In Vivo Egress of an Alphaherpesvirus from Axons

Tomishima, Mark; Enquist, Lynn W.

doi:10.1128/jvi.76.16.8310-8317.2002

Cited by 37 publications

(35 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, two models have been proposed for anterograde axonal transport of HSV-1. The subassembly model proposes the separate transport of viral capsids and glycoproteins with assembly and release by exocytosis either along the axon shaft or at the axon termini ( Figure 3, path A) [90][91][92][93][94][95][96][97][98][99][100][101][102]. The alternative 'married' model proposes that only fully assembled enveloped virions move down axons in vesicles (Figure 3, path B) [103,104].…”

Section: Transport Along Axonsmentioning

confidence: 99%

Transport and egress of herpes simplex virus in neurons

Diefenbach

Miranda-Saksena

Douglas

et al. 2007

Reviews in Medical Virology

166

150

View full text Add to dashboard Cite

The mechanisms of axonal transport of the alphaherpesviruses, HSV and pseudorabies virus (PrV), in neuronal axons are of fundamental interest, particularly in comparison with other viruses, and offer potential sites for antiviral intervention or development of gene therapy vectors. These herpesviruses are transported rapidly along microtubules (MTs) in the retrograde direction from the axon terminus to the dorsal root ganglion and then anterogradely in the opposite direction. Retrograde transport follows fusion and deenvelopment of the viral capsid at the axonal membrane followed by loss of most of the tegument proteins and then binding of the capsid via one or more viral proteins (VPs) to the retrograde molecular motor dynein. The HSV capsid protein pUL35 has been shown to bind to the dynein light chain Tctex1 but is likely to be accompanied by additional dynein binding of an inner tegument protein. The mechanism of anterograde transport is much more controversial with different processes being claimed for PrV and HSV: separate transport of HSV capsid/tegument and glycoproteins versus PrV transport as an enveloped virion. The controversy has not been resolved despite application, in several laboratories, of confocal microscopy (CFM), realtime fluorescence with viruses dual labelled on capsid and glycoprotein, electron microscopy in situ and immunoelectron microscopy. Different processes for each virus seem counterintuitive although they are the most divergent in the alphaherpesvirus subfamily. Current hypotheses suggest that unenveloped HSV capsids complete assembly in the axonal growth cones and varicosities, whereas with PrV unenveloped capsids are only found travelling in a retrograde direction.

show abstract

Section: Transport Along Axonsmentioning

confidence: 99%

Transport and egress of herpes simplex virus in neurons

Diefenbach

Miranda-Saksena

Douglas

et al. 2007

Reviews in Medical Virology

166

150

View full text Add to dashboard Cite

show abstract

“…These specialized connections bring membranes of the two cells in close apposition via transmembrane proteins that reach across the 20-nm cleft and impart stability to the synapse. Other in vivo and in vitro studies similarly report that the spread of PRV from an axon to the surrounding cells occurs at scattered sites along the axon and at neuronal termini (5,45). The synaptic cleft between neurons is not wide enough to accommodate a mature virion, implying that local membrane contortion may accompany transport vesicle fusion with the axonal surface.…”

mentioning

confidence: 90%

Virion-Incorporated Glycoprotein B Mediates Transneuronal Spread of Pseudorabies Virus

Curanovic

Enquist

2009

J Virol

Self Cite

View full text Add to dashboard Cite

Transneuronal spread of pseudorabies virus (PRV) is a multistep process that requires several virally encoded proteins. Previous studies have shown that PRV glycoprotein B (gB), a component of the viral fusion machinery, is required for the transmission of infection to postsynaptic, second-order neurons. We sought to identify the gB-mediated step in viral transmission. We determined that gB is not required for the sorting of virions into axons of infected neurons, anterograde transport, or the release of virions from the axon. trans or cis expression of gB on the cell surface was not sufficient for transneuronal spread of the virus; instead, efficient incorporation of gB into virions was required. Additionally, neuron-to-cell spread of PRV most likely does not proceed through syncytial connections. We conclude that, upon gB-independent release of virions at the site of neuron-cell contacts, the virion-incorporated gB/gH/gL fusion complex mediates entry into the axonally contacted cell by fusion of the closely apposed membranes.Alphaherpesviruses, which constitute a subfamily of the family Herpesviridae, include the human pathogens herpes simplex virus (HSV) and varicella-zoster virus and the swine pathogen pseudorabies virus (PRV). These closely related pantropic, neuroinvasive viruses establish latency in the peripheral nervous systems of their natural hosts. During the normal course of infection, periodic viral reactivation leads to recurrent epithelial lesions (38). Although rare in the natural host, transneuronal spread of the virus from the peripheral to the central nervous system (CNS) results in death or debilitating disease, such as encephalitis or keratitis (50). Nonnatural hosts infected with PRV almost invariably experience viral spread to the CNS and succumb to infection (36).Transneuronal spread of alphaherpesviruses is an incompletely understood multistep process that requires the concerted action of viral and cellular proteins. Following replication in the soma of an infected neuron, viral progeny may spread in the retrograde direction to the presynaptic cell or anterogradely to the postsynaptic cell. During anterograde spread of PRV, virus particles are sorted from the neuronal soma into the cognate axon. Upon entering the axonal compartment, virions are transported in a microtubule-dependent manner toward the synaptically connected cell (41). Recent in vitro evidence suggests that boutons en passant and axon termini serve as sites for PRV spread from the axon (13). Additionally, in vivo experiments demonstrate that the transneuronal spread of alphaherpesviruses is remarkably specific, occurring only between synaptically connected cells (15). This property has made alphaherpesviruses invaluable as neural circuit tracers in studies that aim to map the synaptic architecture of the CNS (14). However, the mechanisms that confer such specificity on the spread of infection are not well understood.The study of mechanisms underlying PRV trafficking revealed that the virally encoded membrane proteins Us9,...

show abstract

“…Formally, it remained possible that packaging-independent pathways could also contribute to neuron-to-target-cell spread. For some alphaherpes viruses, structural glycoproteins are dispensable for neuronal spread (15). To test whether WNV neuron-to-target-cell spread occurred in the absence of viral packing and egress, primary neurons were infected with pseudotyped WNV reporter virus particles (RVP).…”

Section: Wnv Transneuronal Spread Is Mediated By Viral Release From Dmentioning

confidence: 99%

Axonal transport mediates West Nile virus entry into the central nervous system and induces acute flaccid paralysis

Samuel

Wang

Siddharthan

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

194

176

View full text Add to dashboard Cite

West Nile virus (WNV) has emerged as a significant cause of epidemic viral encephalitis and flaccid limb paralysis, yet the mechanism by which it enters the CNS remains uncertain. We used compartmentalized neuron cultures to demonstrate that WNV spreads in both retrograde and anterograde directions via axonal transport. Transneuronal spread of WNV required axonal release of viral particles and was blocked by addition of a therapeutic neutralizing antibody. To test the physiologic significance of axonal transport in vivo, we directly inoculated the sciatic nerve of hamsters with WNV. Intrasciatic infection resulted in paralysis of the hind limb ipsilateral but not contralateral to the injection site. Limb paralysis was blocked either by surgical transection of the sciatic nerve or treatment with the therapeutic neutralizing antibody. Collectively, these studies establish that WNV undergoes bidirectional spread in neurons and that axonal transport promotes viral entry into the CNS and acute limb paralysis. Moreover, antibody therapeutics directly inhibit transneuronal spread of WNV infection and prevent the development of paralysis in vivo.flavivirus ͉ neuron ͉ retrograde ͉ transneuronal spread W est Nile virus (WNV) is a neurotropic member of the Flaviviridae family of RNA viruses and is related to other important arthropod-borne human pathogens. WNV is maintained in an enzootic cycle between mosquitoes and birds and has become an important global cause of epidemic encephalitis. Since its emergence in the United States in 1999, Ϸ26,000 cases of symptomatic WNV infection have been confirmed (www.cdc. gov/ncidod/dvbid/westnile/surv&control.htm#maps), and seroprevalence studies suggest that several million people have been infected (1).Rodent models have provided insight into the mechanisms of WNV spread to the CNS. After s.c. inoculation, WNV-infected dendritic cells traffic to the draining lymph node, resulting in a primary viremia and infection of peripheral tissues. Within 6 days, WNV is cleared from the serum and peripheral organs and enters the CNS and induces neurological disease (reviewed in ref.2). Nonetheless, the specific mechanisms by which WNV or other neurotropic flaviviruses enter into the CNS are largely unknown. CNS infection may occur in part via hematogenous spread, as increased viremia in immunodeficient mice (2) and TNF-␣-mediated changes in blood-brain-barrier permeability correlate with earlier CNS entry (3).Axonal transport from infected peripheral neurons mediates CNS entry and pathogenesis of viruses in the Herpesviridae, Rhabdoviridae, and Picornaviridae families (4-6). Viral spread in neurons is generally mediated by fast axonal transport, a microtubule-associated, anterograde and retrograde transport system. In classical studies, CNS infection of rabies virus or poliovirus was prevented by axonal ligation or degeneration (7,8). Insights into the biology of axonal spread have been facilitated by the development of compartmentalized, or Campenot, chambers for culturing neurons (9). These s...

show abstract

In Vivo Egress of an Alphaherpesvirus from Axons

Cited by 37 publications

References 37 publications

Transport and egress of herpes simplex virus in neurons

Transport and egress of herpes simplex virus in neurons

Virion-Incorporated Glycoprotein B Mediates Transneuronal Spread of Pseudorabies Virus

Axonal transport mediates West Nile virus entry into the central nervous system and induces acute flaccid paralysis

Contact Info

Product

Resources

About