Zika virus 影響neurosphere (from iPS) 小頭症 可能 證據

幹細胞研究揭示寨卡病毒如何引發小頭症 2017年02月20日新華社柏林2月20日電近年來，巴西等美洲國家頻發新生兒小頭症。科學界已證實寨卡病毒感染與小頭症發病存在關聯，卻不清楚病毒怎樣影響胎兒腦部發育。德國研究人員日前表示，他們已經找到寨卡病毒導致小頭症的科學證據。德國科隆大學醫學院等機構研究人員在新一期《細胞－幹細胞》雜誌上報告說，他們將健康人的皮膚細胞"重新編程"，培養成誘導多能幹細胞，進而培養出神經前體細胞。神經前體細胞可分化出多種神經細胞，可謂腦部發育的"起點"。在特定實驗條件下，研究人員讓許多神經前體細胞聚集為大腦類器官，即幾毫米大小、具有三維立體結構的腦神經組織塊，這一過程模擬胚胎大腦的早期發育，並借此觀察病毒感染對胚胎大腦發育的影響。結果發現，寨卡病毒會讓參與細胞分裂的細胞器——中心體出現故障，讓神經前體細胞過早分化為成熟的神經細胞。這種"早熟"看似沒什么危害，但會使大量神經前體細胞不再參與大腦類器官成長為完整大腦的過程，導致胚胎出現小頭症。研究人員介紹，他們在實驗中使用了從小頭畸形胚胎中分離出來的寨卡病毒毒株，實驗結果為寨卡病毒導致小頭症提供了"有說服力的科學證據"。寨卡病毒主要通過埃及伊蚊傳播，也可性傳播。人感染寨卡病毒後可能出現發熱、皮疹、關節痛等類似登革熱的症狀。絕大多數感染者病情溫和，但孕婦需格外小心，一旦感染可能導致胎兒出現小頭畸形。

Zika virus disrupts molecular fingerprinting of human neurospheres/ Scientific Reports 7, Article number: 40780 (2017) 23 January 2017

Abstract Zika virus (ZIKV) has been associated with microcephaly and other brain abnormalities; however, the molecular consequences of ZIKV to human brain development are still not fully understood. Here we describe alterations in human neurospheres derived from induced pluripotent stem (iPS) cells infected with the strain of Zika virus that is circulating in Brazil. Combining proteomics and mRNA transcriptional profiling, over 500 proteins and genes associated with the Brazilian ZIKV infection were found to be differentially expressed. These genes and proteins provide an interactome map, which indicates that ZIKV controls the expression of RNA processing bodies, miRNA biogenesis and splicing factors required for self-replication. It also suggests that impairments in the molecular pathways underpinning cell cycle and neuronal differentiation are caused by ZIKV. These results point to biological mechanisms implicated in brain malformations, which are important to further the understanding of ZIKV infection and can be exploited as therapeutic potential targets to mitigate it.

Introduction Primary Microcephaly is a rare brain malformation characterized by a reduction of the cephalic perimeter. The etiology of microcephaly varies from genetic abnormalities to external agents such as the STORCH factors–Syphilis, Toxoplasma gondii, Rubella, Cytomegalovirus and Herpes virus infections. An increased number of cases of microcephaly associated with Zika virus (ZIKV) has been reported in Brazil and elsewhere. ZIKV belongs to the Flaviviridae family, which also comprises other important pathogens such as Hepatitis C virus (HCV), West Nile virus (WNV), Japanese encephalitis virus (JEV) and dengue virus (DENV). Since the outbreak of ZIKV-associated microcephaly was observed, the cellular effects of ZIKV infection were rapidly explored. ZIKV alters cell cycle and triggers caspase-mediated cell death in iPS-derived neural progenitors. It reduces the growth of brain organoids and impairs neuronal differentiation in vitro. Recent studies using mouse models also confirmed the association between ZIKV infection and brain malformations. RNA data from microcephalic embryonic mice, human fibroblasts and neural progenitors showed deregulation of many individual genes related to viral response. The molecular pathways associated with ZIKV self-replication and its relation to the failure of central nervous system growth is yet to be discovered. Here we examine the interactome map of proteins and genes altered by ZIKV infection. Combining large scale, state of the art transcriptome and proteome analysis, we identified molecular pathways associated with the Brazilian ZIKV infection in human neurospheres. We show that ZIKV alters the molecular fingerprint of neural stem cells by activating responses to viral replication, DNA damage targets, cell cycle arrest, apoptosis, as well as the downregulation of neurogenic programs. These results shed light on potential molecular mechanisms implicated in brain malformations as a result of congenital ZIKV infection.