scholarly journals Lack of Interferon Regulatory Factor 8 Associated with Restricted IFN-gamma expression Augmented Japanese Encephalitis Virus Replication in the Mouse Brain

2021 ◽  
Author(s):  
Aarti Tripathi ◽  
Bhupendra Singh Rawat ◽  
Sankar Addya ◽  
Milan Surjit ◽  
Prafullakumar B. Tailor ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Japanese Encephalitis Virus ◽  
Japanese Encephalitis ◽  
Immune Cells ◽  
Microglial Activation ◽  
Interferon Regulatory Factor ◽  
Encephalitis Virus ◽  
Regulatory Factor ◽  
Myeloid Lineage ◽  
The Brain

Interferon Regulatory Factor 8 (IRF8), a myeloid lineage transcription factor, emerges as an essential regulator for microglia activation. However, the precise role of IRF8 during Japanese encephalitis virus (JEV) infection in the brain remains elusive. Here we report that JEV infection enhances IRF8 expression in the infected mice brain. Comparative transcriptional profiling of whole-brain RNA analysis and validation by qRT-PCR reveals an impaired IFNγ and related gene expression in Irf8 knockout ( Irf8 -/- ) infected mice. Further, Ifnγ knockout ( Ifnγ -/- ) mice exhibit a reduced level of Irf8. Both Ifnγ -/- and Irf8 -/- mice exhibit significantly reduced levels of activated (CD11b + CD45 hi , CD11b + CD45 lo , Cd68, and CD86 ) and infiltrating immune cells (Ly6C + , CD4, and CD8) in the infected brain as compared to WT mice. However, a higher level of granulocyte cells (Ly6G + ) infiltration is evident in Irf8 -/- mice and the increased concentration of TNFα, IL6, MCP1 levels in the brain. Interestingly, neither Irf8 -/- nor Ifnγ -/- has conferred protection against lethal JEV challenge to mice and exhibits augmentation in JEV replication in the brain. The gain of function of Irf8 by overexpressing functional IRF8 in an IRF8 deficient cell line attenuates viral replication and enhances IFNγ production. Overall, we summarise that in the murine model of JEV encephalitis, IRF8 modulation affects JEV replication. We also evidence that lack of Irf8 affects immune cells abundance in circulation and the infected brain leading to a reduction in IFNγ level and increased viral load in the brain. Importance Microglial cells, the resident macrophages in the brain, play a vital role in Japanese encephalitis virus (JEV) pathogenesis. The deregulated activity of microglia can be lethal for the brain. Therefore, it is crucial to understand the regulators that drive microglia's phenotype changes and induce inflammation in the brain. Interferon regulatory factor 8 (IRF8) is a myeloid lineage transcription factor involved in microglial activation. However, the impact of IRF8 modulation on JEV replication remains elusive. Moreover, the pathways regulated by IRF8 to initiate and amplify pathological neuroinflammation are not well understood. Here, we demonstrated the effect of IRF8 modulation on JEV replication, microglial activation, and immune cells infiltration in the brain.

scholarly journals Precise Localization and Dynamic Distribution of Japanese Encephalitis Virus in the Brain Nuclei of Infected Mice

2020 ◽  
Author(s):  
Wei Han ◽  
Mingxing Gao ◽  
Changqing Xie ◽  
Jinhua Zhang ◽  
zikai Zhao ◽  
...  
Keyword(s):  
Nervous System ◽  
Japanese Encephalitis Virus ◽  
Japanese Encephalitis ◽  
Post Infection ◽  
Viral Antigen ◽  
Thalamic Nucleus ◽  
Encephalitis Virus ◽  
3D Images ◽  
The Central Nervous System ◽  
The Brain

AbstractJapanese encephalitis virus (JEV) is a pathogen that causes severe vector-borne zoonotic diseases, thereby posing a serious threat to human health. Although JEV is potentially neurotropic, its pathogenesis and distribution in the host have not been fully elucidated. In this study, an infected mouse model was established using a highly virulent P3 strain of JEV. Immunohistochemistry and in situ hybridization, combined with anatomical imaging of the mouse brain, were used to dynamically localize the virus and construct three-dimensional (3D) images. Consequently, onset of mild clinical symptoms occurred in some mice at 84h post JEV infection, while most mice displayed typical neurological symptoms at 144h post infection. Moreover, brain pathology revealed typical changes associated with non-suppurative encephalitis, which lasted up to 192h. The earliest detection of viral antigen was achieved at 72h post infection, in the thalamus and medulla oblongata. At 144h post infection, the positive viral antigen signals were mainly distributed in the cerebral cortex, olfactory area, basal ganglia, thalamus, and brainstem regions in mice. At 192h post infection, the antigen signals gradually decreased, and the localization of JEV tended to concentrate in the cerebrum and thalamus, while no viral antigen was detected in the brain at 504h post infection. In this model, the viral antigen was first expressed in the reticular thalamic nucleus (Rt), at a consistent concentration. The expression of the viral antigen in the hippocampal CA2 region, the anterior olfactory nucleus, and the deep mesencephalic nucleus was high and persistent. The 3D images showed that viral signals were mostly concentrated in the parietal cortex, occipital lobe, and hippocampus, near the mid-sagittal plane. In the early stages of infection in mice, a large number of viral antigens were detected in denatured and necrotic neurons, suggesting that JEV directly causes neuronal damage. From the time of its entry, JEV is widely distributed in the central nervous system thereby causing extensive damage.Author summaryThere are many theories regarding the mechanism of entry of the Japanese encephalitis virus (JEV) into the nervous system. The inflammation cascade effect, resulting from the virus entering the central nervous system (CNS), is a major cause of brain injury in JEV patients. In this study, we found that the earliest point at which viral antigen was detected in the brain tissues following peripheral infection of JEV was at 72h. The virus was located in the nerve nuclei of the thalamus and medulla oblongata and, subsequently, viral antigens were found in the anterior olfactory nucleus. At 96h post infection, the virus was extensively distributed in the brain tissue, and at 144h-192h the viral antigen was widely distributed and highly concentrated. The viral concentration detected in the ventromedial thalamic nucleus (VM), deep mesencephalic nucleus (DpMe), and motor trigeminal nucleus (Mo5) remained high throughout the experiment. The hypertrophic nerve nuclei of JEV include the early anterior olfactory (AO) nucleus and the late hippocampal CA2 region. In the early stages of viral infection (72-144h post infection), the changes in viral antigen concentration and mortality rate were consistent. It was hypothesized that this stage represents the activation of viral proliferation and brain inflammation.

scholarly journals Review of Emerging Japanese Encephalitis Virus: New Aspects and Concepts about Entry into the Brain and Inter-Cellular Spreading

Pathogens ◽  
2019 ◽  
Vol 8 (3) ◽  
pp. 111 ◽  
Author(s):  
Filgueira ◽  
Lannes
Keyword(s):  
Japanese Encephalitis Virus ◽  
Japanese Encephalitis ◽  
Human Case ◽  
Encephalitis Virus ◽  
The Body ◽  
Host Cells ◽  
Asia Pacific ◽  
Latently Infected ◽  
The Impact ◽  
The Brain

Japanese encephalitis virus (JEV) is an emerging flavivirus of the Asia-Pacific region. More than two billion people live in endemic or epidemic areas and are at risk of infection. Recently, the first autochthonous human case was recorded in Africa, and infected birds have been found in Europe. JEV may spread even further to other continents. The first section of this review covers established and new information about the epidemiology of JEV. The subsequent sections focus on the impact of JEV on humans, including the natural course and immunity. Furthermore, new concepts are discussed about JEV’s entry into the brain. Finally, interactions of JEV and host cells are covered, as well as how JEV may spread in the body through latently infected immune cells and cell-to-cell transmission of virions or via other infectious material, including JEV genomic RNA.

scholarly journals Mechanism of Virulence Attenuation of Glycosaminoglycan-Binding Variants of Japanese Encephalitis Virus and Murray Valley Encephalitis Virus

2002 ◽  
Vol 76 (10) ◽  
pp. 4901-4911 ◽  
Author(s):  
Eva Lee ◽  
Mario Lobigs
Keyword(s):  
Japanese Encephalitis Virus ◽  
Host Cell ◽  
Japanese Encephalitis ◽  
Encephalitis Virus ◽  
Interferon Response ◽  
Spatial Proximity ◽  
Murray Valley Encephalitis Virus ◽  
E Protein ◽  
Virulence Attenuation ◽  
The Brain

ABSTRACT The in vivo mechanism for virulence attenuation of laboratory-derived variants of two flaviviruses in the Japanese encephalitis virus (JEV) serocomplex is described. Host cell adaptation of JEV and Murray Valley encephalitis virus (MVE) by serial passage in adenocarcinoma cells selected for variants characterized by (i) a small plaque phenotype, (ii) increased affinity to heparin-Sepharose, (iii) enhanced susceptibility to inhibition of infectivity by heparin, and (iv) loss of neuroinvasiveness in a mouse model for flaviviral encephalitis. We previously suggested that virulence attenuation of the host cell-adapted variants of MVE is a consequence of their increased dependence on cell surface glycosaminoglycans (GAGs) for attachment and entry (E. Lee and M. Lobigs, J. Virol. 74:8867-8875, 2000). In support of this proposition, we find that GAG-binding variants of JEV and MVE were rapidly removed from the bloodstream and failed to spread from extraneural sites of replication into the brain. Thus, the enhanced affinity of the attenuated variants for GAGs ubiquitously present on cells and extracellular matrices most likely prevented viremia of sufficient magnitude and/or duration required for virus entry into the brain parenchyma. This mechanism may also account, in part, for the attenuation of the JEV SA14-14-2 vaccine, given the sensitivity of the virus to heparin inhibition. A pronounced loss of the capacity of the GAG-binding variants to produce disease was also noted in mice defective in the alpha/beta interferon response, a mouse strain shown here to be highly susceptible to infection with JEV serocomplex flaviviruses. Despite the close genetic relatedness of JEV and MVE, the variants selected for the two viruses were altered at different residues in the envelope (E) protein, viz., Glu306 and Asp390 for JEV and MVE, respectively. In both cases the substitutions gave the protein an increased net positive charge. The close spatial proximity of amino acids 306 and 390 in the predicted E protein structure strongly suggests that the two residues define a receptor-binding domain involved in virus attachment to sulfated proteoglycans.

scholarly journals Autophagy inhibitor treatment alleviates cerebral inflammatory responses in a mouse model of Japanese encephalitis

2020 ◽  
Author(s):  
Jinhua Zhang ◽  
Wei Han ◽  
Changqing Xie ◽  
Mingxing Gao ◽  
Xugang Wang ◽  
...  
Keyword(s):  
Japanese Encephalitis Virus ◽  
Japanese Encephalitis ◽  
Inflammatory Responses ◽  
Degradation Process ◽  
Encephalitis Virus ◽  
Neurological Symptoms ◽  
Epidemic Disease ◽  
Autophagy Pathway ◽  
The Brain

Abstract Background Japanese Encephalitis (JE) is a zoonotic natural epidemic disease caused by Japanese Encephalitis Virus (JEV) infection. Currently, there is no specific medicine for Japanese encephalitis. Autophagy is a lysosomal degradation process that plays an important role in viral infection and cellular immunity. In vitro studies have shown that the Japanese encephalitis virus replication mechanism is related to the autophagy pathway. We hope that by studying the effects of autophagy-regulating drugs on JEV infection and host response in mice, will provide effective clinical trials for autophagy-regulating drugs in the treatment of Japanese encephalitis and other viral infectious diseases. Methods After establishing appropriate animal model. We observed the neurological symptoms of the mice and counted their survival rate. We observed histopathological changes in brain tissues of mice. We compared the extent of neuroinflammatory responses in the brain of mice and explored the signaling processes involved in neuroinflammation. Results We found autophagy inhibitors wortmannin (Wort) and chloroquine (CQ) slow down the occurrence of neurological symptoms and reduce the prevalence of JEV-infected mice. As expected, autophagy inhibitors can inhibit the activation of the PI3K/AKT/NF-kB pathway to alleviate cerebral inflammatory responses in mice, thereby protecting the mice from JEV-induced death. Conclusions Our study suggests that autophagy inhibitors wortmannin and chloroquine could attenuate the inflammatory response in the brain of JEV infected mice, providing a clinical basis for the treatment of Japanese encephalitis

scholarly journals Corilagin attenuates the Parkinsonismin Japanese encephalitis virus induced Parkinsonism

2018 ◽  
Vol 9 (1) ◽  
pp. 13-16 ◽  
Author(s):  
Ding Yanbing ◽  
Huang Lixia ◽  
Chen Jun ◽  
Hu Song ◽  
Yuan Fahu ◽  
...  
Keyword(s):  
Japanese Encephalitis Virus ◽  
Japanese Encephalitis ◽  
Negative Control Group ◽  
Negative Control ◽  
Encephalitis Virus ◽  
Dopa Decarboxylase ◽  
Control Group ◽  
Decarboxylase Inhibitor ◽  
Adult Rats ◽  
The Brain

AbstractThis study evaluates the protective effect of corilagin against Parkinsonismin Japanese encephalitis virus (JEV) induced Parkinson’s disease. The JaGAr-01 strain of virus was used to induce JE. The virus was injected into the rats (13 days age) at the midpoint between the two ears. Adult rats, 12 week after the inoculation of virus, were used for the further study. Corilagin (20 mg/kg) and levodopa with dopa decarboxylase inhibitor (LEV, 10 mg/kg) were administered intraperitoneally for the duration of one week. Bradykinesia and the levels of dopamine in the brain were estimated at the end of protocol. There was a significant decrease inthe motor function in the corilagin, LEV and LEV + corilagin treated groupscompared to the negative control group. However treatment with corilagin, LEV and LEV + corilagin significantly increases the level of dopamine in the brain compared to the negative control group. This study concludes that corilagin ameliorates the Parkinsonismin JEV induced Parkinsonism. Moreover it shows a synergistic effect when treated with LEV. Data presented in the investigation supports that corilagin can be used clinically.

scholarly journals Long non-coding RNA NONSUST006715.1 suppresses Japanese encephalitis virus proliferation in PK-15 cells

2020 ◽  
Author(s):  
Xiaolong Zhou ◽  
Qiongyu Yuan ◽  
Chen Zhang ◽  
Zhenglie Dai ◽  
Chengtao Du ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Japanese Encephalitis Virus ◽  
Japanese Encephalitis ◽  
Encephalitis Virus ◽  
Host Cells ◽  
Rt Pcr ◽  
Transcription Factor Sp1 ◽  
Non Coding Rna ◽  
Long Non Coding Rna

Abstract Background: Japanese encephalitis virus is a mosquito-borne neurotropic flavivirus that causes acute viral encephalitis in humans. Pigs are crucial amplifier host of JEV. Recently, increasing evidences have shown that long non-coding RNAs (lncRNAs) play important roles in virus infection. Methods: The JEV proliferation was evaluated after overexpression or knockdown of lncRNA-NONSUST006715.1 using western blotting and reverse-transcription polymerase chain reaction (RT-PCR). C-C chemokine receptor type 1 (CCR1) was found to regulate the expression of lncRNA-NONSUST006715.1 by inhibitors screen. The expression of lncRNA-NONSUST006715.1 was detected using RT-PCR after overexpression or knockdown of transcription factor SP1. In addition, the enrichments of transcription factor SP1 on the promoter of lncRNA-NONSUST006715.1 were analyzed by chromatin immunoprecipitation. Results: In this study, we demonstrated that swine lncRNA-NONSUST006715.1 could suppress JEV proliferation in PK-15 cells. We also found that CCR1 inhibited the expression of lncRNA-NONSUST006715.1 via the transcription factor SP1. In addition, knockdown of CCR1 could upregulated the expression of SP1 and lncRNA-NONSUST006715.1, resulting in resistance to JEV proliferation. Conclusions: These findings illustrate the importance of lncRNAs in virus proliferation, and reveal how this virus regulates lncRNAs in host cells to promote its proliferation.

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