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Measles virus induces persistent infection by autoregulation of viral replication

View Article: PubMed Central - PubMed

ABSTRACT

Natural infection with measles virus (MV) establishes lifelong immunity. Persistent infection with MV is likely involved in this phenomenon, as non-replicating protein antigens never induce such long-term immunity. Although MV establishes stable persistent infection in vitro and possibly in vivo, the mechanism by which this occurs is largely unknown. Here, we demonstrate that MV changes the infection mode from lytic to non-lytic and evades the innate immune response to establish persistent infection without viral genome mutation. We found that, in the persistent phase, the viral RNA level declined with the termination of interferon production and cell death. Our analysis of viral protein dynamics shows that during the establishment of persistent infection, the nucleoprotein level was sustained while the phosphoprotein and large protein levels declined. The ectopic expression of nucleoprotein suppressed viral replication, indicating that viral replication is self-regulated by nucleoprotein accumulation during persistent infection. The persistently infected cells were able to produce interferon in response to poly I:C stimulation, suggesting that MV does not interfere with host interferon responses in persistent infection. Our results may provide mechanistic insight into the persistent infection of this cytopathic RNA virus that induces lifelong immunity.

No MeSH data available.


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Viral RNA levels and IFN response during the establishment phase of MV persistent infection.The ratios of MV N protein (a), MV-Trailer (b), ifnb1 (c), rig-I (d), and mda5 (e) to gapdh in three independent infections are graphed. Horizontal bars indicate averages. Segmented y-axes are used in (a) and (b). (f) Relative amounts of gapdh are graphed. The cell numbers were adjusted at the time of cell harvest, except at 1 dpi because identical numbers of cells were inoculated the previous day.
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f3: Viral RNA levels and IFN response during the establishment phase of MV persistent infection.The ratios of MV N protein (a), MV-Trailer (b), ifnb1 (c), rig-I (d), and mda5 (e) to gapdh in three independent infections are graphed. Horizontal bars indicate averages. Segmented y-axes are used in (a) and (b). (f) Relative amounts of gapdh are graphed. The cell numbers were adjusted at the time of cell harvest, except at 1 dpi because identical numbers of cells were inoculated the previous day.

Mentions: To investigate the mechanism responsible for the reduction in infectious virion release during the persistent phase of MV infection, MV RNA levels were monitored during the establishment of persistent infection. The gene expressions of IFN-β and IFN response genes MDA5 and RIG-I3132 were also examined because IFN has been suggested to be involved in the establishment of persistent MV infection. MV RNA increased after 1 day of infection and then increased again between 17 and 23 dpi, followed by a decline until 28 dpi (Fig. 3a). After this period, the vRNA level remained low. Gene expression of IFN-β, RIG-I, and MDA5 were also induced in response to vRNA accumulation (Fig. 3a). Although we were unable to accurately determine the percentage of the cells that were infected at 24 h post-infection because of the syncytium, the virus infection clearly did not reach all of the cells at this time point. Thus, the expression levels of MV N protein, IFN-β and IFN response genes that were normalised with gapdh expression levels at 24 h post-infection (Fig. 3b) are probably underestimated. Nevertheless, the expression levels of MV N protein and IFN-β at this time point were higher than those of cells in the persistent phase of MV infection. These data indicate that both IFN production and signalling pathways are functional in the early phase of MV infection, prior to the establishment of persistence. When the persistent infection of MV is established after 28 dpi, the expression of these genes declines to basal levels, at which their expression is maintained. Thus, IFN does not seem to be involved in the maintenance of persistent MV infection.


Measles virus induces persistent infection by autoregulation of viral replication
Viral RNA levels and IFN response during the establishment phase of MV persistent infection.The ratios of MV N protein (a), MV-Trailer (b), ifnb1 (c), rig-I (d), and mda5 (e) to gapdh in three independent infections are graphed. Horizontal bars indicate averages. Segmented y-axes are used in (a) and (b). (f) Relative amounts of gapdh are graphed. The cell numbers were adjusted at the time of cell harvest, except at 1 dpi because identical numbers of cells were inoculated the previous day.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5121633&req=5

f3: Viral RNA levels and IFN response during the establishment phase of MV persistent infection.The ratios of MV N protein (a), MV-Trailer (b), ifnb1 (c), rig-I (d), and mda5 (e) to gapdh in three independent infections are graphed. Horizontal bars indicate averages. Segmented y-axes are used in (a) and (b). (f) Relative amounts of gapdh are graphed. The cell numbers were adjusted at the time of cell harvest, except at 1 dpi because identical numbers of cells were inoculated the previous day.
Mentions: To investigate the mechanism responsible for the reduction in infectious virion release during the persistent phase of MV infection, MV RNA levels were monitored during the establishment of persistent infection. The gene expressions of IFN-β and IFN response genes MDA5 and RIG-I3132 were also examined because IFN has been suggested to be involved in the establishment of persistent MV infection. MV RNA increased after 1 day of infection and then increased again between 17 and 23 dpi, followed by a decline until 28 dpi (Fig. 3a). After this period, the vRNA level remained low. Gene expression of IFN-β, RIG-I, and MDA5 were also induced in response to vRNA accumulation (Fig. 3a). Although we were unable to accurately determine the percentage of the cells that were infected at 24 h post-infection because of the syncytium, the virus infection clearly did not reach all of the cells at this time point. Thus, the expression levels of MV N protein, IFN-β and IFN response genes that were normalised with gapdh expression levels at 24 h post-infection (Fig. 3b) are probably underestimated. Nevertheless, the expression levels of MV N protein and IFN-β at this time point were higher than those of cells in the persistent phase of MV infection. These data indicate that both IFN production and signalling pathways are functional in the early phase of MV infection, prior to the establishment of persistence. When the persistent infection of MV is established after 28 dpi, the expression of these genes declines to basal levels, at which their expression is maintained. Thus, IFN does not seem to be involved in the maintenance of persistent MV infection.

View Article: PubMed Central - PubMed

ABSTRACT

Natural infection with measles virus (MV) establishes lifelong immunity. Persistent infection with MV is likely involved in this phenomenon, as non-replicating protein antigens never induce such long-term immunity. Although MV establishes stable persistent infection in vitro and possibly in vivo, the mechanism by which this occurs is largely unknown. Here, we demonstrate that MV changes the infection mode from lytic to non-lytic and evades the innate immune response to establish persistent infection without viral genome mutation. We found that, in the persistent phase, the viral RNA level declined with the termination of interferon production and cell death. Our analysis of viral protein dynamics shows that during the establishment of persistent infection, the nucleoprotein level was sustained while the phosphoprotein and large protein levels declined. The ectopic expression of nucleoprotein suppressed viral replication, indicating that viral replication is self-regulated by nucleoprotein accumulation during persistent infection. The persistently infected cells were able to produce interferon in response to poly I:C stimulation, suggesting that MV does not interfere with host interferon responses in persistent infection. Our results may provide mechanistic insight into the persistent infection of this cytopathic RNA virus that induces lifelong immunity.

No MeSH data available.


Related in: MedlinePlus