Role of Microglia in Oxidative Toxicity Associated with Encephalomycarditis Virus Infection in the Central Nervous System

Ano, Yasuhisa; Sakudo, Akikazu; Onodera, Takashi

doi:10.3390/ijms13067365

Cited by 6 publications

(6 citation statements)

References 43 publications

(50 reference statements)

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“…PrP is also implicated in regulating the cellular response to stressors, including misfolded proteins, oxidative damage, and nutrient starvation (10,19,26). These stressors induce autophagy as a cell survival mechanism (27).…”

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confidence: 99%

A Proautophagic Antiviral Role for the Cellular Prion Protein Identified by Infection with a Herpes Simplex Virus 1 ICP34.5 Mutant

Korom

Wylie

Wang

et al. 2013

J Virol

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The cellular prion protein (PrP) often plays a cytoprotective role by regulating autophagy in response to cell stress. The stress of infection with intracellular pathogens can stimulate autophagy, and autophagic degradation of pathogens can reduce their replication and thus help protect the infected cells. PrP also restricts replication of several viruses, but whether this activity is related to an effect on autophagy is not known. Herpes simplex virus 1 (HSV-1) effectively counteracts autophagy through binding of its ICP34.5 protein to the cellular proautophagy protein beclin-1. Autophagy can reduce replication of an HSV-1 mutant, ⌬68H, which is incapable of binding beclin-1. We found that deletion of PrP in mice complements the attenuation of ⌬68H, restoring its capacity to replicate in the central nervous system (CNS) to wild-type virus levels after intracranial or corneal infection. Cultured primary astrocytes but not neurons derived from PrP ؊/؊ mice also complemented the attenuation of ⌬68H, enabling ⌬68H to replicate at levels equivalent to wild-type virus. Ultrastructural analysis showed that normal astrocytes exhibited an increase in the number of autophagosomes after infection with ⌬68H compared with wild-type virus, but PrP ؊/؊ astrocytes failed to induce autophagy in response to ⌬68H infection. Redistribution of EGFP-LC3 into punctae occurred more frequently in normal astrocytes infected with ⌬68H than with wild-type virus, but not in PrP ؊/؊ astrocytes, corroborating the ultrastructural analysis results. Our results demonstrate that PrP is critical for inducing autophagy in astrocytes in response to HSV-1 infection and suggest that PrP positively regulates autophagy in the mouse CNS.

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confidence: 99%

A Proautophagic Antiviral Role for the Cellular Prion Protein Identified by Infection with a Herpes Simplex Virus 1 ICP34.5 Mutant

Korom

Wylie

Wang

et al. 2013

J Virol

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“… 55 , 56 EMCV replication in glial cells is known to produce toxic oxidative radicals that have been linked with virus-mediated neurotoxicity. 45 As Mengovirus is a strain of EMCV and serologically identical to EMCV, we hypothesize that a similar mechanism is involved in vMC 24 neurotoxicity. Deletion of the leader gene from Mengovirus to enhance its safety appeared to be an empirical strategy based on the known functions of the leader protein and its proven safety in immunocompetent mice.…”

Section: Discussionmentioning

confidence: 94%

“…EMCV replication in glial cells has been linked to the virus-mediated neurotoxicity. 45 We investigated Mengovirus replication in two mouse glial cell lines, N13 and BV2. Both cell lines were highly permissive to vMC 24 infection ( Figure 2 A), which significantly reduced cell viability ( Figure 2 B).…”

Section: Resultsmentioning

confidence: 99%

MicroRNA-detargeting proves more effective than leader gene deletion for improving safety of oncolytic Mengovirus in a nude mouse model

Suryawanshi

Nace

Russell

et al. 2021

Molecular Therapy - Oncolytics

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A dual microRNA-detargeted oncolytic Mengovirus, vMC 24 NC, proved highly effective against a murine plasmacytoma in an immunocompetent syngeneic mouse model; however, there remains the concern of escape mutant development and the potential for toxicity in severely immunocompromised cancer patients when it is used as an oncolytic virus. Therefore, we sought to compare the safety and efficacy profiles of an attenuated Mengovirus containing a virulence gene deletion versus vMC 24 NC in an immunodeficient xenograft mouse model of human glioblastoma. A Mengovirus construct, vMC 24 ΔL, wherein the gene coding for the leader protein, a virulence factor, was deleted, was used for comparison. The vMC 24 ΔL induced significant levels of toxicity following treatment of subcutaneous human glioblastoma (U87-MG) xenografts as well as when injected intracranially in athymic nude mice, reducing the overall survival. The in vivo toxicity of vMC 24 ΔL was associated with viral replication in nervous and cardiac tissue. In contrast, microRNA-detargeted vMC 24 NC demonstrated excellent efficacy against U87-MG subcutaneous xenografts and improved overall survival significantly compared to that of control mice without toxicity. These results reinforce microRNA-detargeting as an effective strategy for ameliorating unwanted toxicities of oncolytic picornaviruses and substantiate vMC 24 NC as an ideal candidate for clinical development against certain cancers in both immunocompetent and immunodeficient hosts.

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“…Excessively activated microglia has been reported to be the main source of inflammatory cytokines and neurotoxic factors, which aggravate CNS diseases or even lead to death (13,44,45). M1 activated microglia-mediated neuroinflammation is identified as an amplifier of virus-induced neuropathology during MHV infection (46).…”

Section: Discussionmentioning

confidence: 99%

Evidence of Microglial Immune Response Following Coronavirus PHEV Infection of CNS

Shi

et al. 2022

Front. Immunol.

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Porcine hemagglutinating encephalomyelitis virus (PHEV) is a highly neurotropic coronavirus that invades the host central nervous system (CNS) and causes neurological dysfunction. Microglia are key immune cells in the CNS, however, whether and how they response to PHEV infection remains unclear. Herein, microglial activation and proliferation were detected in the CNS of PHEV-infected mice, as along with the proinflammatory response. Moreover, the production of proinflammatory cytokines induced by moderately activated microglia limited viral replication in the early stage of infection. Microglial depletion assays showed that during late infection, excess activation of microglia aggravated neurological symptoms, BBB destruction, and peripheral monocyte/macrophage infiltration into the CNS. Using an in vitro brain slice model, PHEV was identified to specifically and moderately induce microglial activation in the absence of peripheral immune cells infiltration. Consistently, macrophage clearance from circulating blood indicated that peripheral monocytes/macrophages crossing the BBB of mice were responsible for excess activation of microglia and CNS damage in late PHEV infection. Overall, our findings provide evidence supporting a dual role for microglia in the host CNS in response to coronavirus PHEV invasion.

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Role of Microglia in Oxidative Toxicity Associated with Encephalomycarditis Virus Infection in the Central Nervous System

Cited by 6 publications

References 43 publications

A Proautophagic Antiviral Role for the Cellular Prion Protein Identified by Infection with a Herpes Simplex Virus 1 ICP34.5 Mutant

A Proautophagic Antiviral Role for the Cellular Prion Protein Identified by Infection with a Herpes Simplex Virus 1 ICP34.5 Mutant

MicroRNA-detargeting proves more effective than leader gene deletion for improving safety of oncolytic Mengovirus in a nude mouse model

Evidence of Microglial Immune Response Following Coronavirus PHEV Infection of CNS

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