Naaman Hila, Rall Glenn, Matullo Christine, Veksler-Lublinsky Isana, Shemer-Avni Yonat, Gopas Jacob
The Shraga Segal Department of Microbiology and Immunology and Genetics, Faculty of Health Sciences Ben-Gurion University of the Negev, Beer Sheva, Israel.
Fox Chase Cancer Center, Blood Cell Development and Function, Philadelphia, Pennsylvania, United States of America.
PLoS One. 2017 Oct 26;12(10):e0187077. doi: 10.1371/journal.pone.0187077. eCollection 2017.
Measles virus (MV) infects a variety of lymphoid and non-lymphoid peripheral organs. However, in rare cases, the virus can persistently infect cells within the central nervous system. Although some of the factors that allow MV to persist are known, the contribution of host cell-encoded microRNAs (miRNA) have not been described. MiRNAs are a class of noncoding RNAs transcribed from genomes of all multicellular organisms and some viruses, which regulate gene expression in a sequence-specific manner. We have studied the contribution of host cell-encoded miRNAs to the establishment of MV persistent infection in human neuroblastoma cells. Persistent MV infection was accompanied by differences in the expression profile and levels of several host cell-encoded microRNAs as compared to uninfected cells. MV persistence infection of a human neuroblastoma cell line (UKF-NB-MV), exhibit high miRNA-124 expression, and reduced expression of cyclin dependent kinase 6 (CDK6), a known target of miRNA-124, resulting in slower cell division but not cell death. By contrast, acute MV infection of UKF-NB cells did not result in increased miRNA-124 levels or CDK6 reduction. Ectopic overexpression of miRNA-124 affected cell viability only in UKF-NB-MV cells, causing cell death; implying that miRNA-124 over expression can sensitize cells to death only in the presence of MV persistent infection. To determine if miRNA-124 directly contributes to the establishment of MV persistence, UKF-NB cells overexpressing miRNA-124 were acutely infected, resulting in establishment of persistently infected colonies. We propose that miRNA-124 triggers a CDK6-dependent decrease in cell proliferation, which facilitates the establishment of MV persistence in neuroblastoma cells. To our knowledge, this is the first report to describe the role of a specific miRNA in MV persistence.
麻疹病毒（MV）可感染多种外周淋巴器官和非淋巴器官。然而，在极少数情况下，该病毒可在中枢神经系统内持续感染细胞。尽管已知一些使MV持续存在的因素，但宿主细胞编码的微小RNA（miRNA）的作用尚未见报道。miRNA是一类从所有多细胞生物和一些病毒的基因组转录而来的非编码RNA，它们以序列特异性方式调节基因表达。我们研究了宿主细胞编码的miRNA在人神经母细胞瘤细胞中建立MV持续感染过程中的作用。与未感染细胞相比，MV持续感染伴随着几种宿主细胞编码的微小RNA的表达谱和水平的差异。人神经母细胞瘤细胞系（UKF-NB-MV）的MV持续感染表现出高miRNA-124表达，并降低了细胞周期蛋白依赖性激酶6（CDK6）的表达，CDK6是miRNA-124的已知靶标，导致细胞分裂减慢但未导致细胞死亡。相比之下，UKF-NB细胞的急性MV感染并未导致miRNA-124水平升高或CDK6降低。miRNA-124的异位过表达仅在UKF-NB-MV细胞中影响细胞活力，导致细胞死亡；这意味着miRNA-124过表达仅在存在MV持续感染的情况下才能使细胞对死亡敏感。为了确定miRNA-124是否直接有助于MV持续感染的建立，对过表达miRNA-124的UKF-NB细胞进行急性感染，导致建立持续感染的集落。我们提出，miRNA-124触发了CDK6依赖性的细胞增殖减少，这有助于在神经母细胞瘤细胞中建立MV持续感染。据我们所知，这是第一份描述特定miRNA在MV持续感染中作用的报告。
