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A herpesvirus encoded deubiquitinase is a novel neuroinvasive determinant.

Lee JI, Sollars PJ, Baver SB, Pickard GE, Leelawong M, Smith GA - PLoS Pathog. (2009)

Bottom Line: The neuroinvasive property of several alpha-herpesviruses underlies an uncommon infectious process that includes the establishment of life-long latent infections in sensory neurons of the peripheral nervous system.Whether initial entry into the nervous system from peripheral tissues also requires specialized viral functions is not known.These findings indicate that the deubiquitinase contributes to neurovirulence by participating in a previously unrecognized initial step in neuroinvasion.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.

ABSTRACT
The neuroinvasive property of several alpha-herpesviruses underlies an uncommon infectious process that includes the establishment of life-long latent infections in sensory neurons of the peripheral nervous system. Several herpesvirus proteins are required for replication and dissemination within the nervous system, indicating that exploiting the nervous system as a niche for productive infection requires a specialized set of functions encoded by the virus. Whether initial entry into the nervous system from peripheral tissues also requires specialized viral functions is not known. Here we show that a conserved deubiquitinase domain embedded within a pseudorabies virus structural protein, pUL36, is essential for initial neural invasion, but is subsequently dispensable for transmission within and between neurons of the mammalian nervous system. These findings indicate that the deubiquitinase contributes to neurovirulence by participating in a previously unrecognized initial step in neuroinvasion.

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Related in: MedlinePlus

Retrograde transmission defect following anterior chamber injection.Anterior chamber injection route resulting in exposure of viral inoculum to the iris. The route of viral encephalitic spread is indicated: autonomic oculomotor nerve innervation of the iris from the ciliary ganglion (CG), which in turn receives innervation from parasympathetic neurons of the Edinger-Westphal nucleus (EW) of the midbrain. (A) Representative coronal images of EW (shown as a dashed box in coronal illustration) following anterior chamber injection or either wild-type or C26A virus. (B) Co-infection with PRV-152 and the C26A virus. Diffused GFP fluorescence and punctate RFP capsid signals are emitted from PRV-152 and the C26A viruses, respectively. Scale bars = 10 µm.
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ppat-1000387-g004: Retrograde transmission defect following anterior chamber injection.Anterior chamber injection route resulting in exposure of viral inoculum to the iris. The route of viral encephalitic spread is indicated: autonomic oculomotor nerve innervation of the iris from the ciliary ganglion (CG), which in turn receives innervation from parasympathetic neurons of the Edinger-Westphal nucleus (EW) of the midbrain. (A) Representative coronal images of EW (shown as a dashed box in coronal illustration) following anterior chamber injection or either wild-type or C26A virus. (B) Co-infection with PRV-152 and the C26A virus. Diffused GFP fluorescence and punctate RFP capsid signals are emitted from PRV-152 and the C26A viruses, respectively. Scale bars = 10 µm.

Mentions: The data up to this point indicated that the C26A virus was incapable of spread in a subset of neural circuits, but the basis for the selective loss of function could not strictly be attributed to an inability to transport in either retrograde or anterograde circuitry. Because the C26A defect was observed only in retrograde circuits innervating tissues in the anterior chamber of the eye (i.e. iris and ciliary body), which are less efficiently infected following intravitreal injections, animals were next injected in the anterior chamber of the eye directly. This infection route immediately exposes the iris and neighboring ciliary body to the viral inoculum and provides a more reliable infection of the EW with all neuroinvasive strains of PRV examined to date [25]. Consistent with the intravitreal injections, the C26A virus again failed to spread to the brain; no infection was noted in the EW or any other area of the brain in all instances (Figure 4A). In contrast, a revertant of the C26A virus was unimpaired for spread to the EW (Table 1).


A herpesvirus encoded deubiquitinase is a novel neuroinvasive determinant.

Lee JI, Sollars PJ, Baver SB, Pickard GE, Leelawong M, Smith GA - PLoS Pathog. (2009)

Retrograde transmission defect following anterior chamber injection.Anterior chamber injection route resulting in exposure of viral inoculum to the iris. The route of viral encephalitic spread is indicated: autonomic oculomotor nerve innervation of the iris from the ciliary ganglion (CG), which in turn receives innervation from parasympathetic neurons of the Edinger-Westphal nucleus (EW) of the midbrain. (A) Representative coronal images of EW (shown as a dashed box in coronal illustration) following anterior chamber injection or either wild-type or C26A virus. (B) Co-infection with PRV-152 and the C26A virus. Diffused GFP fluorescence and punctate RFP capsid signals are emitted from PRV-152 and the C26A viruses, respectively. Scale bars = 10 µm.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2663050&req=5

ppat-1000387-g004: Retrograde transmission defect following anterior chamber injection.Anterior chamber injection route resulting in exposure of viral inoculum to the iris. The route of viral encephalitic spread is indicated: autonomic oculomotor nerve innervation of the iris from the ciliary ganglion (CG), which in turn receives innervation from parasympathetic neurons of the Edinger-Westphal nucleus (EW) of the midbrain. (A) Representative coronal images of EW (shown as a dashed box in coronal illustration) following anterior chamber injection or either wild-type or C26A virus. (B) Co-infection with PRV-152 and the C26A virus. Diffused GFP fluorescence and punctate RFP capsid signals are emitted from PRV-152 and the C26A viruses, respectively. Scale bars = 10 µm.
Mentions: The data up to this point indicated that the C26A virus was incapable of spread in a subset of neural circuits, but the basis for the selective loss of function could not strictly be attributed to an inability to transport in either retrograde or anterograde circuitry. Because the C26A defect was observed only in retrograde circuits innervating tissues in the anterior chamber of the eye (i.e. iris and ciliary body), which are less efficiently infected following intravitreal injections, animals were next injected in the anterior chamber of the eye directly. This infection route immediately exposes the iris and neighboring ciliary body to the viral inoculum and provides a more reliable infection of the EW with all neuroinvasive strains of PRV examined to date [25]. Consistent with the intravitreal injections, the C26A virus again failed to spread to the brain; no infection was noted in the EW or any other area of the brain in all instances (Figure 4A). In contrast, a revertant of the C26A virus was unimpaired for spread to the EW (Table 1).

Bottom Line: The neuroinvasive property of several alpha-herpesviruses underlies an uncommon infectious process that includes the establishment of life-long latent infections in sensory neurons of the peripheral nervous system.Whether initial entry into the nervous system from peripheral tissues also requires specialized viral functions is not known.These findings indicate that the deubiquitinase contributes to neurovirulence by participating in a previously unrecognized initial step in neuroinvasion.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.

ABSTRACT
The neuroinvasive property of several alpha-herpesviruses underlies an uncommon infectious process that includes the establishment of life-long latent infections in sensory neurons of the peripheral nervous system. Several herpesvirus proteins are required for replication and dissemination within the nervous system, indicating that exploiting the nervous system as a niche for productive infection requires a specialized set of functions encoded by the virus. Whether initial entry into the nervous system from peripheral tissues also requires specialized viral functions is not known. Here we show that a conserved deubiquitinase domain embedded within a pseudorabies virus structural protein, pUL36, is essential for initial neural invasion, but is subsequently dispensable for transmission within and between neurons of the mammalian nervous system. These findings indicate that the deubiquitinase contributes to neurovirulence by participating in a previously unrecognized initial step in neuroinvasion.

Show MeSH
Related in: MedlinePlus