Monkey B virus(Macacine herpesvirus 1; BV) is noted for its extreme neurovirulence in humans. Since the vhs protein encoded by the UL41 gene has been shown to be a neurovirulence factor in the related human herpes sim...Monkey B virus(Macacine herpesvirus 1; BV) is noted for its extreme neurovirulence in humans. Since the vhs protein encoded by the UL41 gene has been shown to be a neurovirulence factor in the related human herpes simplex viruses, the role of the UL41 gene in BV neurovirulence was investigated. BV mutants were constructed that lacked the entire UL41 ORF(Δ41) or had the RNase active site mutated(Δ41A). Neither mutant shut off host protein synthesis, degraded β-actin mRNA, or prevented an IFN-β response, indicating that the vhs protein and its RNase activity are both necessary for these activities. Replication of both mutants in primary mouse cells was impaired and they exhibited a prolonged disease course in mice. Whereas Δ41 infected mice were euthanized for symptoms related to central nervous system(CNS) infection, Δ41A infected mice were euthanized primarily for symptoms of autonomic nervous system dysfunction. While neuroinvasiveness was not affected, lesions in the CNS were more limited in size, anatomical distribution, and severity than for wild-type virus. These results indicate that the vhs protein affects the general replicative efficiency of BV in vivo rather than being a specific neurovirulence factor critical for invasion of or preferential replication in the CNS.展开更多
Infection with severe acute respiratory syndrome coronavirus 2 Omicron variants still causes neurological complications in elderly individuals.However,whether and how aging brains are affected by Omicron variants in t...Infection with severe acute respiratory syndrome coronavirus 2 Omicron variants still causes neurological complications in elderly individuals.However,whether and how aging brains are affected by Omicron variants in terms of neuroinvasiveness and neurovirulence are unknown.Here,we utilize resected paracarcinoma brain tissue from elderly individuals to generate primary brain spheroids(BSs)for investigating the replication capability of live wild-type(WT)strain and Omicron(BA.1/BA.2),as well as the mechanisms underlying their neurobiological effects.We find that both WT and Omicron BA.1/BA.2 are able to enter BSs but weakly replicate.There is no difference between Omicron BA.1/BA.2 and WT strains in neurotropism in aging BSs.However,Omicron BA.1/BA.2 exhibits ameliorating neurological damage.Transcriptional profiling indicates that Omicron BA.1/BA.2 induces a lower neuroinflammatory response than WT strain in elderly BSs,suggesting a mechanistic explanation for their attenuated neuropathogenicity.Moreover,we find that both Omicron BA.1/BA.2 and WT strain infections disrupt neural network activity associated with neurodegenerative disorders by causing neuron degeneration and amyloid-βdeposition in elderly BSs.These results uncover Omicron-specific mechanisms and cellular immune responses associated with severe acute respiratory syndrome coronavirus 2-induced neurological complications.展开更多
Zika virus(ZIKV)can infect a wide range of tissues including the developmental brain of human fetus.Whether specific viral genetic variants are linked to neuropathology is incompletely understood.To address this,we ha...Zika virus(ZIKV)can infect a wide range of tissues including the developmental brain of human fetus.Whether specific viral genetic variants are linked to neuropathology is incompletely understood.To address this,we have intracranially serially passaged a clinical ZIKV isolate(SW01)in neonatal mice and discovered variants that exhibit markedly increased virulence and neurotropism.Deep sequencing analysis combining with molecular virology studies revealed that a single 67D(Aspartic acid)to N(Asparagine)substitution on E protein is sufficient to confer the increased virulence and neurotropism in vivo.Notably,virus clones with D67N mutation had higher viral production and caused more severe cytopathic effect(CPE)in human neural astrocytes U251 cells in vitro,indicating its potential neurological toxicity to human brain.These findings revealed that a single mutation D67N on ZIKV envelope may lead to severe neuro lesion that may help to explain the neurovirulence of ZIKV and suggest monitoring the occurrence of this mutation during nature infection may be important.展开更多
Varicella zoster virus(VZV) is the causative agent of varicella(chicken pox) and herpes zoster(shingles). After primary infection, the virus remains latent in sensory ganglia, and reactivates upon weakening of the cel...Varicella zoster virus(VZV) is the causative agent of varicella(chicken pox) and herpes zoster(shingles). After primary infection, the virus remains latent in sensory ganglia, and reactivates upon weakening of the cellular immune system due to various conditions, erupting from sensory neurons and infecting the corresponding skin tissue. The current varicella vaccine(v-Oka) is highly attenuated in the skin, yet retains its neurovirulence and may reactivate and damage sensory neurons. The reactivation is sometimes associated with postherpetic neuralgia(PHN), a severe pain along the affected sensory nerves that can linger for years, even after the herpetic rash resolves. In addition to the older population that develops a secondary infection resulting in herpes zoster, childhood breakthrough herpes zoster affects a small population of vaccinated children. There is a great need for a neuro-attenuated vaccine that would prevent not only the varicella manifestation, but, more importantly, any establishment of latency, and therefore herpes zoster. The development of a genetically-defined live-attenuated VZV vaccine that prevents neuronal and latent infection, in addition to primary varicella, is imperative for eventual eradication of VZV, and, if fully understood, has vast implications for many related herpesviruses and other viruses with similar pathogenic mechanisms.展开更多
基金supported in part by PHS grants 2P40 OD010988 and 1P40 OD010431
文摘Monkey B virus(Macacine herpesvirus 1; BV) is noted for its extreme neurovirulence in humans. Since the vhs protein encoded by the UL41 gene has been shown to be a neurovirulence factor in the related human herpes simplex viruses, the role of the UL41 gene in BV neurovirulence was investigated. BV mutants were constructed that lacked the entire UL41 ORF(Δ41) or had the RNase active site mutated(Δ41A). Neither mutant shut off host protein synthesis, degraded β-actin mRNA, or prevented an IFN-β response, indicating that the vhs protein and its RNase activity are both necessary for these activities. Replication of both mutants in primary mouse cells was impaired and they exhibited a prolonged disease course in mice. Whereas Δ41 infected mice were euthanized for symptoms related to central nervous system(CNS) infection, Δ41A infected mice were euthanized primarily for symptoms of autonomic nervous system dysfunction. While neuroinvasiveness was not affected, lesions in the CNS were more limited in size, anatomical distribution, and severity than for wild-type virus. These results indicate that the vhs protein affects the general replicative efficiency of BV in vivo rather than being a specific neurovirulence factor critical for invasion of or preferential replication in the CNS.
基金supported by Guangdong Science and Technology Program(2021B1212030007)from Guangdong Provincial Key Laboratory of Pathogen Detection for Emerging Infectious Disease Response,National Natural Science Foundation of China(82372624)National Natural Science Foundation of Guangdong Province(2022A1515012430)+2 种基金China Postdoctoral Science Foundation(2022M723588)Medical Scientific Research Foundation of Guangdong Province(A2023439)GuangDong Basic and Applied Basic Research Foundation(2023A1515110422).
文摘Infection with severe acute respiratory syndrome coronavirus 2 Omicron variants still causes neurological complications in elderly individuals.However,whether and how aging brains are affected by Omicron variants in terms of neuroinvasiveness and neurovirulence are unknown.Here,we utilize resected paracarcinoma brain tissue from elderly individuals to generate primary brain spheroids(BSs)for investigating the replication capability of live wild-type(WT)strain and Omicron(BA.1/BA.2),as well as the mechanisms underlying their neurobiological effects.We find that both WT and Omicron BA.1/BA.2 are able to enter BSs but weakly replicate.There is no difference between Omicron BA.1/BA.2 and WT strains in neurotropism in aging BSs.However,Omicron BA.1/BA.2 exhibits ameliorating neurological damage.Transcriptional profiling indicates that Omicron BA.1/BA.2 induces a lower neuroinflammatory response than WT strain in elderly BSs,suggesting a mechanistic explanation for their attenuated neuropathogenicity.Moreover,we find that both Omicron BA.1/BA.2 and WT strain infections disrupt neural network activity associated with neurodegenerative disorders by causing neuron degeneration and amyloid-βdeposition in elderly BSs.These results uncover Omicron-specific mechanisms and cellular immune responses associated with severe acute respiratory syndrome coronavirus 2-induced neurological complications.
基金supported in part by the following grants:Strategic Priority Research Program of the Chinese Academy of Sciences(XDB29040301 to X.J.)National Key R&D Program of China(2016YFC1201000 to X.J.)+2 种基金Ministry of Science and Technology of China(2016YFE0133500 to X.J.)the National Natural Science Foundation of China(31770190 and 81925025 to CF.Q.)European Union Horizon 2020 Research and Innovation Programme under ZIKAlliance Grant Agreement(734548 to X.J.)
文摘Zika virus(ZIKV)can infect a wide range of tissues including the developmental brain of human fetus.Whether specific viral genetic variants are linked to neuropathology is incompletely understood.To address this,we have intracranially serially passaged a clinical ZIKV isolate(SW01)in neonatal mice and discovered variants that exhibit markedly increased virulence and neurotropism.Deep sequencing analysis combining with molecular virology studies revealed that a single 67D(Aspartic acid)to N(Asparagine)substitution on E protein is sufficient to confer the increased virulence and neurotropism in vivo.Notably,virus clones with D67N mutation had higher viral production and caused more severe cytopathic effect(CPE)in human neural astrocytes U251 cells in vitro,indicating its potential neurological toxicity to human brain.These findings revealed that a single mutation D67N on ZIKV envelope may lead to severe neuro lesion that may help to explain the neurovirulence of ZIKV and suggest monitoring the occurrence of this mutation during nature infection may be important.
文摘Varicella zoster virus(VZV) is the causative agent of varicella(chicken pox) and herpes zoster(shingles). After primary infection, the virus remains latent in sensory ganglia, and reactivates upon weakening of the cellular immune system due to various conditions, erupting from sensory neurons and infecting the corresponding skin tissue. The current varicella vaccine(v-Oka) is highly attenuated in the skin, yet retains its neurovirulence and may reactivate and damage sensory neurons. The reactivation is sometimes associated with postherpetic neuralgia(PHN), a severe pain along the affected sensory nerves that can linger for years, even after the herpetic rash resolves. In addition to the older population that develops a secondary infection resulting in herpes zoster, childhood breakthrough herpes zoster affects a small population of vaccinated children. There is a great need for a neuro-attenuated vaccine that would prevent not only the varicella manifestation, but, more importantly, any establishment of latency, and therefore herpes zoster. The development of a genetically-defined live-attenuated VZV vaccine that prevents neuronal and latent infection, in addition to primary varicella, is imperative for eventual eradication of VZV, and, if fully understood, has vast implications for many related herpesviruses and other viruses with similar pathogenic mechanisms.
