Japanese Encephalitis Virus Research Articles

The potential impacts of vector host species fidelity on zoonotic arbovirus transmission.

The interaction between vector host preference and host availability on vector blood feeding behaviour has important implications for the transmission of vector-borne pathogens. However, to our knowledge, the effect of bias towards feeding on the same host species from which a first meal was taken, termed fidelity, has not been quantified. Using a mathematical model we showed that vector fidelity to the host species they take a first blood meal from leads to non-homogeneous mixing between hosts and vectors. Taking Japanese encephalitis virus (JEV) as a case study, we investigated how vector preference for amplifying vs dead-end hosts and fidelity can influence JEV transmission. We show that in regions where pigs (amplifying hosts) are scarce compared to cattle (dead-end hosts preferred by common JEV vectors), JEV could still be maintained through vector fidelity. Our findings demonstrate the importance of considering fidelity as a potential driver of transmission, particularly in scenarios such as Bangladesh and India where the composition of the host community might initially suggest that transmission is not possible.

DDX3 Regulates the Cap-Independent Translation of the Japanese Encephalitis Virus via Its Interactions with PABP1 and the Untranslated Regions of the Viral Genome.

The translation of global cellular proteins is almost completely repressed in cells with flavivirus infection, while viral translation remains efficient. The mechanisms of flaviviruses evade host translational shutoff are largely unknown. Here, it is found that Japanese encephalitis virus (JEV) can adopt cap-independent (CI) translation to escape the host translational shutoff. Furthermore, the elements DB2 and sHP-SL within 3'UTR are involved in the regulation of CI translation, which is conserved in the genus Orthoflavivirus. By RNA affinity purification and mass spectrometry analysis, cellular DEAD-box protein 3 (DDX3) and poly(A)-binding protein 1 (PABP1) are identified as key factors in regulating CI translation of JEV via their interactions with DB2 and sHP-SL RNA structures. Mechanistically, it is revealed that DDX3 binds to both 5'UTR and 3'UTR of the JEV genome to establish a closed-loop architecture and recruit eIF4G/eIF4A to form the DDX3/PABP1/eIF4G/eIF4A tetrameric complex via its interaction with PABP1, thereby recruiting the ribosomal 43S preinitiation complex (PIC) to the 5'-end of the JEV genome to start translation. These findings demonstrate a noncanonical translation strategy employed by JEV and further reveal the regulatory roles of DDX3 and PABP1 in this mechanism. These results expand the knowledge of the translation initiation regulation in flaviviruses under the state of host translational shutoff, which provides a conserved antiviral target against orthoflavivirus.

Japanese encephalitis virus-associated human microglia induce cell death of human microvascular endothelial cells in receptor-independent infection

IntroductionThe neurotropic virus Japanese encephalitis virus invades the human central nervous system, inducing neuroinflammation and further disruption of the blood-brain barrier. JEV interacts with various cell types of the blood-brain barrier including the endothelial cells. The present work aims to investigate impact of receptor-dependent and independent infection of human microvascular endothelial cells by Japanese encephalitis virus.MethodsReceptor-dependent infection was achieved using cell-free virus while receptor-independent infection was by co-culture of microvascular endothelial cells with virus-associated microglia.ResultsWhile both receptor-dependent and independent infections of human microvascular endothelial cells led to virus propagation, only receptor-independent infection induced cell death of human microvascular endothelial cells. While the CX3CR1-CX3CL1 axis was inefficient in blocking virus rescue and protecting endothelial cell from cell death, transcriptomics analysis identified Tumour Necrosis Factor-related apoptosis inducing ligand and receptors as potential key player leading to endothelial cell death.DiscussionOverall, our findings demonstrate that human microvascular endothelial cells supply virus propagation and Japanese encephalitis virus-associated microglia greatly contribute to endothelial cell death, an important component of the blood brain barrier integrity. Importantly, Tumour Necrosis Factor-related apoptosis inducing ligand and receptors represents a promising therapeutic target preventing microvascular endothelial cell death after neuroinvasion.

JEV NS1' protein enhances cell-to-cell viral spread by inducing the formation of tunneling nanotubes.

JEV NS1' protein enhances cell-to-cell viral spread by inducing the formation of tunneling nanotubes.

RAB4B and Japanese encephalitis virus E protein interaction is essential for viral entry in early endosomes.

RAB4B and Japanese encephalitis virus E protein interaction is essential for viral entry in early endosomes.

A novel immunogen comprising a bc loop and mutant fusion loop epitopes generates potent neutralization and protective abilities against flaviviruses without risk of disease enhancement.

A novel immunogen comprising a bc loop and mutant fusion loop epitopes generates potent neutralization and protective abilities against flaviviruses without risk of disease enhancement.

MTOR Signalling in Arbovirus Infections: Molecular Mechanisms and Therapeutic Opportunities

ABSTRACTArboviruses, including dengue virus (DENV), Zika virus (ZIKV), Japanese encephalitis virus (JEV), and West Nile virus (WNV), are vector‐borne pathogens that exploit the mammalian target of rapamycin (mTOR) signalling pathway to optimise host cellular environments for replication, immune evasion, and pathogenesis. These viruses manipulate mTOR complexes through specific viral proteins, such as DENV NS5 activating mTORC2 to suppress apoptosis and ZIKV NS4A/NS4B inhibiting Akt‐mTORC1 signalling to impair neurogenesis while promoting autophagy. JEV NS1/NS1′ disrupts the blood‐brain barrier by inducing autophagy‐mediated degradation of tight junction proteins via mTOR suppression, contributing to encephalitis. These interactions result in severe pathological outcomes, including immune evasion, metabolic reprogramming, apoptosis suppression, and neurological disorders like microcephaly. Targeting mTOR has emerged as a promising therapeutic approach for arbovirus infections. Rapamycin and its derivatives reduce viral replication and improve survival in preclinical models, while repurposed drugs like niclosamide and chloroquine exhibit antiviral effects against ZIKV. ATP‐competitive inhibitors such as Torin‐1 and natural compounds like resveratrol expand the therapeutic landscape. Combination therapies pairing mTOR inhibitors with antivirals or immune modulators may provide synergistic benefits. This review highlights the molecular mechanisms underlying arbovirus manipulation of mTOR signalling and emphasises the potential of tailored therapeutic interventions targeting these pathways to mitigate arbovirus‐associated diseases.

In silico screening of lactic acid bacteria methanolic extract for potential antiviral activity against Japanese encephalitis virus

In silico screening of lactic acid bacteria methanolic extract for potential antiviral activity against Japanese encephalitis virus

Mitochondria-dependent innate immunity: A potential therapeutic target in Flavivirus infection.

Mitochondria-dependent innate immunity: A potential therapeutic target in Flavivirus infection.

Japanese Encephalitis in Asia: A Comprehensive Review.

Japanese encephalitis (JE) which is caused by Japanese encephalitis virus (JEV) is a significant public health concern in Asia. The JEV is mainly transmitted by Culex mosquitoes breeding in flooded rice fields. The disease can range from mild flu-like symptoms to severe encephalitis and long-term neurological effects with potentially fatal outcomes with a 30% mortality rate. This review aims to gather information on public health importance, JE epidemiology, history, vaccination strategies, and public health interventions in Asian countries. A systematic literature search was conducted using various databases, PubMed, Scopus, Web of Science, and Google Scholar, including publications up to 2024. Search terms included "Japanese encephalitis", "epidemiology", "outbreaks", "prevalence" and "prevention & control". This review highlights the importance of comprehensive vaccination strategies and integrated vector management. Continued efforts are essential to enhance vaccination coverage and strengthen public health infrastructure to mitigate the burden of JE in Asia.

Serological and molecular epidemiology of West Nile, Japanese encephalitis, and tick-borne encephalitis viruses in Africa: a systematic review and meta-analysis

Flaviviruses, including West Nile virus (WNV), Japanese encephalitis virus (JEV), and tick-borne encephalitis virus (TBEV), are significant public health threats in Africa due to their potential to cause severe neurological conditions. Despite recent outbreaks, the region has limited epidemiological and evolutionary data on these viruses. This study aimed to critically and systematically review the available literature on serological and molecular epidemiology of WNV, JEV and TBEV from 2004 to 2024 and examined the phylogenetic relatedness of the African virus strain from 1937 to 2018. PubMed and Google Scholar databases were systematically searched, and 61 articles were identified: WNV (n = 54), TBEV (n = 5), and JEV (n = 2). Using a random-effects meta-analysis model, we estimated the frequency-weighted seroprevalence WNV in humans and animals to be 17.96% (95% CI 12.50, 24.13), with a peak rate of 55% in humans (Egypt) and 93.28% in horses (Nigeria). Phylogenetic analyses of 54 WNV, one JEV, and one TBEV genomes revealed that lineage 2 WNV was implicated in most outbreaks in Africa. These findings reinforced the need to strengthen WNV, JEV, and TBEV surveillance through a One Health and host ecological lens to improve preparedness for potential outbreaks in Africa.

LncRNA JINR1 regulates miR-216b-5p/GRP78 and miR-1-3p/DDX5 axis to promote JEV infection and cell death.

Infection of the central nervous system (CNS) by Japanese encephalitis virus (JEV) or West Nile virus (WNV) leads to neuroinflammation and neuronal cell death. Long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) regulate viral infection by regulating the expression of host genes. However, knowledge about the interplay between lncRNAs and miRNAs during JEN/WNV infection is limited. We show that JEV/WNV infection inhibits the expression of anti-viral host miRNAs miR-216b-5p and miR-1-3p. These miRNAs inhibit the JEV and WNV replication by directly binding with their genome. JINR1 and its interacting protein, RBM10, inhibit the transcription of miR-216b-5p and miR-1-3p. Interestingly, JINR1 also binds and sequesters miR-216b-5p and miR-1-3p, resulting in upregulation of their targets GRP78 and DDX5, respectively, which promote viral infection. Our findings suggest that lncRNA JINR1 is a potential target for developing anti-virals against JEV/WNV infection.

Neutralizing antibodies against the Japanese encephalitis virus are produced by a 12kDa E. coli- expressed envelope protein domain III (EDIII) tagged with a solubility-controlling peptide.

Neutralizing antibodies against the Japanese encephalitis virus are produced by a 12kDa E. coli- expressed envelope protein domain III (EDIII) tagged with a solubility-controlling peptide.

Targeting SARM1 as a novel neuroprotective therapy in neurotropic viral infections

Viral encephalitis, resulting from neurotropic viral infections, leads to severe neurological impairment, inflammation, and exhibits high mortality rates with poor prognosis. Currently, there is a lack of effective targeted treatments for this disease, which poses a significant public health concern. SARM1 has been identified as the pivotal mediator of axonal degeneration and inflammation across various neuropathies, activated by an elevation in the NMN/NAD+ ratio. However, comprehensive in vivo investigations into the role of SARM1-mediated pathogenesis in viral encephalitis are still lacking. In this study, we established mouse models of viral encephalitis using Japanese encephalitis virus (JEV), herpes simplex virus-1 (HSV-1), and rabies virus (RABV) as representative pathogens. Our findings demonstrate that neurotropic virus infections elicit robust axonal degeneration, mitochondrial dysfunction, and profound neuropathological damage in cortical neurons via the activation of SARM1. In mouse models of viral encephalitis, deletion or inhibition of SARM1 effectively preserved axonal morphology and maintained mitochondrial homeostasis, while also attenuating the infiltration of CD45+ leukocytes in the cortex. Consequently, these interventions ameliorated neuropathological damage and enhanced survival outcomes in mice. Our findings suggest that SARM1-mediated axonal degeneration and brain inflammation exacerbate the pathological progression of viral encephalitis. Therapies targeting SARM1 emerge as viable and promising strategies for protecting neuronal function in the context of neurotropic viral infections.

Cross-protection against St. Louis encephalitis virus and Usutu virus by West Nile virus convalescent plasma.

Cross-protection against St. Louis encephalitis virus and Usutu virus by West Nile virus convalescent plasma.

Kyasanur Forest disease virus non-structural protein NS1 forms multimers in solution, with a distinctly identifiable tetrameric state.

Kyasanur Forest disease virus non-structural protein NS1 forms multimers in solution, with a distinctly identifiable tetrameric state.

An Updated Review of Potential Drug Targets for Japanese Encephalitis.

Japanese encephalitis virus (JEV), first identified in 1935, continues to be a major threat to human health, especially in the Asia-Pacific region, where it remains prevalent. JEV, a neurotropic flavivirus, spreads through Culex tritaeniorhynchus mosquito bites and causes severe brain infections with high morbidity and mortality rates. Despite the availability of vaccines, no licensed anti-JEV drugs exist. This review provides a comprehensive overview of the epidemiology, structural and nonstructural proteins, and pathogenesis of JEV and explores potential drug targets. This study highlights both conventional and nonconventional drug targets, with a focus on nonstructural JEV proteins, which may hold promise for therapeutic development. This review also discusses drug targets shared by JEV and other flaviviruses, such as dengue, Zika, and West Nile virus, which reveal common pathways for viral entry and replication, along with distinct mechanisms specific to JEV. Key receptor interactions, including DC-SIGN, TAM receptor, sialic acid, LDLR, and CLEC5A interactions, are involved in JEV transmission and immune evasion. Additionally, the NMDA receptor has been identified as a critical player in JEV pathogenesis, suggesting new opportunities for neuroprotective therapies. A major obstacle in JEV drug development is the blood-brain barrier (BBB), which hinders the delivery of therapeutic agents to the central nervous system (CNS). Recent research has emphasized the need for innovative drug delivery systems that can cross the BBB, reducing viral replication and neural damage. While clinical trials with traditional antivirals have yielded mixed results, live attenuated and inactivated vaccines have shown promise in preventing JEV infection. Additionally, nucleic acid-based therapies, including microRNAs and short hairpin RNAs (shRNAs), are emerging as potential treatments, with nanoparticle-based delivery systems offering solutions to overcome BBB challenges. This review underscores the need for an integrated approach, including improved vaccines, targeted drug delivery strategies, and novel therapeutics, to effectively combat JEV infections on a global scale.

Japanese encephalitis virus NS1 inhibits IFN-β production by interacting with DDX3X.

Japanese encephalitis virus (JEV) is the causative agent of Japanese encephalitis, which poses great threats to the pig farming industry and human health. To establish infection, JEV has evolved sophisticated strategies to overcome the innate immune responses and finish its life cycle. Previous studies have shown that non-structural protein 1 (NS1) is closely related to its pathogenesis, while its molecular mechanism remains elusive. In this study, host protein ATP-dependent RNA helicase DEAD-box helicase 3 X (DDX3X) was screened to bind with NS1, and both ectopically expressed and virally encoded NS1 further confirmed their interaction. We also proved that the β-roll and wing subdomains of NS1 were responsible for their interaction. In DDX3X-overexpressing cells, the replication of JEV was markedly inhibited, while the viral titers were elevated in DDX3X-silencing cells, indicating that DDX3X might serve as an anti-viral factor during JEV infection. Mechanically, overexpression of DDX3X promotes interferon-beta (IFN-β) transcription, while its transcription was decreased in DDX3X-silencing cells. Consistent with IFN-β, some interferon-stimulated genes (ISGs), including protein kinase R (PKR), myxovirus resistance 1 (MX1), guanylate-binding protein 1 (GBP1), and bone marrow stromal antigen 2 (BST2), were also positively related to the DDX3X expression. Taken together, JEV NS1 blocks IFN-β production by interacting with DDX3X to evade the host's innate immune response and facilitate virus replication. This finding will deepen our understanding of JEV immune-evasion strategies and provide targets for JEV attenuation.IMPORTANCEThis study focused on JEV, a threat to pig farming and human health. The key finding is that NS1 binds to host protein DDX3X via its β-roll and wing subdomains. JEV NS1 evades the host immune response by interacting with DDX3X to restrain type I interferon production. These results deepen our understanding of JEV's immune-evasion strategies and offer potential targets for JEV attenuation.

Orthoflavivirus infection and the mTOR signaling pathway.

Each year, mosquito-borne orthoflaviviruses, including Zika virus, dengue virus, and the Japanese encephalitis virus, threaten the health of more than 400 million people worldwide. To date, knowledge about the pathogenic mechanisms underlying orthoflavivirus infection and the interactions of these viruses with host cells is limited. Mammalian target of rapamycin (mTOR) is pivotal for cell growth and metabolism. The downstream targets of mTOR regulate protein translation and cell autophagy to affect orthoflavivirus replication, and its upstream protein AKT performs similar functions. In this work, the mechanism underlying the relationship between the mTOR signaling pathway and orthoflavivirus infection was reviewed from three perspectives: orthoflavivirus structure and life cycle, mTOR structure and signaling pathway, and regulation of the mTOR signaling pathway during orthoflavivirus infection.

Molecular mechanisms of Japanese encephalitis virus infection and advances in vaccine research.

Molecular mechanisms of Japanese encephalitis virus infection and advances in vaccine research.