Making It to the Synapse: Measles Virus Spread in and Among Neurons

Young, Virginia A.; Rall, Glenn F.

doi:10.1007/978-3-540-70617-5_1

Cited by 42 publications

(46 citation statements)

References 160 publications

(204 reference statements)

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“…Staining of the ex vivo cultures with anti-MV F protein Abs showed MV F expression during virus replication in neurons (Fig. 4A), confirming that F expression correlates with spreading (51) and that F is available as a target for MV F-specific peptides.…”

Section: Cholesterol-conjugated Mv-derived Peptides Inhibit MV Infecmentioning

confidence: 54%

Fatal Measles Virus Infection Prevented by Brain-Penetrant Fusion Inhibitors

Welsch

Talekar

Mathieu

et al. 2013

J Virol

106

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e Measles virus (MV) infection causes an acute childhood disease that can include infection of the central nervous system and can rarely progress to severe neurological disease for which there is no specific treatment. We generated potent antiviral peptide inhibitors of MV entry and spreading and MV-induced cell fusion. Dimers of MV-specific peptides derived from the C-terminal heptad repeat region of the MV fusion protein, conjugated to cholesterol, efficiently protect SLAM transgenic mice from fatal MV infection. Fusion inhibitors hold promise for the prophylaxis of MV infection in unvaccinated and immunocompromised people, as well as potential for the treatment of grave neurological complications of measles.

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Section: Cholesterol-conjugated Mv-derived Peptides Inhibit MV Infecmentioning

confidence: 54%

Fatal Measles Virus Infection Prevented by Brain-Penetrant Fusion Inhibitors

Welsch

Talekar

Mathieu

et al. 2013

J Virol

106

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“…CNS complications of MV infection may occur soon after infection in the case of acute encephalomyelitis, or years after infection, as a result of viral persistence in subacute sclerosing panencephalitis (SSPE) and progressive infectious encephalitis or measles inclusion body encephalitis (MIBE). There are no specific therapies for acute complications of MV or for persistent MV infections (85)(86)(87)(88). Since we expect our proposed antiviral strategy to be host factor independent, it will fill a specific need for immunocompromised people at risk for MV infection, who cannot be vaccinated or do not respond adequately to vaccine.…”

Section: Discussionmentioning

confidence: 99%

Prevention of Measles Virus Infection by Intranasal Delivery of Fusion Inhibitor Peptides

Mathieu

Huey

Jurgens

et al. 2015

J Virol

100

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Measles virus (MV) infection is undergoing resurgence and remains one of the leading causes of death among young children worldwide despite the availability of an effective measles vaccine. MV infects its target cells by coordinated action of the MV H and the fusion (F) envelope glycoprotein; upon receptor engagement by H, the prefusion F undergoes a structural transition, extending and inserting into the target cell membrane and then refolding into a postfusion structure that fuses the viral and cell membranes. By interfering with this structural transition of F, peptides derived from the heptad-repeat (HR) regions of F can potently inhibit MV infection at the entry stage. We show here that specific features of H's interaction with its receptors modulate the susceptibility of MV F to peptide fusion inhibitors. A higher concentration of inhibitory peptides is required to inhibit F-mediated fusion when H is engaged to its nectin-4 receptor than when H is engaged to its CD150 receptor. Peptide inhibition of F may be subverted by continued engagement of receptor by H, a finding that highlights the ongoing role of H-receptor interaction after F has been activated and that helps guide the design of more potent inhibitory peptides. Intranasal administration of these peptides results in peptide accumulation in the airway epithelium with minimal systemic levels of peptide and efficiently prevents MV infection in vivo in animal models. The results suggest an antiviral strategy for prophylaxis in vulnerable and/or immunocompromised hosts. IMPORTANCE Measles virus (MV) infection causes an acute illness that may be associated with infection of the central nervous system (CNS)and severe neurological disease. No specific treatment is available. We have shown that parenterally delivered fusion-inhibitory peptides protect mice from lethal CNS MV disease. Here we show, using established small-animal models of MV infection, that fusion-inhibitory peptides delivered intranasally provide effective prophylaxis against MV infection. Since the fusion inhibitors are stable at room temperature, this intranasal strategy is feasible even outside health care settings, could be used to protect individuals and communities in case of MV outbreaks, and could complement global efforts to control measles.

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“…It is tempting to speculate that the p150 isoform of ADAR1 functions as a host restriction factor of respiratory RNA viruses analogous to the role of the cytidine deaminase APOBEC3G, which exerts its antiviral function by generating hypermutations in the proviral DNA of retroviruses, including HIV (25)(26)(27)(28). It is possible that extensive hypermutations of the M gene of MV seen in vivo are the result of the known dispensability of the M protein for viral replication (29), with M gene sequences representing a viral decoy as targets for hypermutation. Significant A-to-G substitutions have also been seen in the viral M gene sequences of influenza A virus recovered from WT animals with intact innate immune responses (30).…”

Section: Discussionmentioning

confidence: 99%

RNA editing enzyme adenosine deaminase is a restriction factor for controlling measles virus replication that also is required for embryogenesis

Ward

George²,

Welch³

et al. 2010

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

189

195

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Measles virus (MV), a member of the family Paramyxoviridae and an exclusively human pathogen, is among the most infectious viruses. A progressive fatal neurodegenerative complication, subacute sclerosing panencephalitis (SSPE), occurs during persistent MV infection of the CNS and is associated with biased hypermutations of the viral genome. The observed hypermutations of A-to-G are consistent with conversions catalyzed by the adenosine deaminase acting on RNA (ADAR1). To evaluate the role of ADAR1 in MV infection, we selectively disrupted expression of the IFN-inducible p150 ADAR1 isoform and found it caused embryonic lethality at embryo day (E) 11-E12. We therefore generated p150-deficient and WT mouse embryo fibroblast (MEF) cells stably expressing the MV receptor signaling lymphocyte activation molecule (SLAM or CD150). The p150 −/− but not WT MEF cells displayed extensive syncytium formation and cytopathic effect (CPE) following infection with MV, consistent with an anti-MV role of the p150 isoform of ADAR1. MV titers were 3 to 4 log higher in p150 −/− cells compared with WT cells at 21 h postinfection, and restoration of ADAR1 in p150 −/− cells prevented MV cytopathology. In contrast to infection with MV, p150 disruption had no effect on vesicular stomatitis virus, reovirus, or lymphocytic choriomeningitis virus replication but protected against CPE resulting from infection with Newcastle disease virus, Sendai virus, canine distemper virus, and influenza A virus. Thus, ADAR1 is a restriction factor in the replication of paramyxoviruses and orthomyxoviruses. M easles virus (MV), a member of the family Paramyxoviridae, infects more than 10 million persons worldwide each year, resulting in several hundred thousand deaths (1, 2). A serious complication is the persistent infection of the CNS known as subacute sclerosing panencephalitis (SSPE) that occurs at a frequency of 4-11 cases per 100,000 cases of MV infection. SSPE is a progressive fatal neurodegenerative disease with characteristic features of replication of MV in neurons in the presence of high titers of MV antibodies, modest infiltration of T and B cells into the CNS, and replication of defective MV in the CNS with biased mutation of U-to-C and A-to-G in the viral genome (3-5). These hypermutations occur primarily in the matrix (M) gene but are also observed to a lesser extent in the fusion (F) and hemagglutinin (H) genes (3, 4). A transgenic mouse model that expresses the human MV receptor CD46 recapitulates all the features of SSPE on infection with MV, with biased hypermutations of U-to-C and A-to-G accounting for more than 95% of point mutations in the M gene (3,4,6). Interestingly, these biased hypermutations play a direct role in the pathogenesis of SSPE by facilitating a significant prolongation of MV persistence within the CNS, as opposed to mere accumulation as a result of persistent infection (7). In support of a direct role of M gene hypermutations in the establishment of SSPE, MV generated by reverse genetics and containing a hypermutated M...

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Making It to the Synapse: Measles Virus Spread in and Among Neurons

Cited by 42 publications

References 160 publications

Fatal Measles Virus Infection Prevented by Brain-Penetrant Fusion Inhibitors

Fatal Measles Virus Infection Prevented by Brain-Penetrant Fusion Inhibitors

Prevention of Measles Virus Infection by Intranasal Delivery of Fusion Inhibitor Peptides

RNA editing enzyme adenosine deaminase is a restriction factor for controlling measles virus replication that also is required for embryogenesis

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