Abstract
Although the replication cycle of parainfluenza virus type 5 (PIV5) is initially severely impaired in cells in an interferon (IFN)-induced antiviral state, the virus still targets STAT1 for degradation. As a consequence, the cells can no longer respond to IFN and after 24−48 h, they go out of the antiviral state and normal virus replication is established. Following infection of cells in an IFN-induced antiviral state, viral nucleocapsid proteins are initially localized within small cytoplasmic bodies, and appearance of these cytoplasmic bodies correlates with the loss of STAT1 from infected cells. In situ hybridization, using probes specific for the NP and L genes, demonstrated the presence of virus genomes within these cytoplasmic bodies. These viral cytoplasmic bodies do not co-localize with cellular markers for stress granules, cytoplasmic P-bodies or autophagosomes. Furthermore, they are not large insoluble aggregates of viral proteins and/or nucleocapsids, as they can simply and easily be dispersed by ‘cold-shocking’ live cells, a process that disrupts the cytoskeleton. Given that during in vivo infections, PIV5 will inevitably infect cells in an IFN-induced antiviral state, we suggest that these cytoplasmic bodies are areas in which PIV5 genomes reside whilst the virus dismantles the antiviral state of the cells. Consequently, viral cytoplasmic bodies may play an important part in the strategy that PIV5 uses to circumvent the IFN system.
Highlights
The interferon (IFN) response is initiated when cells recognize that they have been infected by a virus and respond by producing IFN-a/b, which can act in a paracrine and autocrine manner to upregulate the expression of hundreds of cellular genes, the products of many having direct or indirect antiviral activity
Carlos and others addition of IFN to the culture medium of Vero cells which have been infected with CPI for 12 h, there is a marked alteration in the distribution of the viral nucleocapsid proteins compared with untreated cells, in that they are primarily visualized in cytoplasmic bodies at 36 h p.i. (Fig. 2 and Carlos et al, 2005)
To determine whether virus genomes are present within these cytoplasmic bodies, we employed in situ hybridization using probes specific for sequences within the NP or L genes (Fig. 3a, c), which are found at the 39 and 59 ends of the genome, respectively (Fig. 1)
Summary
The interferon (IFN) response is initiated when cells recognize that they have been infected by a virus and respond by producing IFN-a/b, which can act in a paracrine and autocrine manner to upregulate the expression of hundreds of cellular genes, the products of many having direct or indirect antiviral activity Cells recognize that they have been infected by viruses by having specific intracellular and membrane-bound pattern-recognition receptors (PRRs) which recognize pathogen-associated molecular patterns (PAMPs) within certain products, such as double-stranded RNA or uncapped 59 triphosphorylated single-stranded (ss)RNA, produced during virus replication and which are not found in uninfected cells. Two intracellular PRRs are the DExD/H-box RNA helicases, retinoic acid inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (mda-5) Once activated by their appropriate ligands, these PRRs initiate the IFN induction cascade which culminates in the production of IFN-a/b These subsequently form stable heterodimers and migrate to the nucleus where, together with IFN regulatory factor (IRF)-9, they form an active transcription complex, termed ISGF3, that initiates transcription of the ISGs (reviewed by Stark et al, 1998; Platanias, 2005; Randall & Goodbourn, 2008)
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