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Herpes Simplex Virus 1-Induced Ferroptosis Contributes to Viral Encephalitis
Herpes simplex virus 1 (HSV-1) is a DNA virus belonging to the family Herpesviridae. HSV-1 infection causes severe neurological disease in the central nervous system (CNS), including encephalitis. Ferroptosis is a nonapoptotic form of programmed cell death that contributes to different neurological...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Microbiology
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9973258/ https://www.ncbi.nlm.nih.gov/pubmed/36507835 http://dx.doi.org/10.1128/mbio.02370-22 |
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author | Xu, Xi-Qiu Xu, Tongran Ji, Wenting Wang, Chong Ren, Yujie Xiong, Xiaobei Zhou, Xi Lin, Shu-Hai Xu, Yi Qiu, Yang |
author_facet | Xu, Xi-Qiu Xu, Tongran Ji, Wenting Wang, Chong Ren, Yujie Xiong, Xiaobei Zhou, Xi Lin, Shu-Hai Xu, Yi Qiu, Yang |
author_sort | Xu, Xi-Qiu |
collection | PubMed |
description | Herpes simplex virus 1 (HSV-1) is a DNA virus belonging to the family Herpesviridae. HSV-1 infection causes severe neurological disease in the central nervous system (CNS), including encephalitis. Ferroptosis is a nonapoptotic form of programmed cell death that contributes to different neurological inflammatory diseases. However, whether HSV-1 induces ferroptosis in the CNS and the role of ferroptosis in viral pathogenesis remain unclear. Here, we demonstrate that HSV-1 induces ferroptosis, as hallmarks of ferroptosis, including Fe(2+) overload, reactive oxygen species (ROS) accumulation, glutathione (GSH) depletion, lipid peroxidation, and mitochondrion shrinkage, are observed in HSV-1-infected cultured human astrocytes, microglia cells, and murine brains. Moreover, HSV-1 infection enhances the E3 ubiquitin ligase Keap1 (Kelch-like ECH-related protein 1)-mediated ubiquitination and degradation of nuclear factor E2-related factor 2 (Nrf2), a transcription factor that regulates the expression of antioxidative genes, thereby disturbing cellular redox homeostasis and promoting ferroptosis. Furthermore, HSV-1-induced ferroptosis is tightly associated with the process of viral encephalitis in a mouse model, and the ferroptosis-activated upregulation of prostaglandin-endoperoxide synthase 2 (PTGS2) and prostaglandin E(2) (PGE(2)) plays an important role in HSV-1-caused inflammation and encephalitis. Importantly, the inhibition of ferroptosis by a ferroptosis inhibitor or a proteasome inhibitor to suppress Nrf2 degradation effectively alleviated HSV-1 encephalitis. Together, our findings demonstrate the interaction between HSV-1 infection and ferroptosis and provide novel insights into the pathogenesis of HSV-1 encephalitis. |
format | Online Article Text |
id | pubmed-9973258 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Society for Microbiology |
record_format | MEDLINE/PubMed |
spelling | pubmed-99732582023-03-01 Herpes Simplex Virus 1-Induced Ferroptosis Contributes to Viral Encephalitis Xu, Xi-Qiu Xu, Tongran Ji, Wenting Wang, Chong Ren, Yujie Xiong, Xiaobei Zhou, Xi Lin, Shu-Hai Xu, Yi Qiu, Yang mBio Research Article Herpes simplex virus 1 (HSV-1) is a DNA virus belonging to the family Herpesviridae. HSV-1 infection causes severe neurological disease in the central nervous system (CNS), including encephalitis. Ferroptosis is a nonapoptotic form of programmed cell death that contributes to different neurological inflammatory diseases. However, whether HSV-1 induces ferroptosis in the CNS and the role of ferroptosis in viral pathogenesis remain unclear. Here, we demonstrate that HSV-1 induces ferroptosis, as hallmarks of ferroptosis, including Fe(2+) overload, reactive oxygen species (ROS) accumulation, glutathione (GSH) depletion, lipid peroxidation, and mitochondrion shrinkage, are observed in HSV-1-infected cultured human astrocytes, microglia cells, and murine brains. Moreover, HSV-1 infection enhances the E3 ubiquitin ligase Keap1 (Kelch-like ECH-related protein 1)-mediated ubiquitination and degradation of nuclear factor E2-related factor 2 (Nrf2), a transcription factor that regulates the expression of antioxidative genes, thereby disturbing cellular redox homeostasis and promoting ferroptosis. Furthermore, HSV-1-induced ferroptosis is tightly associated with the process of viral encephalitis in a mouse model, and the ferroptosis-activated upregulation of prostaglandin-endoperoxide synthase 2 (PTGS2) and prostaglandin E(2) (PGE(2)) plays an important role in HSV-1-caused inflammation and encephalitis. Importantly, the inhibition of ferroptosis by a ferroptosis inhibitor or a proteasome inhibitor to suppress Nrf2 degradation effectively alleviated HSV-1 encephalitis. Together, our findings demonstrate the interaction between HSV-1 infection and ferroptosis and provide novel insights into the pathogenesis of HSV-1 encephalitis. American Society for Microbiology 2022-12-12 /pmc/articles/PMC9973258/ /pubmed/36507835 http://dx.doi.org/10.1128/mbio.02370-22 Text en Copyright © 2022 Xu et al. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Research Article Xu, Xi-Qiu Xu, Tongran Ji, Wenting Wang, Chong Ren, Yujie Xiong, Xiaobei Zhou, Xi Lin, Shu-Hai Xu, Yi Qiu, Yang Herpes Simplex Virus 1-Induced Ferroptosis Contributes to Viral Encephalitis |
title | Herpes Simplex Virus 1-Induced Ferroptosis Contributes to Viral Encephalitis |
title_full | Herpes Simplex Virus 1-Induced Ferroptosis Contributes to Viral Encephalitis |
title_fullStr | Herpes Simplex Virus 1-Induced Ferroptosis Contributes to Viral Encephalitis |
title_full_unstemmed | Herpes Simplex Virus 1-Induced Ferroptosis Contributes to Viral Encephalitis |
title_short | Herpes Simplex Virus 1-Induced Ferroptosis Contributes to Viral Encephalitis |
title_sort | herpes simplex virus 1-induced ferroptosis contributes to viral encephalitis |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9973258/ https://www.ncbi.nlm.nih.gov/pubmed/36507835 http://dx.doi.org/10.1128/mbio.02370-22 |
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