傳遞路徑，我們定量了TNF-α訊息傳遞路徑中上游基因的表達，結果顯示，在茲卡病毒感染的細胞中TNF，TRAF2，RIPK1，CIAP1 和 IKBKB基因的表現量上升。並且發現茲卡病毒感染不是利用細胞JNK 磷酸化，而是活化細胞NF-kB 入核來誘導發炎基因的轉錄。此外，茲卡病毒感染細胞會分泌出較高的TNF-α和IL-6細胞激素，並且隨著給予病毒量的增加而細胞產生的細胞激素表現量也跟著增加。接著，我們給予被茲卡病毒感染的CD133+細胞TNF-α中和性抗體，Infliximab，發現會抑制茲卡病毒感染誘導的細胞NF-κB活化入核的表現，並降低細胞釋放出的TNF-α和IL-6表現量。總結出，和登革病毒感染相比，TNF-α 相關的發炎反應可能是茲卡病毒感染影響CD133+神經幹細胞的主要潛在路徑。

Zika virus (ZIKV) and dengue virus (DENV), which share similar genetic sequences and transmission cycles, can cause neurological disorders. During early infection, attention should be paid to the differential diagnosis of neurological symptoms caused by ZIKV or DENV. The neuropathological effect of ZIKV is more significant in the aspects of not only inflammatory harm but also differentiation abnormality, indicating the different pathogenesis of ZIKV and DENV in neural cells. Findings of our laboratory have demonstrated that CD133+ stem cells are highly permissive to DENV. To study the pathological differences between two viruses in CD133+ cells, the neuroblastoma cell line, SK-N-SH with abundant CD133+ cells was utilized as the model in this study. CD133+ cells were sorted from SK-N-SH cells and infected with ZIKV or DENV before RNA sequencing to investigate the gene expression profiles, which showed that ZIKV altered more gene expression in CD133+ cells than DENV and that the inflammatory response through the TNF-α signaling pathway is significantly enhanced by ZIKV. Moreover, the expression of TNF-α signaling-related genes such as TNF, TRAF2, RIPK1, CIAP1, and IKBKB genes was upregulated in ZIKV-infected cells, and ZIKV infection activated the downstream pathway of NF-kB to induce the transcription of inflammatory genes. Additionally, ZIKV infection induced high levels of TNF-α and IL-6. Furthermore, treatment of TNF-α neutralizing antibody, Infliximab, inhibited NF-κB activation and reduced TNF-α and IL-6 expression in ZIKV-infected CD133+ cells. In summary, TNF-α signaling pathway may be the potential signaling pathway influenced by ZIKV infection in neural stem cells.

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