根據之前的研究顯示，人類臍帶血 (HUCB) 及孕婦胎盤會有病毒感染的現象。此外，研究也顯示，登革病毒（DENV）可以有效感染骨髓組織中的造血幹細胞(HSC），並且顯示造血幹細胞或許具有作為病毒潛伏性感染儲存庫的能力。利用細胞表面標誌分子 CD133 及 CD34 作為造血幹細胞的標的，可以發現在人類臍帶血中有大量造血幹細胞存在，而在登革病毒感染的個案中我們可以發現有母子垂直感染的特性，因此，在我的研究中，我們試著探討登革病毒是否可以感染人類臍帶血中的造血幹細胞並改變其特性。結果顯示人類臍帶血細胞確實可以被登革病毒感染，其中帶有CD133 及 CD34細胞表面標誌的造血幹細胞可以作為病毒長期潛伏感染的儲存庫，並且在利用非洲綠猴腎臟細胞 (Vero cell) 共培養後可以重新活化潛伏於造血幹細胞中的登革病毒。
方法：在我的研究中，我們與成大醫院婦產科合作取得新鮮的人類臍帶血檢體後，首先以登革病毒感染臍帶血細胞，再以多色流式細胞儀分析被感染的細胞族群。免疫螢光染色(IFA)被用以證實病毒確實感染造血幹細胞。t-隨機鄰近嵌入法(t-SNE) 則用來分析在登革病毒感染後，非結構蛋白-1 (NS1) 與細胞族群分布及探討登革病毒潛伏於造血幹細胞中的關聯性。
主要發現：人類臍帶血細胞非常易受登革病毒的感染，而在登革病毒感染後可以增加造血幹細胞族群，並且影響造血幹細胞中具分化下游細胞功能相關的GATA轉錄因子1, 2, 3的表達量並改變其平衡。免疫螢光染色(IFA) 則顯示登革病毒感染後，確實發現病毒非結構蛋白-1表現在帶有CD133 及 CD34細胞表面標誌的造血幹細胞。t-隨機鄰近嵌入法(t-SNE) 分析則顯示 CD133+NS1+ 及 CD34+NS1+ 細胞的異質性分布。此外，在長時間感染CD133+ 和 CD34+ 造血幹細胞後，即使上清液中病毒量降低，但卻可以在細胞內發現登革病毒顆粒的存在。
意義：了解造血幹細胞受登革病毒感染的機制可以更進一步知道在懷孕期間感染對於胎兒及母親造成的影響。透過我的研究可以為登革病毒感染提供新觀點以利了解登革病毒如何透過感染造血幹細胞並造成母子垂直感染現象，並且證明登革病毒具有潛伏性及持續性感染的特性，另外也更加了解病毒在細胞的傳播及如何躲避免疫系統。期望以此研究能發展出預防新生兒早產及登革出血熱之相關策略。

Incidence of viral infection has been reported in human umbilical cord blood cells (HUCB) as well as the placenta of pregnant women. Recent studies have shown that Dengue virus (DENV) can efficiently infect bone marrow hematopoietic stem cells (HSC).CD133 and CD34 are known to be markers of HSCs, which are present in abundance in HUCB. Several lines of evidence have suggested (HSCs) being a long-lived reservoir of the virus as a latent infection. In this study, we attempted to explore whether DENV can infect HUCB, as the placenta has been evidenced to be associated with mother- to-infant vertical transmission. Here, we proposed that human UCB cells were permissive to the DENV infection and DENV infected CD133+ and CD34+ HSCs are reservoir of the virus that could be reactivated upon re-culturing in Vero cells.
Methods: In this study, human UCB cells were freshly obtained and subjected to DENV infection. Multicolor flow cytometry (MFCM) was used to demonstrate the phenotypes of the infected HSC populations. Immunofluorescence analysis (IFA) and T-distributed Stochastic Neighbor Embedding (t-SNE) were used to show the association of the DENV antigen, non-structural protein1 (NS1), with HSCs and Vero co-culture platform to recover the virus.
Key findings: UCB cells were highly permissive to DENV infection. DENV altered the phenotype of the infected HSC population, increased the expression of HSCs, and affected the balance of transcription factors (TFs, GATA1/2/3). IFA revealed the association of the DENV antigen, non-structural protein1 (NS1), with CD34 and CD133 cells. T-distributed Stochastic Neighbor Embedding (t-SNE) analysis revealed heterogeneity in the distribution of CD133+NS1+, and CD34+ NS1+ cells. DENV particles were recovered from CD133+ and CD34+ cells even when virus production in the supernatant was negligible even after prolonged infection.
Significance: The evidence of DENV infection in primitive hematopoietic stem cells will give a better understanding of immunological changes in the fetus and response to infection in the mother. The new emerging insight of DENV infections and mode of transmission from mother to newborn via stem cells residing in the UCB will corroborate this research on the mechanism of viral latency and persistent infection, the cell-cell transmission of DENV and DENV immune escape, which is crucial in strategies to develop prevention of pre-term birth and dengue hemorrhagic fever in infants.

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