伴隨登革熱急遽地傳播和全球性的流行，此疾病已成全球居民的健康威脅和負擔。登革熱周期性流行是此疾病能急速傳播的重要因子，然而此現象的起因尚不清楚。大部分的登革病毒感染者是無症狀感染者，少部分為有症狀的登革熱患者。許多證據暗示受感染者康復後可能會成為長期帶原者，且病毒可能會存在於宿主的造血幹細胞及前驅細胞或器官內，隨著這些個體在社區的移動，促進登革熱周期性流行。研究登革病毒是否可以長期存在於曾感染個體及這些個體長期感染後的狀況，將能提供一些新的見解來預防登革熱的流行及降低此疾病對全球公眾衛生健康的威脅和負擔。然而長期地追蹤病毒在感染者體內的狀況是相當大的挑戰。擬人化小鼠可以用來了解病毒與人類之間的關係。因此本研究的目的是建立和描述登革病毒長期感染的擬人化小鼠模式。利用三個目標來完成此目的，第一、我們將建立登革病毒長期感染的擬人化小鼠模式；第二、分析會被登革病毒長期感染的細胞; 第三、了解登革病毒長期感染對動物造成的影響。期望藉由此動物模式可以解釋登革病毒長期帶原的可能性及可能的後果；所得重要結果顯示1)我們成功利用擬人化小鼠建立登革病毒長期感染的模式。2)登革病毒長期感染的擬人化小鼠，其血液和器官內的人類造血幹細胞及前驅細胞，都能分離出有感染性的病毒, 3)同時發現登革病毒會全身性感染這些擬人化小鼠。4)長期病毒感染會導致小鼠顯著性表現出神經性疾病症狀。綜合上述研究結果來暗示曾感染者具有成為長期帶原者的能力，且病毒可能長期感染造血及前驅幹細胞或是多種器官，進而透過病媒蚊、輸血、幹細胞及器官移植，幫助登革病毒周期性流行。因此進行移植治療前，須對來自曾感染者的造血幹細胞及前驅細胞和器官，如腎臟或肝臟進行登革病毒的檢測，將是預防登革熱的可行策略。

With the rapid dissemination and global expansion of dengue virus (DENV), dengue has become a health threat and burden for the residents of the world. Dengue cyclical emergence is a critical factor to contribute to rapid DENV dissemination, and yet the reason is not clearly elucidated. The majority of DENV infected people are asymptomatic, and only a certain percentage of affected subjects develop typical dengue. Cumulative evidence indicates that DENV infected persons may become a carrier, and the virus may reside in hematopoietic stem/ progenitor cells (HSPCs). With the mobility of carries in the community, which could potentially become a hub for the dengue cyclical emergence. Investigating whether DENV can develop a prolonged infection in an infected person and their long-term effects would provide new insights in dengue prevention as well as maneuver the impact of dengue on global public health. However, the major challenge is to prolongedly follow up the status of DENV in infected people. Humanized mice (humice) have been used to study the relationships between the virus and humans. Hence, the goal of this study is to develop and characterize the DENV prolonged infection in humice model. To achieve this goal, three aims were proposed: Aim 1: to develop the DENV prolonged infected humice model; Aim 2: to identify the cell populations that are permissive for DENV in prolongedly infected humice; Aim 3: to document and study the long-term effects in DENV prolongedly infected humice. The cumulative results were following: 1) We successfully established DENV prolonged infected humice; 2) DENV could be recovered from human HSPC in blood and multiple organs of prolonged infected humice; 3) Systemic DENV infection was found in DENV prolonged infected humice; 4) these humice developed signs of neurological disorders. These findings suggest that infected people not only may become DENV carriers but also may be involved in DENV dissemination through the blood transfusion, stem cell or organs transplantations. Therefore, HSPCs and organs such as liver or kidney, prior to transplantation from subjects living in dengue endemic regions should be checked for the DENV, which is one of feasible strategies to prevent and mitigate the spread of the dengue.

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