Peptide inhibitor of Japanese encephalitis virus infection targeting envelope protein domain III

Zu, Xiangyang; Liu, Yang; Wang, Shaobo; Jin, Rui; Zhou, Zheng; Liu, Haibin; Gong, Rui; Xiao, Gengfu; Wang, Wei

doi:10.1016/j.antiviral.2014.01.011

Cited by 37 publications

(22 citation statements)

References 47 publications

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“…Studies have shown that the ED3 domain of the virus envelope can inhibit entry of DENV, WNV, and JEV (32)(33)(34)(35). To test if the ED3 generated in our study could compete with JEV binding to cells (as measured by productive infection, leading to JEV RNA replication, and the virus yield), Neuro2a cells were incubated with JEV ED3 or JEV NS3 for 1 h on ice, followed by infection with JEV.…”

Section: Resultsmentioning

confidence: 99%

GRP78 Is an Important Host Factor for Japanese Encephalitis Virus Entry and Replication in Mammalian Cells

Nain

Mukherjee

Karmakar

et al. 2017

J Virol

123

126

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Japanese encephalitis virus (JEV), a mosquito-borne flavivirus, is the leading cause of viral encephalitis in Southeast Asia with potential to become a global pathogen. Here, we identify glucose-regulated protein 78 (GRP78) as an important host protein for virus entry and replication. Using the plasma membrane fractions from mouse neuronal (Neuro2a) cells, mass spectroscopy analysis identified GRP78 as a protein interacting with recombinant JEV envelope protein domain III. GRP78 was found to be expressed on the plasma membranes of Neuro2a cells, mouse primary neurons, and human epithelial Huh-7 cells. Antibodies against GRP78 significantly inhibited JEV entry in all three cell types, suggesting an important role of the protein in virus entry. Depletion of GRP78 by small interfering RNA (siRNA) significantly blocked JEV entry into Neuro2a cells, further supporting its role in virus uptake. Immunofluorescence studies showed extensive colocalization of GRP78 with JEV envelope protein in virus-infected cells. This interaction was also confirmed by immunoprecipitation studies. Additionally, GRP78 was shown to have an important role in JEV replication, as treatment of cells post-virus entry with subtilase cytotoxin that specifically cleaved GRP78 led to a substantial reduction in viral RNA replication and protein synthesis, resulting in significantly reduced extracellular virus titers. Our results indicate that GRP78, an endoplasmic reticulum chaperon of the HSP70 family, is a novel host factor involved at multiple steps of the JEV life cycle and could be a potential therapeutic target.IMPORTANCE Recent years have seen a rapid spread of mosquito-borne diseases caused by flaviviruses. The flavivirus family includes West Nile, dengue, Japanese encephalitis, and Zika viruses, which are major threats to public health with potential to become global pathogens. JEV is the major cause of viral encephalitis in several parts of Southeast Asia, affecting a predominantly pediatric population with a high mortality rate. This study is focused on identification of crucial host factors that could be targeted to cripple virus infection and ultimately lead to development of effective antivirals. We have identified a cellular protein, GRP78, that plays a dual role in virus entry and virus replication, two crucial steps of the virus life cycle, and thus is a novel host factor that could be a potential therapeutic target.

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Section: Resultsmentioning

confidence: 99%

GRP78 Is an Important Host Factor for Japanese Encephalitis Virus Entry and Replication in Mammalian Cells

Nain

Mukherjee

Karmakar

et al. 2017

J Virol

123

126

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“…These differences may be explained by differential binding and entry efficiency of the viruses to the host cell. JEV interacts with its still unidentified host cell receptor via the viral envelope E protein [35]. Modifications of the E protein can alter JEV binding and penetration into the target cell [36].…”

Section: Discussionmentioning

confidence: 99%

Interactions of human microglia cells with Japanese encephalitis virus

Lannes

Neuhaus

Scolari

et al. 2017

Virol J

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BackgroundJapanese encephalitis virus (JEV) is a neurotropic flavivirus causing mortality and morbidity in humans. Severe Japanese encephalitis cases display strong inflammatory responses in the central nervous system and an accumulation of viral particles in specific brain regions. Microglia cells are the unique brain-resident immune cell population with potent migratory functions and have been proposed to act as a viral reservoir for JEV. Animal models suggest that the targeting of microglia by JEV is partially responsible for inflammatory reactions in the brain. Nevertheless, the interactions between human microglia and JEV are poorly documented.MethodsUsing human primary microglia and a new model of human blood monocyte-derived microglia, the present study explores the interaction between human microglia and JEV as well as the role of these cells in viral transmission to susceptible cells. To achieve this work, vaccine-containing inactivated JEV and two live JEV strains were applied on human microglia.ResultsLive JEV was non-cytopathogenic to human microglia but increased levels of CCL2, CXCL9 and CXCL10 in such cultures. Furthermore, human microglia up-regulated the expression of the fraktalkine receptor CX3CR1 upon exposure to both JEV vaccine and live JEV. Although JEV vaccine enhanced MHC class II on all microglia, live JEV enhanced MHC class II mainly on CX3CR1+ microglia cells. Importantly, human microglia supported JEV replication, but infectivity was only transmitted to neighbouring cells in a contact-dependent manner.ConclusionOur findings suggest that human microglia may be a source of neuronal infection and sustain JEV brain pathogenesis.Electronic supplementary materialThe online version of this article (doi:10.1186/s12985-016-0675-3) contains supplementary material, which is available to authorized users.

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“…These drugs inhibited JEV infection in vitro [123,124] and provided partial protection in vivo when they were intraperitoneally administered before JEV infection [125]. Similarly, a peptide known to bind the E protein inhibited JEV infection in vitro, probably by disrupting the interaction between the virion and cellular receptors [126]. Surfactant-modified nanoscale silicate platelets inhibited viral attachment by interacting electrostatically with the virus [127].…”

Section: Viral Replication Cycle-based Antiviral Drugsmentioning

confidence: 97%

“…[94,95] Minocycline Antioxidant [99,100] Arctigenin Antioxidant [101] Fenofibrate Antioxidant [102] Curcumin Antioxidant [103] Pentoxifylline Assembly or Release [105] Nitazoxanide Early/mid-replication cycle [107] Nucleic acid-based siRNA C, M, E, NS1, NS3, NS4B, NS5 [109][110][111][112][113][114][115] PNA UTR [119] Morpholino oligomer UTR [121,122] Virus replication cycle-based Heparan sulfate Receptor binding [123][124][125] E-binding peptide Receptor binding [126] NSQ Attachment [127] Indirubin Attachment [128] Bovine lactoferrin Receptor binding [129] Griffithsin Receptor binding [130] Recombinant E Receptor binding [131,132] MCPIP1 RNA replication [133] Kaempferol RNA replication [134] SCH16 Translation [138,139] In silico modeling-based Ivermectin NS3 [146] 4-hydroxypanduratin NS2B/NS3 [147] C randomized, double-blind, human clinical trial conducted in India [95]. A variety of virus-infected cells have been shown to produce reactive oxygen species (ROS), which are associated with viral pathogenicity, for example, by inducing cellular apoptosis [96].…”

Section: Categorymentioning

confidence: 99%

Potential chemotherapeutic targets for Japanese encephalitis: current status of antiviral drug development and future challenges

Ishikawa

Konishi

2015

Expert Opinion on Therapeutic Targets

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Although the development of effective anti-JE drugs is an urgent issue, only supportive care is currently available. Recent progress in our understanding of the viral replication machinery and immune evasion strategies has identified new targets for anti-JE drug development. To date, most candidate drugs have only been evaluated in single-drug formulations, and efficient drug delivery to the CNS has virtually not been considered. However, an effective anti-JE treatment is expected to be achieved with multiple-drug formulations and a targeted drug delivery system in the near future.

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Peptide inhibitor of Japanese encephalitis virus infection targeting envelope protein domain III

Cited by 37 publications

References 47 publications

GRP78 Is an Important Host Factor for Japanese Encephalitis Virus Entry and Replication in Mammalian Cells

GRP78 Is an Important Host Factor for Japanese Encephalitis Virus Entry and Replication in Mammalian Cells

Interactions of human microglia cells with Japanese encephalitis virus

Potential chemotherapeutic targets for Japanese encephalitis: current status of antiviral drug development and future challenges

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