MiRNA-124 is a link between measles virus persistent infection and cell division of human neuroblastoma cells

Abstract

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.

High-throughput fluorescence-based screen identifies the neuronal microRNA miR-124 as a positive regulator of alphavirus infection

“…Inhibition of miR-124 expression reduces chikungunya virus (CHIKV) viral production in human cells independently of the direct binding to the viral RNA, supporting the idea that miR-124 may also play a role in the regulation of cellular targets against alphaviruses. This has already been observed for miR-124 regulation of measles virus (47), JEV (48) or HIV (49) infections. In addition, miR-124 expression is modulated by different viruses including ZIKV (50), EV71 (51), HCMV (52) or influenza H1N1 (53) suggesting a possible implication of the miRNA in the regulation of these infections as well.…”

Measles Virus Persistent Infection of Human Induced Pluripotent Stem Cells

“…Recently we have demonstrated that in MV persistently infected human neuroblastoma cells, high expression of miR-124 correlates with reduced cell division (Naaman et al, 2017). In this work we showed that expression of miR-124 in MV persistently infected BGU-iPSCs was upregulated compared to noninfected cells implying that either more cells became miR-124 positive cells and/or that MV infection led to upregulation of miR-124 expression.…”

Small Non-coding RNA Expression Following Respiratory Syncytial Virus or Measles Virus Infection of Neuronal Cells

“…Previous studies from our laboratory have shown that RSV infection of A549 cells modifies miR expression (Bakre et al, 2012(Bakre et al, , 2015(Bakre et al, , 2017) however, information regarding miR expression in RSV-or MeV-infected neuronal SHS cells is inadequate (Naaman et al, 2017;Cakmak Genc et al, 2018;Haralambieva et al, 2018). Neuronal cells are not the primary cell type infected by RSV, but they can be infected and may act as a reservoir of infection.…”

“…Other studies have shown that the pattern of miR expression is modified following RSV infection of nasal epithelial cells (Inchley et al, 2015;Hasegawa et al, 2018), and PBMCs from children (Wang et al, 2017). Deregulated miR expression occurs in MeV-infected human neuroblastoma cells and PBMCs (Inchley et al, 2015;Yis et al, 2015;Naaman et al, 2017;Hasegawa et al, 2018), as well as in PBMCs from RSV-infected children (Wang et al, 2017). It is known that MeV persistence in neuroblastoma cells is assisted by the downregulation of CDK6, a component of cell cycle progression regulated by miRNA-124 (Riddell et al, 2007;Naaman et al, 2017;Griffin et al, 2018).…”