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Tiberti N, Castilletti C, Gobbi FG. Extracellular vesicles in arbovirus infections: from basic biology to potential clinical applications. Front Cell Infect Microbiol 2025; 15:1558520. [PMID: 40357393 PMCID: PMC12066795 DOI: 10.3389/fcimb.2025.1558520] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2025] [Accepted: 04/04/2025] [Indexed: 05/15/2025] Open
Abstract
Arthropod-borne viruses, or arboviruses, are currently considered a global health threat responsible for potentially severe human diseases. The increased population density, changes in land use and climate change are some of the factors that are contributing to the spread of these infections over the last years. The pathogenesis of these diseases and the mechanisms of interaction with the host, especially those leading to the development of severe forms, are yet to be fully understood. In recent years extracellular vesicles (EVs) have emerged as important players in the inter-cellular and host-pathogen interaction arising a lot of interest also in the field of vector-borne viruses. In this context, EVs seem to play a dual role, by either promoting, thus facilitating, or preventing infection. Many studies are showing how viruses can hijack the vesiculation machinery to escape the host immune response and exploit EVs to sustain their replication and propagation, even though EVs shed by immune cells seem essential to promote antiviral responses. In this manuscript we reviewed the current knowledge regarding the association between EVs and vector-borne viruses, paying particular attention to their possible role in disease transmission and dissemination, as well as to their potential as novel tools for clinical applications, spanning from biomarkers of clinical utility to novel therapeutic options.
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Affiliation(s)
- Natalia Tiberti
- Department of Infectious, Tropical Diseases and Microbiology, IRCCS Sacro Cuore Don Calabria Hospital, Negrar di Valpolicella, Verona, Italy
| | - Concetta Castilletti
- Department of Infectious, Tropical Diseases and Microbiology, IRCCS Sacro Cuore Don Calabria Hospital, Negrar di Valpolicella, Verona, Italy
| | - Federico Giovanni Gobbi
- Department of Infectious, Tropical Diseases and Microbiology, IRCCS Sacro Cuore Don Calabria Hospital, Negrar di Valpolicella, Verona, Italy
- Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
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Bai L, Yu L, Ran M, Zhong X, Sun M, Xu M, Wang Y, Yan X, Lee RJ, Tang Y, Xie J. Harnessing the Potential of Exosomes in Therapeutic Interventions for Brain Disorders. Int J Mol Sci 2025; 26:2491. [PMID: 40141135 PMCID: PMC11942545 DOI: 10.3390/ijms26062491] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2025] [Revised: 03/05/2025] [Accepted: 03/07/2025] [Indexed: 03/28/2025] Open
Abstract
Exosomes, which are nano-sized natural vesicles secreted by cells, are crucial for intercellular communication and interactions, playing a significant role in various physiological and pathological processes. Their characteristics, such as low toxicity and immunogenicity, high biocompatibility, and remarkable drug delivery capabilities-particularly their capacity to traverse the blood-brain barrier-make exosomes highly promising vehicles for drug administration in the treatment of brain disorders. This review provides a comprehensive overview of exosome biogenesis and isolation techniques, strategies for the drug loading and functionalization of exosomes, and exosome-mediated blood-brain barrier penetration mechanisms, with a particular emphasis on recent advances in exosome-based drug delivery for brain disorders. Finally, we address the opportunities and challenges associated with utilizing exosomes as a drug delivery system for the brain, summarizing the barriers to clinical translation and proposing future research directions.
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Affiliation(s)
- Lu Bai
- School of Pharmacy and Bioengineering, Chongqing University of Technology, 69 Hongguang Road, Chongqing 400054, China
- Center for Nanomedicine and Gene Therapy, Chongqing University of Technology, 69 Hongguang Road, Chongqing 400054, China
| | - Leijie Yu
- School of Pharmacy and Bioengineering, Chongqing University of Technology, 69 Hongguang Road, Chongqing 400054, China
- Center for Nanomedicine and Gene Therapy, Chongqing University of Technology, 69 Hongguang Road, Chongqing 400054, China
| | - Mengqiong Ran
- School of Pharmacy and Bioengineering, Chongqing University of Technology, 69 Hongguang Road, Chongqing 400054, China
- Center for Nanomedicine and Gene Therapy, Chongqing University of Technology, 69 Hongguang Road, Chongqing 400054, China
| | - Xing Zhong
- School of Pharmacy and Bioengineering, Chongqing University of Technology, 69 Hongguang Road, Chongqing 400054, China
- Center for Nanomedicine and Gene Therapy, Chongqing University of Technology, 69 Hongguang Road, Chongqing 400054, China
| | - Meng Sun
- School of Pharmacy and Bioengineering, Chongqing University of Technology, 69 Hongguang Road, Chongqing 400054, China
- Center for Nanomedicine and Gene Therapy, Chongqing University of Technology, 69 Hongguang Road, Chongqing 400054, China
| | - Minhao Xu
- School of Pharmacy and Bioengineering, Chongqing University of Technology, 69 Hongguang Road, Chongqing 400054, China
- Center for Nanomedicine and Gene Therapy, Chongqing University of Technology, 69 Hongguang Road, Chongqing 400054, China
| | - Yu Wang
- School of Pharmacy and Bioengineering, Chongqing University of Technology, 69 Hongguang Road, Chongqing 400054, China
- Center for Nanomedicine and Gene Therapy, Chongqing University of Technology, 69 Hongguang Road, Chongqing 400054, China
| | - Xinlei Yan
- School of Pharmacy and Bioengineering, Chongqing University of Technology, 69 Hongguang Road, Chongqing 400054, China
- Center for Nanomedicine and Gene Therapy, Chongqing University of Technology, 69 Hongguang Road, Chongqing 400054, China
| | - Robert J. Lee
- School of Pharmacy and Bioengineering, Chongqing University of Technology, 69 Hongguang Road, Chongqing 400054, China
- Center for Nanomedicine and Gene Therapy, Chongqing University of Technology, 69 Hongguang Road, Chongqing 400054, China
| | - Yaqin Tang
- School of Pharmacy and Bioengineering, Chongqing University of Technology, 69 Hongguang Road, Chongqing 400054, China
- Center for Nanomedicine and Gene Therapy, Chongqing University of Technology, 69 Hongguang Road, Chongqing 400054, China
| | - Jing Xie
- School of Pharmacy and Bioengineering, Chongqing University of Technology, 69 Hongguang Road, Chongqing 400054, China
- Center for Nanomedicine and Gene Therapy, Chongqing University of Technology, 69 Hongguang Road, Chongqing 400054, China
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Wang X, Kong N, Wang C, Qin W, Yang X, Yu H, Tong W, Tong G, Li L, Zheng H, Shan T, Liu X. Japanese encephalitis virus NS3 captures the protein translation element by interacting with HNRNPH1 to promote viral replication. Int J Biol Macromol 2025; 289:138826. [PMID: 39694377 DOI: 10.1016/j.ijbiomac.2024.138826] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 12/11/2024] [Accepted: 12/14/2024] [Indexed: 12/20/2024]
Abstract
Japanese encephalitis caused by Japanese encephalitis virus (JEV) infection leads to the central nervous system disorder in human and swine. Viruses utilize the host protein synthesis mechanisms to efficiently translate their RNAs. Herein, we demonstrated that the host transcription factor SOX10 downregulated an RNA-binding protein heterogeneous nuclear ribonucleoprotein H (HNRNPH1) during JEV infection. We further showed that JEV replication was promoted when HNRNPH1 inhibited RIG-I/MDA5 signal pathway to decrease interferon (IFN) expression. Remarkably, the multifunctional enzyme NS3 of JEV can capture HNRNPH1 to recruit poly A-binding protein cytoplasmic 1 (PABPC1) and RNA-independent eukaryotic translation initiation factor 4F complex (eIF4F), ultimately promoting viral replication. Collectively, our results provide new insights into the mechanism underlying JEV replication via the nonstructural protein NS3, which captures the translation regulation element by interacting with HNRNPH1 to promote viral replication.
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Affiliation(s)
- Xingya Wang
- Animal-derived Food Safety Innovation Team, Anhui Agricultural University, Hefei 230036, China; Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai 200241, China
| | - Ning Kong
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai 200241, China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou 225009, China
| | - Chen Wang
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai 200241, China
| | - Wenzhen Qin
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai 200241, China
| | - Xinyu Yang
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai 200241, China
| | - Hai Yu
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai 200241, China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou 225009, China
| | - Wu Tong
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai 200241, China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou 225009, China
| | - Guangzhi Tong
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai 200241, China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou 225009, China
| | - Lin Li
- Animal-derived Food Safety Innovation Team, Anhui Agricultural University, Hefei 230036, China
| | - Hao Zheng
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai 200241, China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou 225009, China.
| | - Tongling Shan
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai 200241, China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou 225009, China.
| | - Xuelan Liu
- Animal-derived Food Safety Innovation Team, Anhui Agricultural University, Hefei 230036, China; Anhui Province Key Lab of Veterinary Pathobiology and Disease Control, Anhui Agricultural University, Hefei 230036, China.
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Gupta A, Bohara VS, Chauhan AS, Mohapatra A, Kaur H, Sharma A, Chaudhary N, Kumar S. Alpha-synuclein expression in neurons modulates Japanese encephalitis virus infection. J Virol 2024; 98:e0041824. [PMID: 39508602 PMCID: PMC11651009 DOI: 10.1128/jvi.00418-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Accepted: 10/02/2024] [Indexed: 11/15/2024] Open
Abstract
Japanese encephalitis virus (JEV) stands as a prominent vector-borne zoonotic pathogen, displaying neurotropism and eliciting Parkinson's disease (PD)-like symptoms among most symptomatic survivors. A characteristic feature of PD is the aggregation of mutated α-synuclein (α-syn) that damages the dopaminergic neurons. Considering this link between JEV-induced PD-like symptoms and α-syn pathogenesis, we explored the role of α-syn in JEV infectivity in neuronal cells. Our investigation revealed a significant increase in endogenous α-syn expression in JEV-infected cells. In addition, exogenous α-syn (Exoα-syn) treatment substantially reduced JEV replication, suggesting its anti-JEV effect. Furthermore, Exoα-syn treatment led to the upregulation of superoxide dismutase 1 (SOD1) and reduction in reactive oxygen species (ROS). The results were validated by endogenous α-syn-silencing, which decreased SOD1 and raised ROS levels in neuronal cells. Similarly, the SOD1 inhibition via LCS-1 also intensified ROS and JEV infection. Silencing of SOD1 in α-syn overexpressing neuro2a cells exhibited increased JEV replication. Overall, our results suggest that α-syn exerts an anti-JEV effect by regulating protein involved in oxidative stress inside neuronal cells. This study contributes valuable insights into the interplay between α-syn expression and JEV infectivity, shedding light on avenues further to investigate the potential role of α-syn in JEV pathogenesis. IMPORTANCE Japanese encephalitis virus (JEV) poses a significant threat, particularly to children. Despite extensive research efforts, the development of effective treatments against JEV has been impeded. One of the major setbacks is a lack of comprehensive understanding of neurotropism. The study focuses on alpha-synuclein (α-syn), a neuronal protein, and aims to determine its role in JEV pathogenesis. The present study reveals that the host cell upregulates α-syn in response to JEV infection. α-syn restrains JEV propagation by modulating superoxide dismutase 1 (SOD1) expression which further blocks JEV-induced ROS generation. Endogenous α-syn silencing led to a decrease in SOD1 expression and increased viral titer. α-syn plays a crucial role in counteracting oxidative stress through SOD1, which is essential for limiting JEV replication. This study provides broader implications for antiviral strategies and their possible role in neurodegenerative diseases; however, there is still much to explore, particularly regarding α-syn aggregation kinetics in JEV infection.
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Affiliation(s)
- Anjali Gupta
- Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India
| | - Vijay Singh Bohara
- Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India
| | - Aditya Singh Chauhan
- Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India
| | - Anshuman Mohapatra
- Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India
| | - Harpreet Kaur
- Division of Epidemiology and Communicable Diseases, Indian Council of Medical Research, Ansari Nagar, New Delhi, India
| | - Ajanta Sharma
- Department of Microbiology, Gauhati Medical College, Guwahati, Assam, India
| | - Nitin Chaudhary
- Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India
| | - Sachin Kumar
- Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India
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Zhou JF, Zhang MR, Wang Q, Li MZ, Bai JS, Dai Q, Zhang YH, Yan MX, Li XH, Chen J, Liu YY, Liu CC, Ye J, Zhou B. Two novel compounds inhibit Flavivirus infection in vitro and in vivo by targeting lipid metabolism. J Virol 2024; 98:e0063524. [PMID: 39158346 PMCID: PMC11406969 DOI: 10.1128/jvi.00635-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Accepted: 07/10/2024] [Indexed: 08/20/2024] Open
Abstract
Flavivirus infection capitalizes on cellular lipid metabolism to remodel the cellular intima, creating a specialized lipid environment conducive to viral replication, assembly, and release. The Japanese encephalitis virus (JEV), a member of the Flavivirus genus, is responsible for significant morbidity and mortality in both humans and animals. Currently, there are no effective antiviral drugs available to combat JEV infection. In this study, we embarked on a quest to identify anti-JEV compounds within a lipid compound library. Our research led to the discovery of two novel compounds, isobavachalcone (IBC) and corosolic acid (CA), which exhibit dose-dependent inhibition of JEV proliferation. Time-of-addition assays indicated that IBC and CA predominantly target the late stage of the viral replication cycle. Mechanistically, JEV nonstructural proteins 1 and 2A (NS1 and NS2A) impede 5'-adenosine monophosphate (AMP)-activated protein kinase (AMPK) activation by obstructing the liver kinase B1 (LKB1)-AMPK interaction, resulting in decreased p-AMPK expression and a consequent upsurge in lipid synthesis. In contrast, IBC and CA may stimulate AMPK by binding to its active allosteric site, thereby inhibiting lipid synthesis essential for JEV replication and ultimately curtailing viral infection. Most importantly, in vivo experiments demonstrated that IBC and CA protected mice from JEV-induced mortality, significantly reducing viral loads in the brain and mitigating histopathological alterations. Overall, IBC and CA demonstrate significant potential as effective anti-JEV agents by precisely targeting AMPK-associated signaling pathways. These findings open new therapeutic avenues for addressing infections caused by Flaviviruses. IMPORTANCE This study is the inaugural utilization of a lipid compound library in antiviral drug screening. Two lipid compounds, isobavachalcone (IBC) and corosolic acid (CA), emerged from the screening, exhibiting substantial inhibitory effects on the Japanese encephalitis virus (JEV) proliferation in vitro. In vivo experiments underscored their efficacy, with IBC and CA reducing viral loads in the brain and mitigating JEV-induced histopathological changes, effectively shielding mice from fatal JEV infection. Intriguingly, IBC and CA may activate 5'-adenosine monophosphate (AMP)-activated protein kinase (AMPK) by binding to its active site, curtailing the synthesis of lipid substances, and thus suppressing JEV proliferation. This indicates AMPK as a potential antiviral target. Remarkably, IBC and CA demonstrated suppression of multiple viruses, including Flaviviruses (JEV and Zika virus), porcine herpesvirus (pseudorabies virus), and coronaviruses (porcine deltacoronavirus and porcine epidemic diarrhea virus), suggesting their potential as broad-spectrum antiviral agents. These findings shed new light on the potential applications of these compounds in antiviral research.
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Affiliation(s)
- Jiang-fei Zhou
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China
| | - Meng-ran Zhang
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China
| | - Qi Wang
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China
| | - Mei-zhen Li
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China
| | - Ji-shan Bai
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China
| | - Qi Dai
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China
| | - Yuan-hang Zhang
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China
| | - Meng-xue Yan
- State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, China
| | - Xiao-han Li
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China
| | - Jing Chen
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China
| | - Ya-yun Liu
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China
| | - Chun-chun Liu
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China
| | - Jing Ye
- State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, China
| | - Bin Zhou
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China
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Luo C, Li M, Bian P, Yang J, Liao X, Dong Y, Ye C, Zhang F, Lv X, Zhang Q, Lei Y. The protective role of Mertk in JEV-induced encephalitis by maintaining the integrity of blood-brain barrier. Virol J 2024; 21:217. [PMID: 39277738 PMCID: PMC11401310 DOI: 10.1186/s12985-024-02472-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Accepted: 08/14/2024] [Indexed: 09/17/2024] Open
Abstract
Japanese encephalitis is an acute infectious disease of the central nervous system caused by neurotropic Japanese encephalitis virus (JEV). As a member of TAM (Tyro3, Axl and Mertk) family, Mertk has involved in multiple biological processes by engaging with its bridging ligands Gas6 and Protein S, including invasion of pathogens, phagocytosis of apoptotic cells, inflammatory response regulation, and the maintenance of blood brain barrier (BBB) integrity. However, its role in encephalitis caused by JEV infection has not been studied in detail. Here, we found that Mertk-/- mice exhibited higher mortality and more rapid disease progression than wild-type mice after JEV challenge. There were no significant differences in viral load and cytokines expression level in peripheral tissues between Wild type and Mertk-/- mice. Furthermore, the absence of Mertk had little effect on the inflammatory response and immunopathological damage while it can cause an increased viral load in the brain. For the in vitro model of BBB, Mertk was shown to maintain the integrity of the BBB. In vivo, Mertk-/- mice exhibited higher BBB permeability and lower BBB integrity. Taken together, our findings demonstrate that Mertk acts as a protective factor in the development of encephalitis induced by JEV infection, which is mainly associated with its beneficial effect on BBB integrity, rather than its regulation of inflammatory response.
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Affiliation(s)
- Chuanyu Luo
- Department of Clinical Laboratory, Norinco General Hospital, Xi'an, 710065, China
| | - Mengyuan Li
- Department of Infectious Diseases, Tangdu Hospital, Air Force Medical University, Xi'an, 710032, China
| | - Peiyu Bian
- Department of Geriatrics, Xijing Hospital, Air Force Medical University, Xi'an, 710032, China
| | - Jiali Yang
- Department of Cell Biology, National Translational Science Center for Molecular Medicine, Air Force Medical University, Xi'an, 710032, China
| | - Xiamei Liao
- Department of Microbiology and Pathogen Biology, School of Basic Medical Sciences, Air Force Medical University, Changle West Road, Xincheng District, Xi'an, 710032, Shaanxi, China
| | - Yangchao Dong
- Department of Microbiology and Pathogen Biology, School of Basic Medical Sciences, Air Force Medical University, Changle West Road, Xincheng District, Xi'an, 710032, Shaanxi, China
| | - Chuantao Ye
- Department of Infectious Diseases, Tangdu Hospital, Air Force Medical University, Xi'an, 710032, China
| | - Fanglin Zhang
- Department of Microbiology and Pathogen Biology, School of Basic Medical Sciences, Air Force Medical University, Changle West Road, Xincheng District, Xi'an, 710032, Shaanxi, China
| | - Xin Lv
- Department of Microbiology and Pathogen Biology, School of Basic Medical Sciences, Air Force Medical University, Changle West Road, Xincheng District, Xi'an, 710032, Shaanxi, China.
| | - Qianqian Zhang
- Department of Microbiology, Medical College, Yan'an University, Yan'an, 716000, China.
| | - Yingfeng Lei
- Department of Microbiology and Pathogen Biology, School of Basic Medical Sciences, Air Force Medical University, Changle West Road, Xincheng District, Xi'an, 710032, Shaanxi, China.
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Mohapatra S, Chakraborty T, Basu A. Japanese Encephalitis virus infection in astrocytes modulate microglial function: Correlation with inflammation and oxidative stress. Cytokine 2023; 170:156328. [PMID: 37567102 DOI: 10.1016/j.cyto.2023.156328] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Revised: 07/31/2023] [Accepted: 08/03/2023] [Indexed: 08/13/2023]
Abstract
BACKGROUND Japanese Encephalitis Virus (JEV) is a neurotropic virus which has the propensity to infect neuronal and glial cells of the brain. Astrocyte-microglia crosstalk leading to the secretion of various factors plays a major role in controlling encephalitis in brain. This study focused on understanding the role of astrocytic mediators that further shaped the microglial response towards JEV infection. METHODS After establishing JEV infection in C8D1A (mouse astrocyte cell line) and primary astrocyte enriched cultures (PAEC), astrocyte supernatant was used for preparation of conditioned media. Astrocyte supernatant was treated with UV to inactivate JEV and the supernatant was added to N9 culture media in ratio 1:1 for preparation of conditioned media. N9 microglial cells post treatment with astrocyte conditioned media and JEV infection were checked for expression of various inflammatory genes by qRT-PCR, levels of secreted cytokines in N9 cell supernatant were checked by cytometric bead array. N9 cell lysates were checked for expression of proteins - pNF-κβ, IBA-1, NS3 and RIG-I by western blotting. Viral titers were measured in N9 supernatant by plaque assays. Immunocytochemistry experiments were done to quantify the number of infected microglial cells after astrocyte conditioned medium treatment. Expression of different antioxidant enzymes was checked in N9 cells by western blotting, levels of reactive oxygen species (ROS) was detected by fluorimetry using DCFDA dye. RESULTS N9 microglial cells post treatment with JEV-infected astrocyte conditioned media and JEV infection were activated, showed an upsurge in expression of inflammatory genes and cytokines both at the transcript and protein levels. These N9 cells showed a decrease in quantity of viral titers and associated viral proteins in comparison to control cells (not treated with conditioned media but infected with JEV). Also, N9 cells upon conditioned media treatment and JEV infection were more prone to undergo oxidative stress as observed by the decreased expression of antioxidant enzymes SOD-1, TRX-1 and increased secretion of reactive oxygen species (ROS). CONCLUSION Astrocytic mediators like TNF-α, MCP-1 and IL-6 influence microglial response towards JEV infection by promoting inflammation and oxidative stress in them. As a result of increased microglial inflammation and secretion of ROS, viral replication is lessened in conditioned media treated and JEV infected microglial cells as compared to control cells with no conditioned media treatment but only JEV infection.
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Affiliation(s)
- Stuti Mohapatra
- National Brain Research Centre, Manesar, Haryana 122052, India
| | | | - Anirban Basu
- National Brain Research Centre, Manesar, Haryana 122052, India.
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Xu W, Yang K, Zheng Y, Cao S, Yan Q, Huang X, Wen Y, Zhao Q, Du S, Lang Y, Zhao S, Wu R. BAK-Mediated Pyroptosis Promotes Japanese Encephalitis Virus Proliferation in Porcine Kidney 15 Cells. Viruses 2023; 15:v15040974. [PMID: 37112954 PMCID: PMC10142372 DOI: 10.3390/v15040974] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 04/08/2023] [Accepted: 04/13/2023] [Indexed: 04/29/2023] Open
Abstract
As a zoonotic virus, Japanese Encephalitis virus (JEV) poses a serious threat to human health and the breeding industry. Regarding the mechanism and complications of tissue inflammation caused by JEV, such as encephalitis and orchitis, there is no effective drug treatment currently, and the mechanism of occurrence has not been thoroughly studied. Therefore, it is necessary to study the mechanism of the inflammatory pathway caused by JEV. As one of the key proteins regulating cell death, BCL2 antagonist/killer (BAK) is also a necessary prerequisite for the release of cellular inflammatory factors. We found that after JEV infection, BAK-knockdown cells died less than normal cells, and the transcription levels of inflammatory factors such as TNF, IFNα, and IL-1β and their corresponding regulatory genes were also significantly reduced. By further verifying protein expression on the cell death pathway, it was found that pyroptotic activation and virus titer were also significantly reduced in BAK.KD cells, suggesting that JEV proliferation might be related to BAK-induced cell death. From our data, we could conclude that JEV utilized the BAK-promoted pyroptotic pathway to release more virions after the final Gasdermin D-N (GSDMD-N) protein pore formation for the purpose of JEV proliferation. Therefore, the study of the endogenous cell death activator protein BAK and the final release pathway of JEV, is expected to provide some new theoretical basis for future research on the screening of targeted drugs for the treatment of inflammatory diseases caused by JEV.
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Affiliation(s)
- Weimin Xu
- Research Center of Swine Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
| | - Ke Yang
- Research Center of Swine Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
| | - Yi Zheng
- Research Center of Swine Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
| | - Sanjie Cao
- Research Center of Swine Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
| | - Qigui Yan
- Research Center of Swine Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
| | - Xiaobo Huang
- Research Center of Swine Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
| | - Yiping Wen
- Research Center of Swine Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
| | - Qin Zhao
- Research Center of Swine Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
| | - Senyan Du
- Research Center of Swine Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
| | - Yifei Lang
- Research Center of Swine Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
| | - Shan Zhao
- Research Center of Swine Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
| | - Rui Wu
- Research Center of Swine Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
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Srivastava KS, Jeswani V, Pal N, Bohra B, Vishwakarma V, Bapat AA, Patnaik YP, Khanna N, Shukla R. Japanese Encephalitis Virus: An Update on the Potential Antivirals and Vaccines. Vaccines (Basel) 2023; 11:vaccines11040742. [PMID: 37112654 PMCID: PMC10146181 DOI: 10.3390/vaccines11040742] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Revised: 02/17/2023] [Accepted: 02/24/2023] [Indexed: 03/29/2023] Open
Abstract
Japanese encephalitis virus (JEV) is the causal agent behind Japanese encephalitis (JE), a potentially severe brain infection that spreads through mosquito bites. JE is predominant over the Asia-Pacific Region and has the potential to spread globally with a higher rate of morbidity and mortality. Efforts have been made to identify and select various target molecules essential in JEV’s progression, but until now, no licensed anti-JEV drug has been available. From a prophylactic point of view, a few licensed JE vaccines are available, but various factors, viz., the high cost and different side effects imposed by them, has narrowed their global use. With an average occurrence of >67,000 cases of JE annually, there is an urgent need to find a suitable antiviral drug to treat patients at the acute phase, as presently only supportive care is available to mitigate infection. This systematic review highlights the current status of efforts put in to develop antivirals against JE and the available vaccines, along with their effectiveness. It also summarizes epidemiology, structure, pathogenesis, and potential drug targets that can be explored to develop a new range of anti-JEV drugs to combat JEV infection globally.
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Sharma KB, Chhabra S, Kalia M. Japanese Encephalitis Virus-Infected Cells. Subcell Biochem 2023; 106:251-281. [PMID: 38159231 DOI: 10.1007/978-3-031-40086-5_10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2024]
Abstract
RNA virus infections have been a leading cause of pandemics. Aided by global warming and increased connectivity, their threat is likely to increase over time. The flaviviruses are one such RNA virus family, and its prototypes such as the Japanese encephalitis virus (JEV), Dengue virus, Zika virus, West Nile virus, etc., pose a significant health burden on several endemic countries. All viruses start off their life cycle with an infected cell, wherein a series of events are set in motion as the virus and host battle for autonomy. With their remarkable capacity to hijack cellular systems and, subvert/escape defence pathways, viruses are able to establish infection and disseminate in the body, causing disease. Using this strategy, JEV replicates and spreads through several cell types such as epithelial cells, fibroblasts, monocytes and macrophages, and ultimately breaches the blood-brain barrier to infect neurons and microglia. The neurotropic nature of JEV, its high burden on the paediatric population, and its lack of any specific antivirals/treatment strategies emphasise the need for biomedical research-driven solutions. Here, we highlight the latest research developments on Japanese encephalitis virus-infected cells and discuss how these can aid in the development of future therapies.
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Affiliation(s)
- Kiran Bala Sharma
- Regional Centre for Biotechnology, NCR Biotech Science Cluster, Faridabad, Haryana, India
| | - Simran Chhabra
- Regional Centre for Biotechnology, NCR Biotech Science Cluster, Faridabad, Haryana, India
| | - Manjula Kalia
- Regional Centre for Biotechnology, NCR Biotech Science Cluster, Faridabad, Haryana, India.
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Pinapati KK, Tandon R, Tripathi P, Srivastava N. Recent advances to overcome the burden of Japanese encephalitis: A zoonotic infection with problematic early detection. Rev Med Virol 2023; 33:e2383. [PMID: 35983697 DOI: 10.1002/rmv.2383] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2022] [Revised: 07/21/2022] [Accepted: 07/29/2022] [Indexed: 01/28/2023]
Abstract
Japanese encephalitis (JE) is a vector-borne neurotropic disease caused by Japanese encephalitis virus (JEV) associated with high mortality rate distributed from Eastern and Southern Asia to Northern Queensland (Australia). The challenges in early detection and lack of point-of-care biomarkers make it the most important Flavivirus causing encephalitis. There is no specific treatment for the disease, although vaccines are licenced. In this review, we focussed on point-of-care biomarkers as early detection tools and developing the effective therapeutic agents that could halt JE. We have also provided molecular details of JEV, disease progression, and its pathogenesis with recent findings which might bring insights to overcome the disease burden.
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Affiliation(s)
- Kishore Kumar Pinapati
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research-Raebareli (NIPER-R), Lucknow, Uttra Pradesh, India
| | - Reetika Tandon
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research-Raebareli (NIPER-R), Lucknow, Uttra Pradesh, India
| | - Pratima Tripathi
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research-Raebareli (NIPER-R), Lucknow, Uttra Pradesh, India
| | - Nidhi Srivastava
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research-Raebareli (NIPER-R), Lucknow, Uttra Pradesh, India
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Soni N, Tripathi A, Mukherjee S, Gupta S, Mohanty S, Basu A, Banerjee A. Bone marrow-derived extracellular vesicles modulate the abundance of infiltrating immune cells in the brain and exert an antiviral effect against the Japanese encephalitis virus. FASEB Bioadv 2022; 4:798-815. [PMID: 36479206 PMCID: PMC9721092 DOI: 10.1096/fba.2022-00071] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 09/02/2022] [Accepted: 09/19/2022] [Indexed: 01/18/2024] Open
Abstract
Mesenchymal stem cells (MSCs) have regenerative capacity and have reported a beneficial effect on the Japanese encephalitis virus (JEV) in an encephalitis model. However, the MSCs do not cross the blood-brain barrier and have other disadvantages limiting their therapeutic utility scope. Recently, there has been a shift in concept from a cell-based to a cell-free approach using MSCs-derived extracellular vesicles (MSC-EVs). The MSC-EVs retain regenerative and immunomodulatory capacity as their parental cells. However, the role of MSC-EVs in limiting JEV pathology remains elusive. In this study, we have used Bone marrow (BM)-derived EV (BM-EVs) and assessed their effect on JEV replication and pathogenesis in primary neuronal stem cells and a murine model. The in vitro and in vivo studies suggested that BM-derived EVs delay JEV-induced symptoms and death in mice, improve the length of survival, accelerate neurogenesis in primary neuronal stem cells, reduce JEV-induced neuronal death, and attenuate viral replication. BM-EVs treatment upregulated interferon-stimulated genes. Flow cytometry analysis revealed a reduction in the frequency of macrophages. At the same time, CD4+ T cells and neutrophils were significantly augmented, accompanied by the alteration of cytokine expression with the administration of BM-EVs, reinforcing the immunomodulatory role of EVs during JEV-induced encephalitis. In conclusion, our study describes the beneficial role of BM-EVs in limiting JEV pathology by attenuating virus replication, enhancing antiviral response, and neurogenesis in primary neuronal stem cells. However, BM-EVs do not seem to protect BBB integrity and alter immune cell infiltration into the treated brain.
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Affiliation(s)
- Naina Soni
- Laboratory of Virology Regional Centre for Biotechnology Faridabad India
| | - Aarti Tripathi
- Laboratory of Virology Regional Centre for Biotechnology Faridabad India
| | - Sriparna Mukherjee
- National Brain Research Centre Manesar India
- Department of Pharmacology and Physiology Pavilion Roger-Gaudry, Universite de Montréal Montréal Québec Canada
| | - Suchi Gupta
- DBT-Centre of Excellence for Stem Cell Research, Stem Cell Facility All India Institute of Medical Sciences New Delhi India
| | - Sujata Mohanty
- DBT-Centre of Excellence for Stem Cell Research, Stem Cell Facility All India Institute of Medical Sciences New Delhi India
| | | | - Arup Banerjee
- Laboratory of Virology Regional Centre for Biotechnology Faridabad India
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Sahu RC, Suthar T, Pathak A, Jain K. Interventions for the Prevention and Treatment of Japanese Encephalitis. Curr Infect Dis Rep 2022; 24:189-204. [PMID: 36187900 PMCID: PMC9510552 DOI: 10.1007/s11908-022-00786-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/15/2022] [Indexed: 11/04/2022]
Abstract
Purpose of Review Japanese encephalitis (JE), a clinical indication of JE virus–induced brain inflammation, is the most prevalent cause of viral encephalitis in the world. This review gives a comprehensive update on the epidemiology, clinical features, therapeutic trials and approaches for preventing the spread of JE. It also outlines the different JE vaccines used in various countries and recommendations for administration of JE vaccines. Recent Findings According to the WHO, annual incidence of JE is estimated to be approximately 68,000 cases worldwide. It is widespread across Asia–Pacific, with a potential for worldwide transmission. In endemic locations, JE is believed to affect children below 6 years of age, but in newly affected areas, both adults and children are at risk due to a lack of protective antibodies. Various vaccines have been developed for the prevention of JE and are being administered in endemic countries. Summary JE is a neuroinvasive disease that causes symptoms ranging from simple fever to severe encephalitis and death. Despite a vast number of clinical trials on various drugs, there is still no complete cure available, and it can only be prevented by adequate vaccination. Various nanotechnological approaches for the prevention and treatment of JE are outlined in this review.
Supplementary Information The online version contains supplementary material available at 10.1007/s11908-022-00786-1.
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Hoad VC, Kiely P, Seed CR, Viennet E, Gosbell IB. An Outbreak of Japanese Encephalitis Virus in Australia; What Is the Risk to Blood Safety? Viruses 2022; 14:1935. [PMID: 36146742 PMCID: PMC9501196 DOI: 10.3390/v14091935] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 08/26/2022] [Accepted: 08/29/2022] [Indexed: 11/16/2022] Open
Abstract
A widespread outbreak of Japanese encephalitis virus (JEV) was detected in mainland Australia in 2022 in a previous non-endemic area. Given JEV is known to be transfusion-transmissible, a rapid blood-safety risk assessment was performed using a simple deterministic model to estimate the risk to blood safety over a 3-month outbreak period during which 234,212 donors attended. The cumulative estimated incidence in donors was 82 infections with an estimated 4.26 viraemic components issued, 1.58 resulting in transfusion-transmission and an estimated risk of encephalitis of 1 in 4.3 million per component transfused over the risk period. Australia has initiated a robust public health response, including vector control, animal control and movement, and surveillance. Unlike West Nile virus, there is an effective vaccine that is being rolled-out to those at higher risk. Risk evaluation considered options such as restricting those potentially at risk to plasma for fractionation, which incorporates additional pathogen reduction, introducing a screening test, physicochemical pathogen reduction, quarantine, post donation illness policy changes and a new donor deferral. However, except for introducing a new deferral to potentially cover rare flavivirus risks, no option resulted in a clear risk reduction benefit but all posed threats to blood sufficiency or cost. Therefore, the blood safety risk was concluded to be tolerable without specific mitigations.
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Affiliation(s)
- Veronica C. Hoad
- Clinical Services and Research, Australian Red Cross Lifeblood, West Melbourne, VIC 3003, Australia
| | - Philip Kiely
- Clinical Services and Research, Australian Red Cross Lifeblood, West Melbourne, VIC 3003, Australia
| | - Clive R. Seed
- Clinical Services and Research, Australian Red Cross Lifeblood, West Melbourne, VIC 3003, Australia
| | - Elvina Viennet
- Clinical Services and Research, Australian Red Cross Lifeblood, West Melbourne, VIC 3003, Australia
- School of Biomedical Sciences, Queensland University of Technology, Kelvin Grove, QLD 4059, Australia
| | - Iain B. Gosbell
- Clinical Services and Research, Australian Red Cross Lifeblood, West Melbourne, VIC 3003, Australia
- School of Medicine, Western Sydney University, Penrith, NSW 2751, Australia
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Abstract
Flaviviruses are a spectrum of vector-borne RNA viruses that cause potentially severe diseases in humans including encephalitis, acute-flaccid paralysis, cognitive disorders and foetal abnormalities. Japanese encephalitis virus (JEV), Zika virus (ZIKV), West Nile virus (WNV) and Dengue virus (DENV) are globally emerging pathogens that lead to epidemics and outbreaks with continued transmission to newer geographical areas over time. In the past decade, studies have focussed on understanding the pathogenic mechanisms of these viruses in a bid to alleviate their disease burden. MicroRNAs (miRNAs) are short single-stranded RNAs that have emerged as master-regulators of cellular gene expression. The dynamics of miRNAs within a cell have the capacity to modulate hundreds of genes and, consequently, their physiological manifestation. Increasing evidence suggests their role in host response to disease and infection including cell survival, intracellular viral replication and immune activation. In this review, we aim to comprehensively update published evidence on the role of miRNAs in host cells infected with the common neurotropic flaviviruses, with an increased focus on neuropathogenic mechanisms. In addition, we briefly cover therapeutic advancements made in the context of miRNA-based antiviral strategies.
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Nucleotide-Binding Oligomerization Domain 1 (NOD1) Positively Regulates Neuroinflammation during Japanese Encephalitis Virus Infection. Microbiol Spectr 2022; 10:e0258321. [PMID: 35638852 PMCID: PMC9241932 DOI: 10.1128/spectrum.02583-21] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Japanese encephalitis virus (JEV) is a neurotropic flavivirus that invades the central nervous system and causes neuroinflammation and extensive neuronal cell death. Nucleotide-binding oligomerization domain 1 (NOD1) is a type of pattern recognition receptor that plays a regulatory role in both bacterial and nonbacterial infections. However, the role of NOD1 in JEV-induced neuroinflammation remains undisclosed. In this study, we evaluated the effect of NOD1 activation on the progression of JEV-induced neuroinflammation using a human astrocytic cell line and NOD1 knockout mice. The results showed that JEV infection upregulated the mRNA and protein expression of NOD1, ultimately leading to an enhanced neuroinflammatory response in vivo and in vitro. Inhibition of NOD1 in cultured cells or mice significantly abrogated the inflammatory response triggered by JEV infection. Moreover, compared to the wild-type mice, the NOD1 knockout mice showed resistance to JEV infection. Mechanistically, the NOD1-mediated neuroinflammatory response was found to be associated with increased expression or activation/phosphorylation of downstream receptor-interacting protein 2 (RIPK2), mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK), Jun N-terminal protein kinase (JNK), and NF-κB signaling molecules. Thus, NOD1 targeting could be a therapeutic approach to treat Japanese encephalitis. IMPORTANCE Neuroinflammation is the main pathological manifestation of Japanese encephalitis (JE) and the most important factor leading to morbidity and death in humans and animals infected by JEV. An in-depth understanding of the basic mechanisms of neuroinflammation will contribute to research on JE treatment. This study proved that JEV infection can activate the NOD1-RIPK2 signal cascade to induce neuroinflammation through the proven downstream MAPK, ERK, JNK, and NF-κB signal pathway. Thus, our study unveiled NOD1 as a potential target for therapeutic intervention for JE.
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Fan Y, Chen Z, Zhang M. Role of exosomes in the pathogenesis, diagnosis, and treatment of central nervous system diseases. Lab Invest 2022; 20:291. [PMID: 35761337 PMCID: PMC9235237 DOI: 10.1186/s12967-022-03493-6] [Citation(s) in RCA: 87] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2022] [Accepted: 06/20/2022] [Indexed: 12/11/2022]
Abstract
Central nervous system (CNS) diseases, such as multiple sclerosis, Alzheimer's disease (AD), and Parkinson’s disease (PD), affect millions of people around the world. Great efforts were put in disease related research, but few breakthroughs have been made in the diagnostic and therapeutic approaches. Exosomes are cell-derived extracellular vesicles containing diverse biologically active molecules secreted by their cell of origin. These contents, including nucleic acids, proteins, lipids, amino acids, and metabolites, can be transferred between different cells, tissues, or organs, regulating various intercellular cross-organ communications and normal and pathogenic processes. Considering that cellular environment and cell state strongly impact the content and uptake efficiency of exosomes, their detection in biological fluids and content composition analysis potentially offer a multicomponent diagnostic readout of several human diseases. Recently, studies have found that aberrant secretion and content of exosomes are closely related to the pathogenesis of CNS diseases. Besides, loading natural cargoes, exosomes can deliver drugs cross the blood brain barrier, making them emerging candidates of biomarkers and therapeutics for CNS diseases. In this review, we summarize and discuss the advanced research progress of exosomes in the pathological processes of several CNS diseases in regarding with neuroinflammation, CNS repair, and pathological protein aggregation. Moreover, we propose the therapeutic strategies of applying exosomes to the diagnosis, early detection, and treatment of CNS diseases.
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Affiliation(s)
- Yishu Fan
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Zhuohui Chen
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Mengqi Zhang
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, China. .,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China.
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18
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Li X, Li J, Wu G, Wang M, Jing Z. Detection of Japanese Encephalitis by Metagenomic Next-Generation Sequencing of Cerebrospinal Fluid: A Case Report and Literature Review. Front Cell Neurosci 2022; 16:856512. [PMID: 35250491 PMCID: PMC8892252 DOI: 10.3389/fncel.2022.856512] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Accepted: 01/25/2022] [Indexed: 12/28/2022] Open
Abstract
Japanese encephalitis (JE) is an acute viral central nervous system disease, although less than 1% of patients infected with Japanese encephalitis virus (JEV) result in JE, which has an extremely poor prognosis. The Routine detection methods for JEV are time-consuming or limited by hospital conditions, therefore, need the quicker and sensitive techniques to detect JEV. Here, we reported a 14-year-old female who was admitted to our hospital with a severe fever, progressively headache and unconsciousness. Based on the clinical presentation, Preliminary diagnosis on admission indicated central nervous system infection of suspected viral meningoencephalitis or autoimmune encephalitis. The patient's symptoms were unrelieved after being treated with empiric antiviral therapy. Magnetic resonance imaging (MRI) showed that the lesions were located in the bilateral thalamus, head of caudate nucleus, and right lenticular nucleus, so we had to consider the possibility of Flaviviruses infection. We sent the cerebrospinal fluid (CSF) for metagenomic next-generation sequencing (mNGS) immediately, subsequent result suggested the infection caused by JEV. Two days later the results of the serum agglutination test confirmed that virus immunoglobulin M antibody positive. After a week treatment with intravenous immunoglobulin (IVIG), meanwhile, the lumbar puncture was used to check the pressure and various indicators of the CSF again to evaluate the treatment effect, An decrease in the number of WBC indicates, protein and unique RNA reads that the previous experimental treatment was effective, accompany by temperature and consciousness of the patient was normalized. Two weeks after admission, the patient was transferred to the rehabilitation hospital, MR showed the lesions had disappeared completely after 2 months of follow-up. We believed that mNGS may be an effective method for rapid identification of JE.
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Affiliation(s)
- Xin Li
- Department of Neurology, Lanzhou University Second Hospital, Lanzhou, China
| | - Jing Li
- Department of Neurology, Lanzhou University Second Hospital, Lanzhou, China
| | - Guode Wu
- Department of Neurology, Lanzhou University Second Hospital, Lanzhou, China
| | - Manxia Wang
- Department of Neurology, Lanzhou University Second Hospital, Lanzhou, China
- *Correspondence: Manxia Wang
| | - Zhang Jing
- Department of Magnetic Resonance, Lanzhou University Second Hospital, Lanzhou, China
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Ashraf U, Ding Z, Deng S, Ye J, Cao S, Chen Z. Pathogenicity and virulence of Japanese encephalitis virus: Neuroinflammation and neuronal cell damage. Virulence 2021; 12:968-980. [PMID: 33724154 PMCID: PMC7971234 DOI: 10.1080/21505594.2021.1899674] [Citation(s) in RCA: 75] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 02/12/2021] [Accepted: 03/03/2021] [Indexed: 01/22/2023] Open
Abstract
Thousands of human deaths occur annually due to Japanese encephalitis (JE), caused by Japanese encephalitis virus. During the virus infection of the central nervous system, reactive gliosis, uncontrolled inflammatory response, and neuronal cell death are considered as the characteristic features of JE. To date, no specific treatment has been approved to overcome JE, indicating a need for the development of novel therapies. In this article, we focused on basic biological mechanisms in glial (microglia and astrocytes) and neuronal cells that contribute to the onset of neuroinflammation and neuronal cell damage during Japanese encephalitis virus infection. We also provided comprehensive knowledge about anti-JE therapies tested in clinical or pre-clinical settings, and discussed recent therapeutic strategies that could be employed for JE treatment. The improved understanding of JE pathogenesis might lay a foundation for the development of novel therapies to halt JE.Abbreviations AKT: a serine/threonine-specific protein kinase; AP1: activator protein 1; ASC: apoptosis-associated speck-like protein containing a CARD; ASK1: apoptosis signal-regulated kinase 1; ATF3/4/6: activating transcription factor 3/4/6; ATG5/7: autophagy-related 5/7; BBB: blood-brain barrier; Bcl-3/6: B-cell lymphoma 3/6 protein; CCL: C-C motif chemokine ligand; CCR2: C-C motif chemokine receptor 2; CHOP: C/EBP homologous protein; circRNA: circular RNA; CNS: central nervous system; CXCL: C-X-C motif chemokine ligand; dsRNA: double-stranded RNA; EDEM1: endoplasmic reticulum degradation enhancer mannosidase alpha-like 1; eIF2-ɑ: eukaryotic initiation factor 2 alpha; ER: endoplasmic reticulum; ERK: extracellular signal-regulated kinase; GRP78: 78-kDa glucose-regulated protein; ICAM: intercellular adhesion molecule; IFN: interferon; IL: interleukin; iNOS: inducible nitric oxide synthase; IRAK1/2: interleukin-1 receptor-associated kinase 1/2; IRE-1: inositol-requiring enzyme 1; IRF: interferon regulatory factor; ISG15: interferon-stimulated gene 15; JE: Japanese encephalitis; JEV: Japanese encephalitis virus; JNK: c-Jun N-terminal kinase; LAMP2: lysosome-associated membrane protein type 2; LC3-I/II: microtubule-associated protein 1 light chain 3-I/II; lncRNA: long non-coding RNA; MAPK: mitogen-activated protein kinase; miR/miRNA: microRNA; MK2: mitogen-activated protein kinase-activated protein kinase 2; MKK4: mitogen-activated protein kinase kinase 4; MLKL: mixed-linage kinase domain-like protein; MMP: matrix metalloproteinase; MyD88: myeloid differentiation factor 88; Nedd4: neural precursor cell-expressed developmentally downregulated 4; NF-κB: nuclear factor kappa B; NKRF: nuclear factor kappa B repressing factor; NLRP3: NLR family pyrin domain containing 3; NMDAR: N-methyl-D-aspartate receptor; NO: nitric oxide; NS2B/3/4: JEV non-structural protein 2B/3/4; P: phosphorylation. p38: mitogen-activated protein kinase p38; PKA: protein kinase A; PAK4: p21-activated kinase 4; PDFGR: platelet-derived growth factor receptor; PERK: protein kinase R-like endoplasmic reticulum kinase; PI3K: phosphoinositide 3-kinase; PTEN: phosphatase and tensin homolog; Rab7: Ras-related GTPase 7; Raf: proto-oncogene tyrosine-protein kinase Raf; Ras: a GTPase; RIDD: regulated IRE-1-dependent decay; RIG-I: retinoic acid-inducible gene I; RIPK1/3: receptor-interacting protein kinase 1/3; RNF11/125: RING finger protein 11/125; ROS: reactive oxygen species; SHIP1: SH2-containing inositol 5' phosphatase 1; SOCS5: suppressor of cytokine signaling 5; Src: proto-oncogene tyrosine-protein kinase Src; ssRNA = single-stranded RNA; STAT: signal transducer and activator of transcription; TLR: toll-like receptor; TNFAIP3: tumor necrosis factor alpha-induced protein 3; TNFAR: tumor necrosis factor alpha receptor; TNF-α: tumor necrosis factor-alpha; TRAF6: tumor necrosis factor receptor-associated factor 6; TRIF: TIR-domain-containing adapter-inducing interferon-β; TRIM25: tripartite motif-containing 25; VCAM: vascular cell adhesion molecule; ZO-1: zonula occludens-1.
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Affiliation(s)
- Usama Ashraf
- State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, Hubei, P. R. China
- The Cooperative Innovation Center for Sustainable Pig Production, Huazhong Agricultural University, Wuhan, Hubei, P. R. China
| | - Zhen Ding
- Department of Preventive Veterinary Medicine, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang, Jiangxi, P. R. China
- Key Laboratory for Animal Health of Jiangxi Province, Nanchang, Jiangxi, P. R. China
| | - Shunzhou Deng
- Department of Preventive Veterinary Medicine, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang, Jiangxi, P. R. China
- Key Laboratory for Animal Health of Jiangxi Province, Nanchang, Jiangxi, P. R. China
| | - Jing Ye
- State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, Hubei, P. R. China
- The Cooperative Innovation Center for Sustainable Pig Production, Huazhong Agricultural University, Wuhan, Hubei, P. R. China
| | - Shengbo Cao
- State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, Hubei, P. R. China
- The Cooperative Innovation Center for Sustainable Pig Production, Huazhong Agricultural University, Wuhan, Hubei, P. R. China
| | - Zheng Chen
- Department of Preventive Veterinary Medicine, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang, Jiangxi, P. R. China
- Key Laboratory for Animal Health of Jiangxi Province, Nanchang, Jiangxi, P. R. China
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Lack of Interferon Regulatory Factor 8 Associated with Restricted IFN-gamma expression Augmented Japanese Encephalitis Virus Replication in the Mouse Brain. J Virol 2021; 95:e0040621. [PMID: 34379515 PMCID: PMC8513486 DOI: 10.1128/jvi.00406-21] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
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+CD45hi, CD11b+CD45lo, 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.
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21
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Chauhan S, Rathore DK, Sachan S, Lacroix-Desmazes S, Gupta N, Awasthi A, Vrati S, Kalia M. Japanese Encephalitis Virus Infected Human Monocyte-Derived Dendritic Cells Activate a Transcriptional Network Leading to an Antiviral Inflammatory Response. Front Immunol 2021; 12:638694. [PMID: 34220803 PMCID: PMC8247639 DOI: 10.3389/fimmu.2021.638694] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Accepted: 05/04/2021] [Indexed: 12/29/2022] Open
Abstract
A comprehensive understanding of the human immune response to virus infection is imperative for developing effective therapies, antivirals, and vaccines. Dendritic cells (DCs) are among the first cells to encounter the virus and are also key antigen-presenting cells that link the innate and adaptive immune system. In this study, we focus on the human immune response to the mosquito-borne Japanese encephalitis virus (JEV), which is the leading cause of virus-induced encephalitis in south-east Asia and has the potential to become a global pathogen. We describe the gene regulatory circuit of JEV infection in human monocyte-derived DCs (moDCs) along with its functional validation. We observe that JEV can productively infect human moDCs leading to robust transcriptional activation of the interferon and NF-κB-mediated antiviral and inflammatory pathways. This is accompanied with DC maturation and release of pro-inflammatory cytokines and chemokines TNFα, IL-6, IL-8, IL-12, MCP-1. and RANTES. JEV-infected moDCs activated T-regulatory cells (Tregs) in allogenic mixed lymphocyte reactions (MLR) as seen by upregulated FOXP3 mRNA expression, suggestive of a host response to reduce virus-induced immunopathology. The virus also downregulated transcripts involved in Peroxisome Proliferator Activated Receptor (PPAR) signalling and fatty acid metabolism pathways suggesting that changes in cellular metabolism play a crucial role in driving the DC maturation and antiviral responses. Collectively, our data describe and corroborate the human DC transcriptional network that is engaged upon JEV sensing.
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Affiliation(s)
| | | | - Shilpa Sachan
- Vaccine Immunology Laboratory, National Institute of Immunology, New Delhi, India
| | - Sebastien Lacroix-Desmazes
- Institut National de la Santé et de la Recherche Médicale, Centre de Recherche des Cordeliers, Sorbonne Université, Université de Paris, Paris, France
| | - Nimesh Gupta
- Vaccine Immunology Laboratory, National Institute of Immunology, New Delhi, India
| | - Amit Awasthi
- Translational Health Science & Technology Institute, Faridabad, India
| | - Sudhanshu Vrati
- Translational Health Science & Technology Institute, Faridabad, India
- Regional Centre for Biotechnology, Faridabad, India
| | - Manjula Kalia
- Translational Health Science & Technology Institute, Faridabad, India
- Regional Centre for Biotechnology, Faridabad, India
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22
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Patil AM, Choi JY, Park SO, Uyangaa E, Kim B, Kim K, Eo SK. Type I IFN signaling limits hemorrhage-like disease after infection with Japanese encephalitis virus through modulating a prerequisite infection of CD11b +Ly-6C + monocytes. J Neuroinflammation 2021; 18:136. [PMID: 34130738 PMCID: PMC8204625 DOI: 10.1186/s12974-021-02180-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Accepted: 05/20/2021] [Indexed: 12/20/2022] Open
Abstract
Background The crucial role of type I interferon (IFN-I, IFN-α/β) is well known to control central nervous system (CNS) neuroinflammation caused by neurotrophic flaviviruses such as Japanese encephalitis virus (JEV) and West Nile virus. However, an in-depth analysis of IFN-I signal-dependent cellular factors that govern CNS-restricted tropism in JEV infection in vivo remains to be elucidated. Methods Viral dissemination, tissue tropism, and cytokine production were examined in IFN-I signal-competent and -incompetent mice after JEV inoculation in tissues distal from the CNS such as the footpad. Bone marrow (BM) chimeric models were used for defining hematopoietic and tissue-resident cells in viral dissemination and tissue tropism. Results The paradoxical and interesting finding was that IFN-I signaling was essentially required for CNS neuroinflammation following JEV inoculation in distal footpad tissue. IFN-I signal-competent mice died after a prolonged neurological illness, but IFN-I signal-incompetent mice all succumbed without neurological signs. Rather, IFN-I signal-incompetent mice developed hemorrhage-like disease as evidenced by thrombocytopenia, functional injury of the liver and kidney, increased vascular leakage, and excessive cytokine production. This hemorrhage-like disease was closely associated with quick viral dissemination and impaired IFN-I innate responses before invasion of JEV into the CNS. Using bone marrow (BM) chimeric models, we found that intrinsic IFN-I signaling in tissue-resident cells in peripheral organs played a major role in inducing the hemorrhage-like disease because IFN-I signal-incompetent recipients of BM cells from IFN-I signal-competent mice showed enhanced viral dissemination, uncontrolled cytokine production, and increased vascular leakage. IFN-I signal-deficient hepatocytes and enterocytes were permissive to JEV replication with impaired induction of antiviral IFN-stimulated genes, and neuron cells derived from both IFN-I signal-competent and -incompetent mice were vulnerable to JEV replication. Finally, circulating CD11b+Ly-6C+ monocytes infiltrated into the distal tissues inoculated by JEV participated in quick viral dissemination to peripheral organs of IFN-I signal-incompetent mice at an early stage. Conclusion An IFN-I signal-dependent model is proposed to demonstrate how CD11b+Ly-6C+ monocytes are involved in restricting the tissue tropism of JEV to the CNS.
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Affiliation(s)
- Ajit Mahadev Patil
- College of Veterinary Medicine and Bio-Safety Research Institute, Jeonbuk National University, Iksan, 54596, Republic of Korea
| | - Jin Young Choi
- College of Veterinary Medicine and Bio-Safety Research Institute, Jeonbuk National University, Iksan, 54596, Republic of Korea
| | - Seong Ok Park
- College of Veterinary Medicine and Bio-Safety Research Institute, Jeonbuk National University, Iksan, 54596, Republic of Korea
| | - Erdenebelig Uyangaa
- College of Veterinary Medicine and Bio-Safety Research Institute, Jeonbuk National University, Iksan, 54596, Republic of Korea
| | - Bumseok Kim
- College of Veterinary Medicine and Bio-Safety Research Institute, Jeonbuk National University, Iksan, 54596, Republic of Korea
| | - Koanhoi Kim
- Department of Pharmacology, School of Medicine, Pusan National University, Yangsan, 50612, Republic of Korea
| | - Seong Kug Eo
- College of Veterinary Medicine and Bio-Safety Research Institute, Jeonbuk National University, Iksan, 54596, Republic of Korea.
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23
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Differential miRNA Expression Profiling Reveals Correlation of miR125b-5p with Persistent Infection of Japanese Encephalitis Virus. Int J Mol Sci 2021; 22:ijms22084218. [PMID: 33921710 PMCID: PMC8073291 DOI: 10.3390/ijms22084218] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 04/13/2021] [Accepted: 04/14/2021] [Indexed: 12/13/2022] Open
Abstract
MicroRNAs (miRNAs) play versatile roles in multiple biological processes. However, little is known about miRNA’s involvement in flavivirus persistent infection. Here, we used an miRNA array analysis of Japanese encephalitis virus (JEV)-infected cells to search for persistent infection-associated miRNAs in comparison to acute infection. Among all differentially expressed miRNAs, the miR-125b-5p is the most significantly increased one. The high level of miR-125b-5p in persistently JEV-infected cells was confirmed by Northern analysis and real-time quantitative polymerase chain reaction. As soon as the cells established a persistent infection, a significantly high expression of miR-125b-5p was readily observed. Transfecting excess quantities of a miR-125b-5p mimic into acutely infected cells reduced genome replication and virus titers. Host targets of miR125b-5p were analyzed by target prediction algorithms, and six candidates were confirmed by a dual-luciferase reporter assay. These genes were upregulated in the acutely infected cells and sharply declined in the persistently infected cells. The transfection of the miR125b-5p mimic reduced the expression levels of Stat3, Map2k7, and Triap1. Our studies indicated that miR-125b-5p targets both viral and host sequences, suggesting its role in coordinating viral replication and host antiviral responses. This is the first report to characterize the potential roles of miR-125b-5p in persistent JEV infections.
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24
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Liu YG, Chen Y, Wang X, Zhao P, Zhu Y, Qi Z. Ezrin is essential for the entry of Japanese encephalitis virus into the human brain microvascular endothelial cells. Emerg Microbes Infect 2021; 9:1330-1341. [PMID: 32538298 PMCID: PMC7473060 DOI: 10.1080/22221751.2020.1757388] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Japanese encephalitis virus (JEV) remains the predominant cause of viral encephalitis worldwide. It reaches the central nervous system upon crossing the blood-brain barrier through pathogenic mechanisms that are not completely understood. Here, using a high-throughput siRNA screening assay combined with verification experiments, we found that JEV enters the primary human brain microvascular endothelial cells (HBMEC) through a caveolae-mediated endocytic pathway. The role of ezrin, an essential host factor for JEV entry based on our screening, in caveolae-mediated JEV internalization was investigated. We observed that JEV internalization in HBMEC is largely dependent on ezrin-mediated actin cytoskeleton polymerization. Moreover, Src, a protein predicted by a STRING database search, was found to be required in JEV entry. By a variety of pharmacological inhibition and immunoprecipitation assays, we found that Src, ezrin, and caveolin-1 were sequentially activated and formed a complex during JEV infection. A combination of in vitro kinase assay and subcellular analysis demonstrated that ezrin is essential for Src-caveolin-1 interactions. In vivo, both Src and ezrin inhibitors protected ICR suckling mice against JEV-induced mortality and diminished mouse brain viral load. Therefore, JEV entry into HBMEC requires the activation of the Src-ezrin-caveolin-1 signalling axis, which provides potential targets for restricting JEV infection.
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Affiliation(s)
- Yan-Gang Liu
- Department of Microbiology, Shanghai Key Laboratory of Medical Biodefense, Naval Medical University (Second Military Medical University), Shanghai, People's Republic of China
| | - Yang Chen
- Department of Microbiology, Shanghai Key Laboratory of Medical Biodefense, Naval Medical University (Second Military Medical University), Shanghai, People's Republic of China.,College of Basic Medicine, Naval Medical University (Second Military Medical University Shanghai), Shanghai, People's Republic of China
| | - Xiaohang Wang
- Department of Microbiology, Shanghai Key Laboratory of Medical Biodefense, Naval Medical University (Second Military Medical University), Shanghai, People's Republic of China.,College of Basic Medicine, Naval Medical University (Second Military Medical University Shanghai), Shanghai, People's Republic of China
| | - Ping Zhao
- Department of Microbiology, Shanghai Key Laboratory of Medical Biodefense, Naval Medical University (Second Military Medical University), Shanghai, People's Republic of China
| | - Yongzhe Zhu
- Department of Microbiology, Shanghai Key Laboratory of Medical Biodefense, Naval Medical University (Second Military Medical University), Shanghai, People's Republic of China
| | - Zhongtian Qi
- Department of Microbiology, Shanghai Key Laboratory of Medical Biodefense, Naval Medical University (Second Military Medical University), Shanghai, People's Republic of China
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25
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Stonedahl S, Clarke P, Tyler KL. The Role of Microglia during West Nile Virus Infection of the Central Nervous System. Vaccines (Basel) 2020; 8:E485. [PMID: 32872152 PMCID: PMC7563127 DOI: 10.3390/vaccines8030485] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Revised: 08/22/2020] [Accepted: 08/26/2020] [Indexed: 12/28/2022] Open
Abstract
Encephalitis resulting from viral infections is a major cause of hospitalization and death worldwide. West Nile Virus (WNV) is a substantial health concern as it is one of the leading causes of viral encephalitis in the United States today. WNV infiltrates the central nervous system (CNS), where it directly infects neurons and induces neuronal cell death, in part, via activation of caspase 3-mediated apoptosis. WNV infection also induces neuroinflammation characterized by activation of innate immune cells, including microglia and astrocytes, production of inflammatory cytokines, breakdown of the blood-brain barrier, and infiltration of peripheral leukocytes. Microglia are the resident immune cells of the brain and monitor the CNS for signs of injury or pathogens. Following infection with WNV, microglia exhibit a change in morphology consistent with activation and are associated with increased expression of proinflammatory cytokines. Recent research has focused on deciphering the role of microglia during WNV encephalitis. Microglia play a protective role during infections by limiting viral growth and reducing mortality in mice. However, it also appears that activated microglia are triggered by T cells to mediate synaptic elimination at late times during infection, which may contribute to long-term neurological deficits following a neuroinvasive WNV infection. This review will discuss the important role of microglia in the pathogenesis of a neuroinvasive WNV infection. Knowledge of the precise role of microglia during a WNV infection may lead to a greater ability to treat and manage WNV encephalitis.
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Affiliation(s)
- Sarah Stonedahl
- Department of Immunology and Microbiology University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA;
| | - Penny Clarke
- Department of Neurology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Kenneth L. Tyler
- Department of Immunology and Microbiology, Infectious Disease, Medicine and Neurology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
- Department of Veterans Affairs, Aurora, CO 80045, USA
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