MiR-124 CONTRIBUTES TO THE ESTABLISHMENT OF MEASLES VIRUS PERSISTENT INFECTION IN HUMAN NEUROBLASTOMA CELLS AND INDUCES APOPTOSIS WHEN OVEREXPRESSED

The measles virus (MV) may invade the central nervous system and develop a non-cytopathic, persistent infection mainly within neurons. The factors that allow this otherwise highly cytopathic virus to persist remain largely unknown.

MicroRNAs (miRs) are a class of ~22 nt-long noncoding RNAs, transcribed from all multicellular organisms and some DNA viruses. Individual miRs may regulate several hundred genes.

Here we have studied the potential contribution of host cell-encoded miRs to maintenance of MV persistent infections in human neuroblastoma cells (UKF-NB and - UKF-NB-MV.

We have shown that the MV (which does not encode miRs) modulates the expression- profile and levels of host cell-encoded miRs in persistently infected cells. miR124 is strongly expressed UKF-NB-MV but not in the non-infected UKF-NB cells. Cell division protein kinase 6 (CDK6) is an important regulator of cell cycle progression regulating G1/S transition. CDK6 is a target of mir124. We found a low CDK6 protein expression in UKF-NB-MV as compared to control UKF-NB cells. In addition we show that non-infected cells grow twice as fast as persistent MV cells, possibly due to low CDK6 expression in these cells.

When miR124-GFP was overexpressed in UKF-NB-MV cells, the cells died by apoptosis and CDK6 was further reduced. Cells transfected with ANTAGOmiR124 to inhibit miR124 expression, they divided rapidly, CDK6 was up-regulated and apoptosis was not observed.

We hypothesize that persistent MV slows down cell division through induction of miR124 and down regulating CDK6. Over expression of miR124 induces apoptosis thus contributing to the conversion from persistent to lytic infection.