Compartmented neuronal cultures reveal two distinct mechanisms for alpha herpesvirus escape from genome silencing.

Alpha herpesvirus genomes encode the capacity to establish quiescent infections (i.e. latency) in the peripheral nervous system for the life of their hosts. Multiple times during latency, viral genomes can reactivate to start a productive infection, enabling spread of progeny virions to other hosts....

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Main Authors: Orkide O Koyuncu, Margaret A MacGibeny, Ian B Hogue, Lynn W Enquist
Format: Article
Language:English
Published: Public Library of Science (PLoS) 2017-10-01
Series:PLoS Pathogens
Online Access:http://europepmc.org/articles/PMC5658187?pdf=render
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author Orkide O Koyuncu
Margaret A MacGibeny
Ian B Hogue
Lynn W Enquist
author_facet Orkide O Koyuncu
Margaret A MacGibeny
Ian B Hogue
Lynn W Enquist
author_sort Orkide O Koyuncu
collection DOAJ
description Alpha herpesvirus genomes encode the capacity to establish quiescent infections (i.e. latency) in the peripheral nervous system for the life of their hosts. Multiple times during latency, viral genomes can reactivate to start a productive infection, enabling spread of progeny virions to other hosts. Replication of alpha herpesviruses is well studied in cultured cells and many aspects of productive replication have been identified. However, many questions remain concerning how a productive or a quiescent infection is established. While infections in vivo often result in latency, infections of dissociated neuronal cultures in vitro result in a productive infection unless lytic viral replication is suppressed by DNA polymerase inhibitors or interferon. Using primary peripheral nervous system neurons cultured in modified Campenot tri-chambers, we previously reported that reactivateable, quiescent infections by pseudorabies virus (PRV) can be established in the absence of any inhibitor. Such infections were established in cell bodies only when physically isolated axons were infected at a very low multiplicity of infection (MOI). In this report, we developed a complementation assay in compartmented neuronal cultures to investigate host and viral factors in cell bodies that prevent establishment of quiescent infection and promote productive replication of axonally delivered genomes (i.e. escape from silencing). Stimulating protein kinase A (PKA) signaling pathways in isolated cell bodies, or superinfecting cell bodies with either UV-inactivated PRV or viral light particles (LP) promoted escape from genome silencing and prevented establishment of quiescent infection but with different molecular mechanisms. Activation of PKA in cell bodies triggers a slow escape from silencing in a cJun N-terminal kinase (JNK) dependent manner. However, escape from silencing is induced rapidly by infection with UVPRV or LP in a PKA- and JNK-independent manner. We suggest that viral tegument proteins delivered to cell bodies engage multiple signaling pathways that block silencing of viral genomes delivered by low MOI axonal infection.
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spelling doaj.art-d754fc43169e4fe7b51917f94c5f497d2022-12-22T00:29:16ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742017-10-011310e100660810.1371/journal.ppat.1006608Compartmented neuronal cultures reveal two distinct mechanisms for alpha herpesvirus escape from genome silencing.Orkide O KoyuncuMargaret A MacGibenyIan B HogueLynn W EnquistAlpha herpesvirus genomes encode the capacity to establish quiescent infections (i.e. latency) in the peripheral nervous system for the life of their hosts. Multiple times during latency, viral genomes can reactivate to start a productive infection, enabling spread of progeny virions to other hosts. Replication of alpha herpesviruses is well studied in cultured cells and many aspects of productive replication have been identified. However, many questions remain concerning how a productive or a quiescent infection is established. While infections in vivo often result in latency, infections of dissociated neuronal cultures in vitro result in a productive infection unless lytic viral replication is suppressed by DNA polymerase inhibitors or interferon. Using primary peripheral nervous system neurons cultured in modified Campenot tri-chambers, we previously reported that reactivateable, quiescent infections by pseudorabies virus (PRV) can be established in the absence of any inhibitor. Such infections were established in cell bodies only when physically isolated axons were infected at a very low multiplicity of infection (MOI). In this report, we developed a complementation assay in compartmented neuronal cultures to investigate host and viral factors in cell bodies that prevent establishment of quiescent infection and promote productive replication of axonally delivered genomes (i.e. escape from silencing). Stimulating protein kinase A (PKA) signaling pathways in isolated cell bodies, or superinfecting cell bodies with either UV-inactivated PRV or viral light particles (LP) promoted escape from genome silencing and prevented establishment of quiescent infection but with different molecular mechanisms. Activation of PKA in cell bodies triggers a slow escape from silencing in a cJun N-terminal kinase (JNK) dependent manner. However, escape from silencing is induced rapidly by infection with UVPRV or LP in a PKA- and JNK-independent manner. We suggest that viral tegument proteins delivered to cell bodies engage multiple signaling pathways that block silencing of viral genomes delivered by low MOI axonal infection.http://europepmc.org/articles/PMC5658187?pdf=render
spellingShingle Orkide O Koyuncu
Margaret A MacGibeny
Ian B Hogue
Lynn W Enquist
Compartmented neuronal cultures reveal two distinct mechanisms for alpha herpesvirus escape from genome silencing.
PLoS Pathogens
title Compartmented neuronal cultures reveal two distinct mechanisms for alpha herpesvirus escape from genome silencing.
title_full Compartmented neuronal cultures reveal two distinct mechanisms for alpha herpesvirus escape from genome silencing.
title_fullStr Compartmented neuronal cultures reveal two distinct mechanisms for alpha herpesvirus escape from genome silencing.
title_full_unstemmed Compartmented neuronal cultures reveal two distinct mechanisms for alpha herpesvirus escape from genome silencing.
title_short Compartmented neuronal cultures reveal two distinct mechanisms for alpha herpesvirus escape from genome silencing.
title_sort compartmented neuronal cultures reveal two distinct mechanisms for alpha herpesvirus escape from genome silencing
url http://europepmc.org/articles/PMC5658187?pdf=render
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AT ianbhogue compartmentedneuronalculturesrevealtwodistinctmechanismsforalphaherpesvirusescapefromgenomesilencing
AT lynnwenquist compartmentedneuronalculturesrevealtwodistinctmechanismsforalphaherpesvirusescapefromgenomesilencing