RARE DISEASE
Japanese encephalitis
Japanese encephalitis
Japanese encephalitis
Drug discovery
3
drugs
With orphan designations
Overview
Japanese encephalitis (JE) is a mosquito-borne flavivirus endemic to Asia and the Western Pacific, transmitted primarily by Culex mosquitoes in rural agricultural regions. It causes acute encephalitis with a 20–30% mortality rate and permanent neurologic sequelae in 30–50% of survivors [1][5][16]. Diagnosis relies on IgM antibody detection in CSF or serum [1][6]. Prevention centers on vaccination (e.g., SA 14-14-2) and vector control [1][16].
Population
Categories: rare infectious diseases, rare neurological diseases
Research Papers
1,698 drug discovery papers about Japanese encephalitis, with 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,698 drug discovery papers about Japanese encephalitis, with 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
proteins
2026-08-13 | NLRC5 restricts Japanese encephalitis virus replication and neuroinflammation by interacting with the viral NS3 protein in an IFN-γ-dependent manner.
NLRC5 is a known activator of MHC class I genes and a regulator of type I interferon activity. Although its expression increases in brains infected with Japanese encephalitis virus (JEV), its specific contribution to JEV pathogenesis and neuroinflammation remains unclear. We utilised in vitro cell cultures, in silico modelling, and in vivo mouse knockdown models of NLRC5 to investigate its impact on JEV replication, antiviral immune responses, central nervous system (CNS) inflammation, and overall disease progression. JEV infection upregulated NLRC5 expression in the brain, microglia, and non-neuronal cells, but not in neuronal cells. However, NLRC5 expression could be induced in neuroblastoma cells via IFN-γ treatment. Experimental modulation demonstrated that the typical antiviral restriction of JEV replication by IFN-γ is lost in NLRC5-deficient cells. Evaluation of stable cell lines expressing different NLRC5 variants showed that cytoplasmic retention and NLRC5 leucine-rich repeats (LRRs) are essential for viral restriction. Mechanistically, in silico modelling, co-immunoprecipitation, and immunofluorescence confirmed that NLRC5 binds directly to the viral NS3 protein in an LRR-dependent manner. In mouse models, in vivo knockdown of NLRC5 in the brain significantly accelerated clinical disease progression, heightened mortality, and triggered uncontrolled viral replication, indicated by elevated viral titers and NS3/NS1 expression. This viral surge induced severe neuroinflammation, as evidenced by significantly elevated levels of ASC and cleaved caspase-3 in NLRC5-deficient brains. These findings demonstrate that NLRC5 functions as a cell-type-specific antiviral regulator during JEV infection. It suppresses viral replication by directly binding to and degrading the viral NS3 protein. Loss of NLRC5 impairs IFN-γ-mediated antiviral restriction, leading to enhanced viral replication, severe neuroinflammation, and accelerated disease progression in vivo.
2026-06-22 | Integrative modelling of innate immune response dynamics during virus infection.
Positive-sense RNA viruses that constitute a large class of human pathogens employ various strategies to suppress and evade host immune defenses. Understanding the dynamic interaction between the viral life cycle and immune signaling is crucial to designing effective antiviral strategies. Although significant progress has been made, quantitative models that can accurately capture the intricate interactions and the intertwined dynamics during viral infection of cells remain missing. In this study, we develop a comprehensive mathematical model that integrates the intracellular viral life cycle with key cellular innate immune pathways, including RIG-I-mediated detection and JAK-STAT signaling. The model provides mechanistic insights into long-standing observations, capturing both virus-specific dynamics and innate immune response, and the key components driving their coupled dynamics. For example, a comparison of viruses shows how the Japanese Encephalitis virus undergoes a dramatic reduction in viral load in cells, due to its rapid replication that robustly activates the RIG-I pathway, in contrast to the poor immune control of Hepatitis C virus. More importantly, our model demonstrates how virus-host interactions exhibit a sharp transition boundary behavior, where minor differences in immune strength or viral suppression capacity can determine whether infections resolve or persist. We propose that ISG mRNA translation and viral replication predominantly dictate these bimodal infection outcomes. Additionally, the model not only recapitulates IFN desensitization but also identifies the molecular players involved. We demonstrate how our model's ability to capture IFN dynamics allows us to predict optimal timing and dosing strategies for interferon-based prophylactic therapies. Together, our approach reveals fundamental features that govern the delicate balance between the establishment of infection and immune control in RNA virus infections.
2026-04-07 | Antimicrobial peptide WK-13-3D inhibits Japanese encephalitis virus infection by interacting with viral particles, potentially targeting the envelope protein.
Despite causing fatal encephalitis and long-term neurological, cognitive, and behavioral impairments in survivors, no antiviral drugs are currently available to treat Japanese encephalitis virus (JEV) infections, highlighting the urgent need for effective therapies. Antimicrobial peptides (AMPs) exhibit broad-spectrum antibiotic activity; LL-37 is one such AMP that demonstrates a broad antiviral effect against various viruses. However, some viruses resist LL-37 and its analogues, emphasizing the importance of studying the impact of specific antimicrobial peptides on different viruses. In this study, we found that the synthetic LL-37 analogue peptide WK-13-3D has strong antiviral activity against JEV. Notably, pre-treatment or co-incubation during virus adsorption led to a noticeable reduction in infection levels in human glioblastoma (T98G) cells. Mechanistically, WK-13-3D inhibits JEV infection by directly binding to the viral particle, potentially Envelope (E) protein and preventing internalization. This peptide conferred protection against mortality in JEV-infected mice. In vivo, pre-treating JEV with WK-13-3D provided complete protection against death, compared to only 16.66% survival in the control group. Overall, these results suggest that WK-13-3D could be a promising candidate for further development as an immediate post-exposure antiviral treatment or prophylactic intervention for JEV infection.
2026-02-13 | Porcine USP18 inhibits Japanese encephalitis virus replication by regulating the type I interferon signaling pathway.
Ubiquitin-specific peptidase 18 (USP18) possesses both deubiquitinating and deISGylating activities and plays a crucial role in regulating innate immune responses and antiviral defense. However, the function of USP18 in Japanese encephalitis virus (JEV) replication remains unclear. In this study, the expression pattern of the porcine USP18 gene following JEV infection was examined by quantitative real-time PCR (qRT-PCR) and Western blot analysis. The effects of USP18 overexpression and siRNA-mediated knockdown on JEV replication and the expression of type I interferon (IFN-I) signaling pathway genes were examined. Protein-protein interactions between USP18 and IFN-I pathway components were predicted by AlphaFold3 and validated by co-immunoprecipitation (Co-IP) and confocal immunofluorescence colocalization assays. The results showed that JEV infection significantly upregulated USP18 expression. Overexpression of USP18 significantly inhibited JEV replication, whereas USP18 knockdown enhanced viral replication and suppressed IFN-I signaling-related gene expression. Moreover, USP18 was found to interact with the key IFN-I signaling proteins IRF3 and MAVS, and USP18 promoted IRF3 phosphorylation, suggesting that USP18 suppresses JEV replication by positively regulating IFN-I-mediated antiviral responses. These findings provide new insights into the antiviral mechanism of porcine USP18 and offer potential molecular targets for disease-resistant breeding and antiviral therapy in pigs.
2026-01-27 | NUP98 regulates orthoflavivirus replication through interaction with vRNA and can be targeted for antiviral purposes.
The nuclear pore complex (NPC) is composed of multiple nucleoporins (NUPs) and enables the exchange of RNA and proteins between the nucleus and cytoplasm. NUP98 is one of the major components of the NPC, being involved in the RNA export pathway by interacting with several transport factors. Previous studies have suggested both proviral and antiviral functions of NUP98 in viral infection, yet little is known about its function in orthoflavivirus infection. In this study we show that NUP98 is a proviral cellular protein that is recruited to the cytoplasm during orthoflavivirus infection. We observe that NUP98 is found specifically in the vicinity of the replication vesicles during infections with tick-borne encephalitis virus, Japanese encephalitis virus, and yellow fever virus. Furthermore, using surface plasmon resonance, cross-link immunoprecipitation, and cross-link immunoprecipitation-sequencing we observe that the C-terminal domain of NUP98 directly interacts with a conserved site of the viral RNA (vRNA) in the E coding region promoting viral replication. We identified a peptide that binds to NUP98 that is antivirally active against several orthoflaviviruses by outcompeting the binding between NUP98 and vRNA, making NUP98 an attractive target for antiviral development.
vaccines
2026-08-05 | Japanese Encephalitis in Bangladesh: A Decade of Hospital-Based Sentinel Surveillance, 2007-2016
Japanese encephalitis (JE) is a mosquito-borne flavivirus disease amplified by pigs and transmitted by Culex mosquitoes breeding in irrigated rice paddies -- a One Health disease at the intersection of livestock husbandry, agriculture, and human health. This study compiles a decade of hospital-based sentinel surveillance data for Bangladesh into a single reproducible summary. No public API or dashboard exists for this disease, and no second published source was found to cross-validate the data against -- disclosed explicitly, unlike the companion HPAI, rabies, and Nipah virus analyses in this series. Key findings: (1) of 6,525 tested acute meningitis-encephalitis syndrome patients at four sentinel hospitals (Rangpur, Rajshahi, Chittagong, Khulna), 548 (8%) were confirmed JE cases, 2007-2016; (2) cases spanned 36 of 64 districts (56%), concentrated in the northwest; (3) 193 cases (35%) were aged 15 years or younger; (4) cases were sharply seasonal -- 436 (80%) had onset July-November, peaking in October, consistent with monsoon-driven Culex mosquito breeding in rice paddies; (5) approximately 50% of pigs in the Rajshahi catchment were JEV-seropositive by age 3, direct evidence of the amplifying-host cycle; (6) the apparent case rise after 2010 coincides with the Rangpur site joining surveillance that year, likely reflecting expanded capacity rather than purely rising incidence. Data source: transcribed with full citation from Paul et al. (2020, International Journal of Infectious Diseases, doi:10.1016/j.ijid.2020.07.026). All analysis code and data are available at: https://github.com/khalilurrrahmanridoykhan/bangladesh-je-2007-2016
2026-07-07 | Japanese encephalitis in Nepal: closing the adult immunity gap.
Japanese encephalitis (JE) in Nepal is undergoing an epidemiological shift from a predominantly pediatric, Terai-centered disease to a geographically broader threat affecting susceptible adults. Despite successful childhood vaccination, the 2025 resurgence, with 175 confirmed cases and 34 deaths, exposed a major immunity gap among older cohorts, particularly adults over 40 years. Expanding transmission into hill districts and higher-altitude areas, likely influenced by climate variability, land-use change, and vector ecology, further challenges existing control strategies. Because JE overlaps clinically and radiologically with other endemic encephalitides, rapid laboratory confirmation is essential. Nepal's emerging adult vaccination policy should be integrated with climate-informed surveillance, One Health data systems, vector control, and survivor rehabilitation before future monsoon-driven outbreaks.
2026-07-04 | Japanese Encephalitis With a Characteristic Neuropathological Distribution Following Early MRI-Based Diagnosis: An Autopsy Case.
Japanese encephalitis (JE) is a mosquito-borne viral infection of the central nervous system for which no specific antiviral treatment is available. We report the case of a 79-year-old man residing in Kumamoto Prefecture, southwestern Japan, with JE who presented with fever, impaired consciousness, and respiratory failure, and subsequently died of multiple organ failure despite early supportive care. Magnetic resonance imaging (MRI) revealed characteristic bilateral thalamic lesions, leading to an early clinical suspicion of JE before serological confirmation. Neuropathological findings, particularly, the involvement of the thalamus, substantia nigra, hippocampus, and anterior horn of the spinal cord, were consistent with previously reported cases of JE, while also demonstrating a broader distribution of lesions than suggested by antemortem MRI. As most cases of JE occur in unvaccinated individuals, vaccination should be considered in middle-aged and older adults, particularly, those with low antibody titers against the JE virus.
2026-06-26 | Nucleotide variations in 3' untranslated region contribute to the enhanced virulence and replication efficiency of reemerging Japanese encephalitis virus genotype V.
Japanese encephalitis virus, a major causative agent of viral encephalitis in Asia, is classified into five genotypes. Genotype V (GV) has reemerged after more than 50 years of apparent absence, following identification of the sole GV isolate - the Muar strain - in 1952. Newly reemerged GV strains are genetically distinct from the ancestral Muar strain. In this study, we compared virulence and replication efficiency between the newly reemerged XZ0934 strain and the ancestral Muar strain. Viral titers in cultured cells, as well as viremia and mortality in mice infected with the XZ0934 strain, were significantly higher than those observed with the Muar strain, indicating enhanced virulence and replication efficiency of the XZ0934 strain. Multiple nucleotide variations in the 3' untranslated region (3'UTR) were identified between the XZ0934 and Muar strains; such variations contributed to the increased virulence and replication efficiency of the XZ0934 strain. These nucleotide variations resulted in substantial differences in the stem - loop (SL) I, SLII, and 3'SL structures of the 3'UTR and led to differential production of subgenomic flaviviral RNA (sfRNA). The variations also were responsible for differential inhibition of type I interferon production in vitro and in vivo between the two strains. These effects collectively contributed to the enhanced virulence and replication efficiency of the XZ0934 strain relative to the Muar strain. Our findings provide insight into the role of genetic variation in determining virulence and replication efficiency between newly reemerged and ancestral GV strains, as well as the molecular basis underlying GV virus reemergence.
2026-06-04 | [Expert consensus on key issues in japanese encephalitis prevention and control in China (2026 edition)].
Japanese encephalitis (JE) is an acute infectious disease of the central nervous system caused by the Japanese encephalitis virus (JEV) and transmitted by mosquitoes. It is characterized by a high case fatality rate and severe sequelae, representing one of the major public health concerns in China. Since the inclusion of the JE vaccine in the National Immunization Program in 2008, the incidence of the disease has significantly declined. However, in recent years, challenges such as viral genotype shifts, an increasing number of adult cases, the emergence of new endemic foci, and insufficient cross-protection of current vaccines have become increasingly prominent, posing new challenges to existing prevention and control strategies. This consensus systematically reviews the key issues in the current prevention and control of JE, covering aspects including etiology, epidemiology, clinical manifestations, diagnostic techniques, and vaccination. It aims to provide a scientific basis for consolidating the achievements in disease control and optimizing prevention and control strategies. The consensus emphasizes the need to establish a nationwide unified viral genotype surveillance network, improve adult immunization strategies, promote the development of multivalent/broad-spectrum vaccines, and build a comprehensive prevention and control system characterized by "immunization as the foundation, environmental management as the core, surveillance and early warning as the support, and emergency response as the guarantee, " thereby providing practical guidance for the effective control of JE.
small molecules
2026-08-13 | Cross-Family Mechanistic Analysis of Plant Alkaloids Against Neglected Arboviruses and Related RNA Viruses.
Neglected arboviruses dengue (DENV), Zika (ZIKV), yellow fever (YFV), Japanese encephalitis (JEV), and chikungunya collectively affect hundreds of millions of people annually, yet no specific antiviral drug has been approved for any of them. Alkaloids, nitrogen-containing specialized metabolites produced by diverse plant families, have emerged as a promising source of broad-spectrum antiviral scaffolds. This review compiles and critically analyzes over 100 alkaloid-virus pairs across several RNA virus families, providing a comparative mechanistic analysis. Lycorine, narciclasine, emetine, and berbamine, among others, exhibit potent activity against phylogenetically distant viruses, with the most potent activities reported against flaviviruses (narciclasine: EC50 0.02 µM against DENV, ZIKV, YFV, and JEV; pancratistatine: 0.0063 µM against ZIKV). Structure-activity analysis of multiple alkaloid classes identifies key pharmacophoric features, including the phenanthridine nucleus (lycorine derivatives) and the bis-benzylisoquinoline scaffold (tetrandrine, berbamine), as determinants of antiviral potency, selectivity, and broad-spectrum activity. Genetic resistance data in West Nile virus challenge the widely accepted model of lycorine as a direct nucleoside inhibitor, instead pointing toward the involvement of the membrane-associated NS4A-2K-NS4B replication complex, though direct validation remains limited for other flaviviruses. Converging structural, biochemical, and transcriptomic evidence suggests that ribosome-mediated translational stress may represent an additional host-directed antiviral mechanism for isoquinoline-type alkaloids, though the causal chain from ribosome binding to activation of the integrated stress response and to antiviral effect has not been established. The present analysis highlights that in vivo validation remains limited to a few alkaloid-virus pairs. Unbiased target deconvolution and formal testing of the ribosome/integrated stress response hypothesis stand out as essential research priorities.
2026-08-13 | Magnolol Modulates the RIG-I/NF-κB Signaling Pathway to Alleviate JEV Infection-Induced ST Cell Damage.
Japanese encephalitis virus (JEV) is a zoonotic pathogen. Infection in breeding boars triggers severe testicular inflammatory storms, resulting in testicular swelling, asthenospermia, oligozoospermia and even irreversible loss of reproductive capacity. Magnolol, a natural extract, exhibits remarkable anti-inflammatory and antioxidant activities. This study utilized swine testicular (ST) cells as an in vitro model to explore magnolol's protective effects against JEV-mediated inflammation and its underlying mechanism. ST cells were infected with JEV at an MOI of 1 and treated with magnolol at 8, 12 and 16 μg/mL. We detected pro-inflammatory cytokine expression, performed 4D-FastDIA quantitative proteomics to screen differentially expressed proteins, verified key RIG-I and NF-κB cascade molecules at mRNA and protein levels, and tracked p65 nuclear translocation through immunofluorescence. The data showed that JEV significantly elevated TNF-α, IL-1β, IL-6, IL-8 and CCL5, while magnolol reduced these cytokines in a dose-dependent manner. JEV reshaped the proteome of innate immunity and inflammation, and excessively activated the RIG-I/NF-κB axis to increase IKKβ, TRAF2, TRAF6 transcription and p65 phosphorylation and nuclear import; 24 h treatment with 16 μg/mL magnolol greatly restrained this overactivation. In summary, magnolol alleviates JEV-triggered inflammatory injury by inhibiting the RIG-I/NF-κB pathway, offering experimental evidence for its use as a natural agent to mitigate JEV-induced cellular inflammatory response in boars.
2026-08-12 | Bergamottin, a bioactive component of bergamot: dual inhibition of Japanese encephalitis virus internalization and genome replication.
Japanese encephalitis virus (JEV) is associated with high mortality and severe neurological sequelae, and existing prevention and control strategies remain insufficient. Therefore, the development of novel antiviral agents is of critical public health importance. This study systematically evaluated the antiviral activity and underlying mechanism of bergamottin, a natural product. Bergamottin exhibited significant dose-dependent inhibitory effects against JEV in multiple cell lines, including BHK-21, HuH-7, and Vero cells, demonstrating potent antiviral efficacy. Mechanistic investigations revealed that bergamottin primarily targeted the internalization and replication stages of the JEV life cycle, thereby effectively suppressing viral proliferation. Additionally, adaptive mutation screening indicated that the D389G mutation in envelope protein E confers drug resistance by potentially changing E protein conformation or reducing endocytic efficiency. In vivo experiment, bergamottin significantly reduced viral loads in mouse brain tissue and effectively improved the survival rate of infected mice. Our findings indicated that bergamottin exerted antiviral activity by dual targeting of key steps in the viral life cycle, making it a highly promising candidate for anti-JEV therapy. Further exploration of the antiviral properties of bergamottin is expected to facilitate its clinical development as a treatment for JEV infection.
2026-08-03 | Oral lipid prodrug V2043 (1-O-octadecyl-2-O-benzyl-sn-glyceryl-P-remdesivir nucleoside) protects mice from lethal dengue infection.
Dengue virus and related flaviviruses are significant threats to global health, with no approved antiviral treatments available. Remdesivir triphosphate (RVn-TP) is a nucleotide analog that inhibits RNA-dependent RNA polymerases from many clinically important RNA viruses, including dengue virus. An orally bioavailable prodrug that efficiently delivers RVn-TP could facilitate early treatment for non-hospitalized dengue patients. To that end, we developed 1-O-octadecyl-2-O-benzyl-sn-glyceryl-P-remdesivir nucleoside (V2043, ODBG-P-RVn), a phospholipid prodrug that achieves RVn-TP delivery through improved oral bioavailability, potency, and pharmacokinetics. Here, we show that when compared to the parent compound remdesivir nucleoside (RVn), V2043 is a more potent in vitro inhibitor of multiple flaviviruses, including dengue, Zika, West Nile, and Japanese encephalitis viruses. In lethal prophylactic and therapeutic mouse models that recapitulate key aspects of severe dengue in humans, once-daily oral V2043 significantly decreased dengue serum viremia, clinical severity, weight loss, and mortality. Additionally, oral V2043 was well tolerated when administered daily for 14 days. These results demonstrate the potential therapeutic efficacy of V2043 to treat several clinically relevant flaviviruses, including dengue virus, the most prevalent and widespread arbovirus infection in the world.
2026-07-23 | Trifluoperazine exhibits broad-spectrum antiviral activity against arboviruses.
The recurrent outbreaks and geographical expansion of mosquito-borne arboviruses pose a significant challenge to public health worldwide. The disease outcome for arboviral infections ranges from acute febrile illness to severe conditions such as encephalitis, hemorrhagic shock, and mortality. Current treatment options for these viruses are limited to supportive care, necessitating an urgent need for a safe and effective broad-spectrum antiviral. In this study, we have identified trifluoperazine (TFP), an FDA-approved antipsychotic, as a potent broad-spectrum antiviral against Japanese encephalitis virus (JEV), Dengue virus (DENV), and Chikungunya virus (CHIKV) infections. The antiviral effect of TFP was also seen in the animal models of JEV and CHIKV with significantly reduced disease severity. Mechanistically, TFP treatment increased the phosphorylation of eIF2a and induced an adaptive ER stress response in diverse cell types. Alleviation of TFP-induced ER stress by chemical chaperone 4PBA abolished the antiviral activity of the drug and rescued virus replication in cells and CHIKV mice model. The robust in vitro and in vivo efficacy of the drug against arboviruses highlights the potential for repurposing TFP as a broad-spectrum antiviral candidate and underscores the importance of ER stress as a therapeutic target.
oligonucleotides
2026-01-28 | Opportunities and Challenges of mRNA and VLP Technologies for Pan-Flavivirus Vaccine Development: Focus on Conserved Quaternary Epitope Conformations.
Mosquito-borne flaviviruses, including Dengue virus (DENV), Japanese encephalitis virus (JEV), West Nile virus (WNV), Yellow fever virus (YFV), and Zika virus (ZIKV), continue to present a significant threat to public health worldwide. In 2024, these viruses accounted for 11,717 reported cases in the United States and more than 7.6 million cases globally. As of early 2025, according to CDC data, 1830 cases of dengue had already been reported, with 1584 transmitted locally within the U.S. Despite the considerable burden that these diseases pose, no specific antiviral treatments exist. A very limited number of virus-specific vaccines have been licensed, such as those for YFV, JEV, and, with specific constraints, for DENV. To date, no pan-flavivirus vaccine is available. This review examines the potential of emerging vaccine platforms-particularly messenger RNA and virus-like particles-as promising tools in the pursuit of a broadly protective flavivirus vaccine. We analyze current strategies for inducing cross-neutralizing immune responses and discuss how these technologies could support the presentation of conserved quaternary epitope conformations, which are increasingly recognized as critical targets for establishing potent immune responses. We review key advances in virology, immune response, and immunogen delivery systems to highlight the potential for developing a pan-flavivirus vaccine.
2025-10-25 | RNAi therapeutics targeting Japanese encephalitis virus: Gene targets, delivery platforms, and translational barriers.
Japanese encephalitis virus (JEV), a neurotropic flavivirus, is a leading cause of viral encephalitis in Asia, particularly affecting children and causing significant morbidity and mortality. Despite the availability of vaccines and vector control strategies, their limited efficacy against emerging genotypes and incomplete coverage necessitate alternative antiviral approaches. RNA interference (RNAi) has emerged as a promising therapeutic modality by exploiting post-transcriptional gene silencing to inhibit viral replication. Notably, conserved viral genes-such as capsid (C), envelope (E), NS3, and NS5-represent optimal RNAi targets across JEV genotypes due to their essential roles in the viral life cycle and minimal sequence variability. Recent advances in delivery platforms, including lipid nanoparticles, lentiviral vectors, and artificial microRNAs, have significantly improved RNAi stability, blood-brain barrier (BBB) penetration, and cell-specific targeting. Comparative insights from related flaviviruses such as Dengue and Zika have further informed effective RNAi design. Preclinical studies have demonstrated potent antiviral effects, with >90 % suppression of viral RNA, substantial reductions in brain viral load, and enhanced survival in murine models. However, clinical translation remains challenged by delivery efficiency, immune activation, off-target effects, and the potential for viral escape mutations. This review summarizes the current landscape of RNAi-based therapeutics for JEV, emphasizing conserved gene targets, delivery innovations, and translational hurdles, and outlines future directions for integrating RNAi into next-generation antiviral strategies.
2025-06-16 | Multi-omics analysis uncovers differential growth kinetics of Japanese Encephalitis Virus in human and porcine macrophages
Japanese encephalitis virus (JEV), a mosquito-borne neurotropic virus, poses a significant threat to juvenile humans, while causing mild symptoms in pigs, except piglets. Pigs with high viremia are amplifier hosts, whereas humans with lower viremia are dead-end hosts. The molecular mechanisms behind the varying viremia levels in pigs and humans remain poorly understood. A comparative multi-omics study was conducted on JEV-infected macrophages, the early site of JEV replication in both species. We identified 24 key determinants potentially regulating viral growth. Functional validation of three antiviral factors - LGALS1, ssc-miR-133a-3p, and hsa-miR-3614-5p, and two proviral factors - MIF and VMP1, in macrophages showed that the upregulation of MIF and VMP1, and downregulation of ssc-miR-133a-3p, enhanced JEV replication in pigs. In contrast, the downregulation of MIF and VMP1 and upregulation of hsa-miR-3614-5p reduced JEV replication in human macrophages. These findings provide critical insights into JEV infection and its species-specific dynamics.
2025-05-20 | Next-gen vaccine design: Integrating proteomics and bioinformatics for japanese encephalitis
Japanese encephalitis is the most neglected tropical disease induced by a neuroinvasive flavivirus, which refers to the Japanese encephalitis virus (JEV). To date, no successful treatment strategies are available for this disease. Thus, utilizing immunoinformatics and reverse vaccinology, we designed a novel mRNA vaccine (JE-mVax) targeting the viral capsid protein, a precursor to the membrane M protein, and envelope protein using T and B lymphocyte epitopes. The epitopes were incorporated into JE-mVax after being validated as antigenic, non-allergenic, and non-toxic. Moreover, the epitopes achieved global coverage of 100% (combined MHC-I and MHC-II epitopes). Notably, the tertiary structure of JE-mVax achieved a TM-score of 0.49±0.15 and a C score of -1.90. After refinement, the structure demonstrated 93.617% amino acid residues in the most favorable region, an ERRAT score of 73.9899, and a Z score of -5.58. Subsequently, docking analysis showed that the JE-mVax had the lowest energy scores of -986.0 and -1314.2 KJ/mol for TLR-2 and TLR-4. However, the MMGBSA and molecular dynamic simulation analysis also validated this statement. Additionally, the JE-mVax exhibited efficient cloning in E. coli strains, and the immune simulation predicted that it might significantly induce T and B cells. Finally, MFE values of -355.20 kcal/mol (optimal) and -211.56 kcal/mol (centroid) predicted mRNA's marginal structural integrity and stability during host entrance, transcription, and expression. Nonetheless, comprehensive in vitro and in vivo validation is required to definitively demonstrate the vaccine candidate's safety and effectiveness profile.
2025-04-18 | 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.
other
2026-07-18 | Engineered Extracellular Vesicle-Delivered CRISPR/Cas13d for Alleviating Japanese Encephalitis Virus-Induced Brain Injury
This research investigates an engineered extracellular vesicle (EV)-based strategy for delivering programmable CRISPR/Cas13d components across the blood–brain barrier (BBB) to inhibit Japanese encephalitis virus (JEV) infection. We developed RVG-functionalized targeted engineered EVs, termed TEEVs, for brain-targeted delivery of high-fidelity RfxCas13d mRNA and JEV-targeting CRISPR RNAs (crRNAs). The CD63–L7Ae/C/D box system was used to actively enrich Cas13d mRNA and tandem crRNAs within EVs, while RVG surface functionalization was introduced to enhance BBB crossing and uptake by target cells. In vitro, TEEVs showed greater cellular uptake than non-targeted engineered EVs and crossed the BBB-like endothelial barrier in a Transwell co-culture model. TEEVs also suppressed JEV replication and preserved barrier integrity. In vivo biodistribution analyses showed enhanced brain accumulation following intravenous administration. In a lethal mouse model of JEV infection, TEEV treatment reduced brain viral loads, inflammatory responses, BBB disruption, and neuropathological injury and improved survival.
2026-07-02 | FcγRIIA signalling as a host-associated determinant of endosomal trafficking and antibody-dependent enhancement in flavivirus infection.
Antibody-dependent enhancement (ADE) is a major determinant of disease severity in flavivirus infections, yet the host-associated factors that regulate the transition from antibody-mediated uptake to productive infection remain incompletely defined. Fc gamma receptor IIA (FcγRIIA/CD32A), an activating Fc receptor expressed on myeloid cells, represents a key host determinant linking pre-existing immunity to viral entry pathways. Here, we investigated how FcγRIIA signalling influences intracellular trafficking and ADE efficiency across dengue virus (DENV), Zika virus (ZIKV), and Japanese encephalitis virus (JEV). Using BHK-21 cells expressing either wild-type FcγRIIA (WT) or a cytoplasmic-truncated variant lacking the immunoreceptor tyrosine-based activation motif (ITAM), we show that immune-complex internalization occurs independently of the cytoplasmic domain, but that signalling competence significantly modulates downstream infection efficiency. WT cells generally showed higher ADE efficiency, whereas cytoplasmic-truncated receptors preserved ADE activity but showed virus-dependent reductions in enhancement magnitude. FcγRIIA signalling altered the intracellular routing of virus-antibody complexes. WT receptors promoted rapid trafficking from EEA1-positive early endosomes to Rab7-positive late endosomes, whereas signalling-deficient receptors displayed delayed progression and increased association with IRAP- and Rab14-positive compartments. These trafficking differences correlated with virus-specific patterns of enhancement, with DENV showing the strongest dependence on late endosomal maturation, while ZIKV and JEV utilized more flexible or alternative pathways. Transcriptomic analysis revealed minimal differences between WT and truncated receptors at later time points, indicating that FcγRIIA primarily modulates early post-entry events rather than sustained transcriptional responses. Collectively, these findings identify FcγRIIA signalling as a host-associated determinant that regulates the intracellular fate of virus-antibody complexes and influences ADE efficiency through modulation of endosomal trafficking dynamics. The work provides a mechanistic framework linking host receptor signalling to variability in infection outcomes under conditions of pre-existing immunity, with implications for understanding disease heterogeneity and optimizing vaccine and antibody-based interventions.
2026-05-22 | Immunity-oriented drug strategies for viral encephalitis: Acyclovir, antiepileptics and corticosteroids in neurological intensive care.
Viral encephalitis (VE), is a life-threatening neurological disorder marked by inflammation of brain parenchyma, driven by direct viral cytotoxicity and host immune-mediated injury. Globally, its incidence ranges from 1.4 to 13.8 cases per 100,000 individuals annually, with significant morbidity and mortality in endemic regions such as India, among children. Neurotropic viruses including herpes simplex virus (HSV), Japanese encephalitis virus (JEV) and West Nile virus, enter central nervous system via hematogenous or neuronal routes, triggering viral replication, cytokine release and blood-brain barrier disruption, resulting in seizures, cerebral edema and long-term neurological deficits. Current management in neurological intensive care relies on immunity-oriented strategies: Acyclovir as first-line antiviral for HSV and varicella-zoster virus, antiepileptics to control seizures and limit secondary neuronal injury and corticosteroids to modulate harmful neuroinflammation and cerebral edema. Emerging therapies, including novel antivirals (favipiravir, remdesivir, brincidofovir), monoclonal antibodies, cytokine inhibitors (tocilizumab, anakinra) and B-cell/plasma cell-targeted agents (rituximab, daratumumab), offer promise by simultaneously addressing viral replication and immune dysregulation. Personalized biomarker-guided integrating pathogen-directed and host-targeted therapies may optimize outcomes, reduce neuronal injury and improve recovery. This review underscores the importance of a multidimensional, immunity-oriented treatment paradigm, highlighting both established and emerging strategies to enhance prognosis and long-term neurological functions in patients with viral encephalitis.
2026-04-17 | Human antibodies against West Nile and related orthoflaviviruses.
West Nile virus (WNV) is a mosquito-borne pathogen of global concern that can cause fatal neuroinvasive disease. No specific prophylaxis or treatment exists for WNV or related orthoflavivirus infections, and the determinants of human disease severity remain poorly understood. Here, we report that neutralizing autoantibodies against type I interferons do not impair antiviral antibody development. Among the fully human monoclonal antibodies with potent neutralizing activity against WNV that were discovered, W010 targets a unique epitope within the envelope protein domain III (EDIII) and confers both pre- and post-exposure protection in a murine WNV model, even when interferon signaling is impaired. A second protective antibody, W014, exhibits broad cross-neutralization of other pathogenic orthoflavivirus members, including Japanese encephalitis virus, Murray Valley encephalitis virus, Saint Louis encephalitis virus, and Usutu virus. These findings identify key neutralizing epitopes on WNV EDIII and provide candidates for the development of antibody-based interventions against encephalitic orthoflavivirus infections.
2026-03-18 | Spatial transcriptomics uncovers vasculature-centered cellular interactions driving Japanese encephalitis progression in a mouse model.
The cellular interactions that drive the neuropathology of most neuroinvasive viruses remain elusive. We used Japanese encephalitis virus (JEV) to infect female BALB/c mice and applied Stereo-seq to simultaneously capture host and viral transcriptomes in situ, thereby constructing a comprehensive spatiotemporal atlas of Japanese encephalitis (JE) pathogenesis. Our analysis pinpoints Ly6c2+ monocytes as the primary virus carrier, the most abundant infiltrating immune cell type, and a major source of IFN-γ in the infected mouse brain. Following infection, Ackr1+ endothelial cell activation is linked to blood-brain barrier disruption and immune cell chemotaxis, particularly Ly6c2+ monocytes. The crosstalk between these two cell types appears to orchestrate the pronounced inflammation and cell death, including pyroptosis and necroptosis, which radiate from the vasculature to different brain regions. Disrupting the activation and interactions of these two cell types may help mitigate JE progression. This study also provides a technical framework for investigating the pathogenesis of other neurotropic viruses.
proteins
2026-08-13 | NLRC5 restricts Japanese encephalitis virus replication and neuroinflammation by interacting with the viral NS3 protein in an IFN-γ-dependent manner.
NLRC5 is a known activator of MHC class I genes and a regulator of type I interferon activity. Although its expression increases in brains infected with Japanese encephalitis virus (JEV), its specific contribution to JEV pathogenesis and neuroinflammation remains unclear. We utilised in vitro cell cultures, in silico modelling, and in vivo mouse knockdown models of NLRC5 to investigate its impact on JEV replication, antiviral immune responses, central nervous system (CNS) inflammation, and overall disease progression. JEV infection upregulated NLRC5 expression in the brain, microglia, and non-neuronal cells, but not in neuronal cells. However, NLRC5 expression could be induced in neuroblastoma cells via IFN-γ treatment. Experimental modulation demonstrated that the typical antiviral restriction of JEV replication by IFN-γ is lost in NLRC5-deficient cells. Evaluation of stable cell lines expressing different NLRC5 variants showed that cytoplasmic retention and NLRC5 leucine-rich repeats (LRRs) are essential for viral restriction. Mechanistically, in silico modelling, co-immunoprecipitation, and immunofluorescence confirmed that NLRC5 binds directly to the viral NS3 protein in an LRR-dependent manner. In mouse models, in vivo knockdown of NLRC5 in the brain significantly accelerated clinical disease progression, heightened mortality, and triggered uncontrolled viral replication, indicated by elevated viral titers and NS3/NS1 expression. This viral surge induced severe neuroinflammation, as evidenced by significantly elevated levels of ASC and cleaved caspase-3 in NLRC5-deficient brains. These findings demonstrate that NLRC5 functions as a cell-type-specific antiviral regulator during JEV infection. It suppresses viral replication by directly binding to and degrading the viral NS3 protein. Loss of NLRC5 impairs IFN-γ-mediated antiviral restriction, leading to enhanced viral replication, severe neuroinflammation, and accelerated disease progression in vivo.
2026-06-22 | Integrative modelling of innate immune response dynamics during virus infection.
Positive-sense RNA viruses that constitute a large class of human pathogens employ various strategies to suppress and evade host immune defenses. Understanding the dynamic interaction between the viral life cycle and immune signaling is crucial to designing effective antiviral strategies. Although significant progress has been made, quantitative models that can accurately capture the intricate interactions and the intertwined dynamics during viral infection of cells remain missing. In this study, we develop a comprehensive mathematical model that integrates the intracellular viral life cycle with key cellular innate immune pathways, including RIG-I-mediated detection and JAK-STAT signaling. The model provides mechanistic insights into long-standing observations, capturing both virus-specific dynamics and innate immune response, and the key components driving their coupled dynamics. For example, a comparison of viruses shows how the Japanese Encephalitis virus undergoes a dramatic reduction in viral load in cells, due to its rapid replication that robustly activates the RIG-I pathway, in contrast to the poor immune control of Hepatitis C virus. More importantly, our model demonstrates how virus-host interactions exhibit a sharp transition boundary behavior, where minor differences in immune strength or viral suppression capacity can determine whether infections resolve or persist. We propose that ISG mRNA translation and viral replication predominantly dictate these bimodal infection outcomes. Additionally, the model not only recapitulates IFN desensitization but also identifies the molecular players involved. We demonstrate how our model's ability to capture IFN dynamics allows us to predict optimal timing and dosing strategies for interferon-based prophylactic therapies. Together, our approach reveals fundamental features that govern the delicate balance between the establishment of infection and immune control in RNA virus infections.
2026-04-07 | Antimicrobial peptide WK-13-3D inhibits Japanese encephalitis virus infection by interacting with viral particles, potentially targeting the envelope protein.
Despite causing fatal encephalitis and long-term neurological, cognitive, and behavioral impairments in survivors, no antiviral drugs are currently available to treat Japanese encephalitis virus (JEV) infections, highlighting the urgent need for effective therapies. Antimicrobial peptides (AMPs) exhibit broad-spectrum antibiotic activity; LL-37 is one such AMP that demonstrates a broad antiviral effect against various viruses. However, some viruses resist LL-37 and its analogues, emphasizing the importance of studying the impact of specific antimicrobial peptides on different viruses. In this study, we found that the synthetic LL-37 analogue peptide WK-13-3D has strong antiviral activity against JEV. Notably, pre-treatment or co-incubation during virus adsorption led to a noticeable reduction in infection levels in human glioblastoma (T98G) cells. Mechanistically, WK-13-3D inhibits JEV infection by directly binding to the viral particle, potentially Envelope (E) protein and preventing internalization. This peptide conferred protection against mortality in JEV-infected mice. In vivo, pre-treating JEV with WK-13-3D provided complete protection against death, compared to only 16.66% survival in the control group. Overall, these results suggest that WK-13-3D could be a promising candidate for further development as an immediate post-exposure antiviral treatment or prophylactic intervention for JEV infection.
2026-02-13 | Porcine USP18 inhibits Japanese encephalitis virus replication by regulating the type I interferon signaling pathway.
Ubiquitin-specific peptidase 18 (USP18) possesses both deubiquitinating and deISGylating activities and plays a crucial role in regulating innate immune responses and antiviral defense. However, the function of USP18 in Japanese encephalitis virus (JEV) replication remains unclear. In this study, the expression pattern of the porcine USP18 gene following JEV infection was examined by quantitative real-time PCR (qRT-PCR) and Western blot analysis. The effects of USP18 overexpression and siRNA-mediated knockdown on JEV replication and the expression of type I interferon (IFN-I) signaling pathway genes were examined. Protein-protein interactions between USP18 and IFN-I pathway components were predicted by AlphaFold3 and validated by co-immunoprecipitation (Co-IP) and confocal immunofluorescence colocalization assays. The results showed that JEV infection significantly upregulated USP18 expression. Overexpression of USP18 significantly inhibited JEV replication, whereas USP18 knockdown enhanced viral replication and suppressed IFN-I signaling-related gene expression. Moreover, USP18 was found to interact with the key IFN-I signaling proteins IRF3 and MAVS, and USP18 promoted IRF3 phosphorylation, suggesting that USP18 suppresses JEV replication by positively regulating IFN-I-mediated antiviral responses. These findings provide new insights into the antiviral mechanism of porcine USP18 and offer potential molecular targets for disease-resistant breeding and antiviral therapy in pigs.
2026-01-27 | NUP98 regulates orthoflavivirus replication through interaction with vRNA and can be targeted for antiviral purposes.
The nuclear pore complex (NPC) is composed of multiple nucleoporins (NUPs) and enables the exchange of RNA and proteins between the nucleus and cytoplasm. NUP98 is one of the major components of the NPC, being involved in the RNA export pathway by interacting with several transport factors. Previous studies have suggested both proviral and antiviral functions of NUP98 in viral infection, yet little is known about its function in orthoflavivirus infection. In this study we show that NUP98 is a proviral cellular protein that is recruited to the cytoplasm during orthoflavivirus infection. We observe that NUP98 is found specifically in the vicinity of the replication vesicles during infections with tick-borne encephalitis virus, Japanese encephalitis virus, and yellow fever virus. Furthermore, using surface plasmon resonance, cross-link immunoprecipitation, and cross-link immunoprecipitation-sequencing we observe that the C-terminal domain of NUP98 directly interacts with a conserved site of the viral RNA (vRNA) in the E coding region promoting viral replication. We identified a peptide that binds to NUP98 that is antivirally active against several orthoflaviviruses by outcompeting the binding between NUP98 and vRNA, making NUP98 an attractive target for antiviral development.
vaccines
2026-08-05 | Japanese Encephalitis in Bangladesh: A Decade of Hospital-Based Sentinel Surveillance, 2007-2016
Japanese encephalitis (JE) is a mosquito-borne flavivirus disease amplified by pigs and transmitted by Culex mosquitoes breeding in irrigated rice paddies -- a One Health disease at the intersection of livestock husbandry, agriculture, and human health. This study compiles a decade of hospital-based sentinel surveillance data for Bangladesh into a single reproducible summary. No public API or dashboard exists for this disease, and no second published source was found to cross-validate the data against -- disclosed explicitly, unlike the companion HPAI, rabies, and Nipah virus analyses in this series. Key findings: (1) of 6,525 tested acute meningitis-encephalitis syndrome patients at four sentinel hospitals (Rangpur, Rajshahi, Chittagong, Khulna), 548 (8%) were confirmed JE cases, 2007-2016; (2) cases spanned 36 of 64 districts (56%), concentrated in the northwest; (3) 193 cases (35%) were aged 15 years or younger; (4) cases were sharply seasonal -- 436 (80%) had onset July-November, peaking in October, consistent with monsoon-driven Culex mosquito breeding in rice paddies; (5) approximately 50% of pigs in the Rajshahi catchment were JEV-seropositive by age 3, direct evidence of the amplifying-host cycle; (6) the apparent case rise after 2010 coincides with the Rangpur site joining surveillance that year, likely reflecting expanded capacity rather than purely rising incidence. Data source: transcribed with full citation from Paul et al. (2020, International Journal of Infectious Diseases, doi:10.1016/j.ijid.2020.07.026). All analysis code and data are available at: https://github.com/khalilurrrahmanridoykhan/bangladesh-je-2007-2016
2026-07-07 | Japanese encephalitis in Nepal: closing the adult immunity gap.
Japanese encephalitis (JE) in Nepal is undergoing an epidemiological shift from a predominantly pediatric, Terai-centered disease to a geographically broader threat affecting susceptible adults. Despite successful childhood vaccination, the 2025 resurgence, with 175 confirmed cases and 34 deaths, exposed a major immunity gap among older cohorts, particularly adults over 40 years. Expanding transmission into hill districts and higher-altitude areas, likely influenced by climate variability, land-use change, and vector ecology, further challenges existing control strategies. Because JE overlaps clinically and radiologically with other endemic encephalitides, rapid laboratory confirmation is essential. Nepal's emerging adult vaccination policy should be integrated with climate-informed surveillance, One Health data systems, vector control, and survivor rehabilitation before future monsoon-driven outbreaks.
2026-07-04 | Japanese Encephalitis With a Characteristic Neuropathological Distribution Following Early MRI-Based Diagnosis: An Autopsy Case.
Japanese encephalitis (JE) is a mosquito-borne viral infection of the central nervous system for which no specific antiviral treatment is available. We report the case of a 79-year-old man residing in Kumamoto Prefecture, southwestern Japan, with JE who presented with fever, impaired consciousness, and respiratory failure, and subsequently died of multiple organ failure despite early supportive care. Magnetic resonance imaging (MRI) revealed characteristic bilateral thalamic lesions, leading to an early clinical suspicion of JE before serological confirmation. Neuropathological findings, particularly, the involvement of the thalamus, substantia nigra, hippocampus, and anterior horn of the spinal cord, were consistent with previously reported cases of JE, while also demonstrating a broader distribution of lesions than suggested by antemortem MRI. As most cases of JE occur in unvaccinated individuals, vaccination should be considered in middle-aged and older adults, particularly, those with low antibody titers against the JE virus.
2026-06-26 | Nucleotide variations in 3' untranslated region contribute to the enhanced virulence and replication efficiency of reemerging Japanese encephalitis virus genotype V.
Japanese encephalitis virus, a major causative agent of viral encephalitis in Asia, is classified into five genotypes. Genotype V (GV) has reemerged after more than 50 years of apparent absence, following identification of the sole GV isolate - the Muar strain - in 1952. Newly reemerged GV strains are genetically distinct from the ancestral Muar strain. In this study, we compared virulence and replication efficiency between the newly reemerged XZ0934 strain and the ancestral Muar strain. Viral titers in cultured cells, as well as viremia and mortality in mice infected with the XZ0934 strain, were significantly higher than those observed with the Muar strain, indicating enhanced virulence and replication efficiency of the XZ0934 strain. Multiple nucleotide variations in the 3' untranslated region (3'UTR) were identified between the XZ0934 and Muar strains; such variations contributed to the increased virulence and replication efficiency of the XZ0934 strain. These nucleotide variations resulted in substantial differences in the stem - loop (SL) I, SLII, and 3'SL structures of the 3'UTR and led to differential production of subgenomic flaviviral RNA (sfRNA). The variations also were responsible for differential inhibition of type I interferon production in vitro and in vivo between the two strains. These effects collectively contributed to the enhanced virulence and replication efficiency of the XZ0934 strain relative to the Muar strain. Our findings provide insight into the role of genetic variation in determining virulence and replication efficiency between newly reemerged and ancestral GV strains, as well as the molecular basis underlying GV virus reemergence.
2026-06-04 | [Expert consensus on key issues in japanese encephalitis prevention and control in China (2026 edition)].
Japanese encephalitis (JE) is an acute infectious disease of the central nervous system caused by the Japanese encephalitis virus (JEV) and transmitted by mosquitoes. It is characterized by a high case fatality rate and severe sequelae, representing one of the major public health concerns in China. Since the inclusion of the JE vaccine in the National Immunization Program in 2008, the incidence of the disease has significantly declined. However, in recent years, challenges such as viral genotype shifts, an increasing number of adult cases, the emergence of new endemic foci, and insufficient cross-protection of current vaccines have become increasingly prominent, posing new challenges to existing prevention and control strategies. This consensus systematically reviews the key issues in the current prevention and control of JE, covering aspects including etiology, epidemiology, clinical manifestations, diagnostic techniques, and vaccination. It aims to provide a scientific basis for consolidating the achievements in disease control and optimizing prevention and control strategies. The consensus emphasizes the need to establish a nationwide unified viral genotype surveillance network, improve adult immunization strategies, promote the development of multivalent/broad-spectrum vaccines, and build a comprehensive prevention and control system characterized by "immunization as the foundation, environmental management as the core, surveillance and early warning as the support, and emergency response as the guarantee, " thereby providing practical guidance for the effective control of JE.
small molecules
2026-08-13 | Cross-Family Mechanistic Analysis of Plant Alkaloids Against Neglected Arboviruses and Related RNA Viruses.
Neglected arboviruses dengue (DENV), Zika (ZIKV), yellow fever (YFV), Japanese encephalitis (JEV), and chikungunya collectively affect hundreds of millions of people annually, yet no specific antiviral drug has been approved for any of them. Alkaloids, nitrogen-containing specialized metabolites produced by diverse plant families, have emerged as a promising source of broad-spectrum antiviral scaffolds. This review compiles and critically analyzes over 100 alkaloid-virus pairs across several RNA virus families, providing a comparative mechanistic analysis. Lycorine, narciclasine, emetine, and berbamine, among others, exhibit potent activity against phylogenetically distant viruses, with the most potent activities reported against flaviviruses (narciclasine: EC50 0.02 µM against DENV, ZIKV, YFV, and JEV; pancratistatine: 0.0063 µM against ZIKV). Structure-activity analysis of multiple alkaloid classes identifies key pharmacophoric features, including the phenanthridine nucleus (lycorine derivatives) and the bis-benzylisoquinoline scaffold (tetrandrine, berbamine), as determinants of antiviral potency, selectivity, and broad-spectrum activity. Genetic resistance data in West Nile virus challenge the widely accepted model of lycorine as a direct nucleoside inhibitor, instead pointing toward the involvement of the membrane-associated NS4A-2K-NS4B replication complex, though direct validation remains limited for other flaviviruses. Converging structural, biochemical, and transcriptomic evidence suggests that ribosome-mediated translational stress may represent an additional host-directed antiviral mechanism for isoquinoline-type alkaloids, though the causal chain from ribosome binding to activation of the integrated stress response and to antiviral effect has not been established. The present analysis highlights that in vivo validation remains limited to a few alkaloid-virus pairs. Unbiased target deconvolution and formal testing of the ribosome/integrated stress response hypothesis stand out as essential research priorities.
2026-08-13 | Magnolol Modulates the RIG-I/NF-κB Signaling Pathway to Alleviate JEV Infection-Induced ST Cell Damage.
Japanese encephalitis virus (JEV) is a zoonotic pathogen. Infection in breeding boars triggers severe testicular inflammatory storms, resulting in testicular swelling, asthenospermia, oligozoospermia and even irreversible loss of reproductive capacity. Magnolol, a natural extract, exhibits remarkable anti-inflammatory and antioxidant activities. This study utilized swine testicular (ST) cells as an in vitro model to explore magnolol's protective effects against JEV-mediated inflammation and its underlying mechanism. ST cells were infected with JEV at an MOI of 1 and treated with magnolol at 8, 12 and 16 μg/mL. We detected pro-inflammatory cytokine expression, performed 4D-FastDIA quantitative proteomics to screen differentially expressed proteins, verified key RIG-I and NF-κB cascade molecules at mRNA and protein levels, and tracked p65 nuclear translocation through immunofluorescence. The data showed that JEV significantly elevated TNF-α, IL-1β, IL-6, IL-8 and CCL5, while magnolol reduced these cytokines in a dose-dependent manner. JEV reshaped the proteome of innate immunity and inflammation, and excessively activated the RIG-I/NF-κB axis to increase IKKβ, TRAF2, TRAF6 transcription and p65 phosphorylation and nuclear import; 24 h treatment with 16 μg/mL magnolol greatly restrained this overactivation. In summary, magnolol alleviates JEV-triggered inflammatory injury by inhibiting the RIG-I/NF-κB pathway, offering experimental evidence for its use as a natural agent to mitigate JEV-induced cellular inflammatory response in boars.
2026-08-12 | Bergamottin, a bioactive component of bergamot: dual inhibition of Japanese encephalitis virus internalization and genome replication.
Japanese encephalitis virus (JEV) is associated with high mortality and severe neurological sequelae, and existing prevention and control strategies remain insufficient. Therefore, the development of novel antiviral agents is of critical public health importance. This study systematically evaluated the antiviral activity and underlying mechanism of bergamottin, a natural product. Bergamottin exhibited significant dose-dependent inhibitory effects against JEV in multiple cell lines, including BHK-21, HuH-7, and Vero cells, demonstrating potent antiviral efficacy. Mechanistic investigations revealed that bergamottin primarily targeted the internalization and replication stages of the JEV life cycle, thereby effectively suppressing viral proliferation. Additionally, adaptive mutation screening indicated that the D389G mutation in envelope protein E confers drug resistance by potentially changing E protein conformation or reducing endocytic efficiency. In vivo experiment, bergamottin significantly reduced viral loads in mouse brain tissue and effectively improved the survival rate of infected mice. Our findings indicated that bergamottin exerted antiviral activity by dual targeting of key steps in the viral life cycle, making it a highly promising candidate for anti-JEV therapy. Further exploration of the antiviral properties of bergamottin is expected to facilitate its clinical development as a treatment for JEV infection.
2026-08-03 | Oral lipid prodrug V2043 (1-O-octadecyl-2-O-benzyl-sn-glyceryl-P-remdesivir nucleoside) protects mice from lethal dengue infection.
Dengue virus and related flaviviruses are significant threats to global health, with no approved antiviral treatments available. Remdesivir triphosphate (RVn-TP) is a nucleotide analog that inhibits RNA-dependent RNA polymerases from many clinically important RNA viruses, including dengue virus. An orally bioavailable prodrug that efficiently delivers RVn-TP could facilitate early treatment for non-hospitalized dengue patients. To that end, we developed 1-O-octadecyl-2-O-benzyl-sn-glyceryl-P-remdesivir nucleoside (V2043, ODBG-P-RVn), a phospholipid prodrug that achieves RVn-TP delivery through improved oral bioavailability, potency, and pharmacokinetics. Here, we show that when compared to the parent compound remdesivir nucleoside (RVn), V2043 is a more potent in vitro inhibitor of multiple flaviviruses, including dengue, Zika, West Nile, and Japanese encephalitis viruses. In lethal prophylactic and therapeutic mouse models that recapitulate key aspects of severe dengue in humans, once-daily oral V2043 significantly decreased dengue serum viremia, clinical severity, weight loss, and mortality. Additionally, oral V2043 was well tolerated when administered daily for 14 days. These results demonstrate the potential therapeutic efficacy of V2043 to treat several clinically relevant flaviviruses, including dengue virus, the most prevalent and widespread arbovirus infection in the world.
2026-07-23 | Trifluoperazine exhibits broad-spectrum antiviral activity against arboviruses.
The recurrent outbreaks and geographical expansion of mosquito-borne arboviruses pose a significant challenge to public health worldwide. The disease outcome for arboviral infections ranges from acute febrile illness to severe conditions such as encephalitis, hemorrhagic shock, and mortality. Current treatment options for these viruses are limited to supportive care, necessitating an urgent need for a safe and effective broad-spectrum antiviral. In this study, we have identified trifluoperazine (TFP), an FDA-approved antipsychotic, as a potent broad-spectrum antiviral against Japanese encephalitis virus (JEV), Dengue virus (DENV), and Chikungunya virus (CHIKV) infections. The antiviral effect of TFP was also seen in the animal models of JEV and CHIKV with significantly reduced disease severity. Mechanistically, TFP treatment increased the phosphorylation of eIF2a and induced an adaptive ER stress response in diverse cell types. Alleviation of TFP-induced ER stress by chemical chaperone 4PBA abolished the antiviral activity of the drug and rescued virus replication in cells and CHIKV mice model. The robust in vitro and in vivo efficacy of the drug against arboviruses highlights the potential for repurposing TFP as a broad-spectrum antiviral candidate and underscores the importance of ER stress as a therapeutic target.
oligonucleotides
2026-01-28 | Opportunities and Challenges of mRNA and VLP Technologies for Pan-Flavivirus Vaccine Development: Focus on Conserved Quaternary Epitope Conformations.
Mosquito-borne flaviviruses, including Dengue virus (DENV), Japanese encephalitis virus (JEV), West Nile virus (WNV), Yellow fever virus (YFV), and Zika virus (ZIKV), continue to present a significant threat to public health worldwide. In 2024, these viruses accounted for 11,717 reported cases in the United States and more than 7.6 million cases globally. As of early 2025, according to CDC data, 1830 cases of dengue had already been reported, with 1584 transmitted locally within the U.S. Despite the considerable burden that these diseases pose, no specific antiviral treatments exist. A very limited number of virus-specific vaccines have been licensed, such as those for YFV, JEV, and, with specific constraints, for DENV. To date, no pan-flavivirus vaccine is available. This review examines the potential of emerging vaccine platforms-particularly messenger RNA and virus-like particles-as promising tools in the pursuit of a broadly protective flavivirus vaccine. We analyze current strategies for inducing cross-neutralizing immune responses and discuss how these technologies could support the presentation of conserved quaternary epitope conformations, which are increasingly recognized as critical targets for establishing potent immune responses. We review key advances in virology, immune response, and immunogen delivery systems to highlight the potential for developing a pan-flavivirus vaccine.
2025-10-25 | RNAi therapeutics targeting Japanese encephalitis virus: Gene targets, delivery platforms, and translational barriers.
Japanese encephalitis virus (JEV), a neurotropic flavivirus, is a leading cause of viral encephalitis in Asia, particularly affecting children and causing significant morbidity and mortality. Despite the availability of vaccines and vector control strategies, their limited efficacy against emerging genotypes and incomplete coverage necessitate alternative antiviral approaches. RNA interference (RNAi) has emerged as a promising therapeutic modality by exploiting post-transcriptional gene silencing to inhibit viral replication. Notably, conserved viral genes-such as capsid (C), envelope (E), NS3, and NS5-represent optimal RNAi targets across JEV genotypes due to their essential roles in the viral life cycle and minimal sequence variability. Recent advances in delivery platforms, including lipid nanoparticles, lentiviral vectors, and artificial microRNAs, have significantly improved RNAi stability, blood-brain barrier (BBB) penetration, and cell-specific targeting. Comparative insights from related flaviviruses such as Dengue and Zika have further informed effective RNAi design. Preclinical studies have demonstrated potent antiviral effects, with >90 % suppression of viral RNA, substantial reductions in brain viral load, and enhanced survival in murine models. However, clinical translation remains challenged by delivery efficiency, immune activation, off-target effects, and the potential for viral escape mutations. This review summarizes the current landscape of RNAi-based therapeutics for JEV, emphasizing conserved gene targets, delivery innovations, and translational hurdles, and outlines future directions for integrating RNAi into next-generation antiviral strategies.
2025-06-16 | Multi-omics analysis uncovers differential growth kinetics of Japanese Encephalitis Virus in human and porcine macrophages
Japanese encephalitis virus (JEV), a mosquito-borne neurotropic virus, poses a significant threat to juvenile humans, while causing mild symptoms in pigs, except piglets. Pigs with high viremia are amplifier hosts, whereas humans with lower viremia are dead-end hosts. The molecular mechanisms behind the varying viremia levels in pigs and humans remain poorly understood. A comparative multi-omics study was conducted on JEV-infected macrophages, the early site of JEV replication in both species. We identified 24 key determinants potentially regulating viral growth. Functional validation of three antiviral factors - LGALS1, ssc-miR-133a-3p, and hsa-miR-3614-5p, and two proviral factors - MIF and VMP1, in macrophages showed that the upregulation of MIF and VMP1, and downregulation of ssc-miR-133a-3p, enhanced JEV replication in pigs. In contrast, the downregulation of MIF and VMP1 and upregulation of hsa-miR-3614-5p reduced JEV replication in human macrophages. These findings provide critical insights into JEV infection and its species-specific dynamics.
2025-05-20 | Next-gen vaccine design: Integrating proteomics and bioinformatics for japanese encephalitis
Japanese encephalitis is the most neglected tropical disease induced by a neuroinvasive flavivirus, which refers to the Japanese encephalitis virus (JEV). To date, no successful treatment strategies are available for this disease. Thus, utilizing immunoinformatics and reverse vaccinology, we designed a novel mRNA vaccine (JE-mVax) targeting the viral capsid protein, a precursor to the membrane M protein, and envelope protein using T and B lymphocyte epitopes. The epitopes were incorporated into JE-mVax after being validated as antigenic, non-allergenic, and non-toxic. Moreover, the epitopes achieved global coverage of 100% (combined MHC-I and MHC-II epitopes). Notably, the tertiary structure of JE-mVax achieved a TM-score of 0.49±0.15 and a C score of -1.90. After refinement, the structure demonstrated 93.617% amino acid residues in the most favorable region, an ERRAT score of 73.9899, and a Z score of -5.58. Subsequently, docking analysis showed that the JE-mVax had the lowest energy scores of -986.0 and -1314.2 KJ/mol for TLR-2 and TLR-4. However, the MMGBSA and molecular dynamic simulation analysis also validated this statement. Additionally, the JE-mVax exhibited efficient cloning in E. coli strains, and the immune simulation predicted that it might significantly induce T and B cells. Finally, MFE values of -355.20 kcal/mol (optimal) and -211.56 kcal/mol (centroid) predicted mRNA's marginal structural integrity and stability during host entrance, transcription, and expression. Nonetheless, comprehensive in vitro and in vivo validation is required to definitively demonstrate the vaccine candidate's safety and effectiveness profile.
2025-04-18 | 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.
other
2026-07-18 | Engineered Extracellular Vesicle-Delivered CRISPR/Cas13d for Alleviating Japanese Encephalitis Virus-Induced Brain Injury
This research investigates an engineered extracellular vesicle (EV)-based strategy for delivering programmable CRISPR/Cas13d components across the blood–brain barrier (BBB) to inhibit Japanese encephalitis virus (JEV) infection. We developed RVG-functionalized targeted engineered EVs, termed TEEVs, for brain-targeted delivery of high-fidelity RfxCas13d mRNA and JEV-targeting CRISPR RNAs (crRNAs). The CD63–L7Ae/C/D box system was used to actively enrich Cas13d mRNA and tandem crRNAs within EVs, while RVG surface functionalization was introduced to enhance BBB crossing and uptake by target cells. In vitro, TEEVs showed greater cellular uptake than non-targeted engineered EVs and crossed the BBB-like endothelial barrier in a Transwell co-culture model. TEEVs also suppressed JEV replication and preserved barrier integrity. In vivo biodistribution analyses showed enhanced brain accumulation following intravenous administration. In a lethal mouse model of JEV infection, TEEV treatment reduced brain viral loads, inflammatory responses, BBB disruption, and neuropathological injury and improved survival.
2026-07-02 | FcγRIIA signalling as a host-associated determinant of endosomal trafficking and antibody-dependent enhancement in flavivirus infection.
Antibody-dependent enhancement (ADE) is a major determinant of disease severity in flavivirus infections, yet the host-associated factors that regulate the transition from antibody-mediated uptake to productive infection remain incompletely defined. Fc gamma receptor IIA (FcγRIIA/CD32A), an activating Fc receptor expressed on myeloid cells, represents a key host determinant linking pre-existing immunity to viral entry pathways. Here, we investigated how FcγRIIA signalling influences intracellular trafficking and ADE efficiency across dengue virus (DENV), Zika virus (ZIKV), and Japanese encephalitis virus (JEV). Using BHK-21 cells expressing either wild-type FcγRIIA (WT) or a cytoplasmic-truncated variant lacking the immunoreceptor tyrosine-based activation motif (ITAM), we show that immune-complex internalization occurs independently of the cytoplasmic domain, but that signalling competence significantly modulates downstream infection efficiency. WT cells generally showed higher ADE efficiency, whereas cytoplasmic-truncated receptors preserved ADE activity but showed virus-dependent reductions in enhancement magnitude. FcγRIIA signalling altered the intracellular routing of virus-antibody complexes. WT receptors promoted rapid trafficking from EEA1-positive early endosomes to Rab7-positive late endosomes, whereas signalling-deficient receptors displayed delayed progression and increased association with IRAP- and Rab14-positive compartments. These trafficking differences correlated with virus-specific patterns of enhancement, with DENV showing the strongest dependence on late endosomal maturation, while ZIKV and JEV utilized more flexible or alternative pathways. Transcriptomic analysis revealed minimal differences between WT and truncated receptors at later time points, indicating that FcγRIIA primarily modulates early post-entry events rather than sustained transcriptional responses. Collectively, these findings identify FcγRIIA signalling as a host-associated determinant that regulates the intracellular fate of virus-antibody complexes and influences ADE efficiency through modulation of endosomal trafficking dynamics. The work provides a mechanistic framework linking host receptor signalling to variability in infection outcomes under conditions of pre-existing immunity, with implications for understanding disease heterogeneity and optimizing vaccine and antibody-based interventions.
2026-05-22 | Immunity-oriented drug strategies for viral encephalitis: Acyclovir, antiepileptics and corticosteroids in neurological intensive care.
Viral encephalitis (VE), is a life-threatening neurological disorder marked by inflammation of brain parenchyma, driven by direct viral cytotoxicity and host immune-mediated injury. Globally, its incidence ranges from 1.4 to 13.8 cases per 100,000 individuals annually, with significant morbidity and mortality in endemic regions such as India, among children. Neurotropic viruses including herpes simplex virus (HSV), Japanese encephalitis virus (JEV) and West Nile virus, enter central nervous system via hematogenous or neuronal routes, triggering viral replication, cytokine release and blood-brain barrier disruption, resulting in seizures, cerebral edema and long-term neurological deficits. Current management in neurological intensive care relies on immunity-oriented strategies: Acyclovir as first-line antiviral for HSV and varicella-zoster virus, antiepileptics to control seizures and limit secondary neuronal injury and corticosteroids to modulate harmful neuroinflammation and cerebral edema. Emerging therapies, including novel antivirals (favipiravir, remdesivir, brincidofovir), monoclonal antibodies, cytokine inhibitors (tocilizumab, anakinra) and B-cell/plasma cell-targeted agents (rituximab, daratumumab), offer promise by simultaneously addressing viral replication and immune dysregulation. Personalized biomarker-guided integrating pathogen-directed and host-targeted therapies may optimize outcomes, reduce neuronal injury and improve recovery. This review underscores the importance of a multidimensional, immunity-oriented treatment paradigm, highlighting both established and emerging strategies to enhance prognosis and long-term neurological functions in patients with viral encephalitis.
2026-04-17 | Human antibodies against West Nile and related orthoflaviviruses.
West Nile virus (WNV) is a mosquito-borne pathogen of global concern that can cause fatal neuroinvasive disease. No specific prophylaxis or treatment exists for WNV or related orthoflavivirus infections, and the determinants of human disease severity remain poorly understood. Here, we report that neutralizing autoantibodies against type I interferons do not impair antiviral antibody development. Among the fully human monoclonal antibodies with potent neutralizing activity against WNV that were discovered, W010 targets a unique epitope within the envelope protein domain III (EDIII) and confers both pre- and post-exposure protection in a murine WNV model, even when interferon signaling is impaired. A second protective antibody, W014, exhibits broad cross-neutralization of other pathogenic orthoflavivirus members, including Japanese encephalitis virus, Murray Valley encephalitis virus, Saint Louis encephalitis virus, and Usutu virus. These findings identify key neutralizing epitopes on WNV EDIII and provide candidates for the development of antibody-based interventions against encephalitic orthoflavivirus infections.
2026-03-18 | Spatial transcriptomics uncovers vasculature-centered cellular interactions driving Japanese encephalitis progression in a mouse model.
The cellular interactions that drive the neuropathology of most neuroinvasive viruses remain elusive. We used Japanese encephalitis virus (JEV) to infect female BALB/c mice and applied Stereo-seq to simultaneously capture host and viral transcriptomes in situ, thereby constructing a comprehensive spatiotemporal atlas of Japanese encephalitis (JE) pathogenesis. Our analysis pinpoints Ly6c2+ monocytes as the primary virus carrier, the most abundant infiltrating immune cell type, and a major source of IFN-γ in the infected mouse brain. Following infection, Ackr1+ endothelial cell activation is linked to blood-brain barrier disruption and immune cell chemotaxis, particularly Ly6c2+ monocytes. The crosstalk between these two cell types appears to orchestrate the pronounced inflammation and cell death, including pyroptosis and necroptosis, which radiate from the vasculature to different brain regions. Disrupting the activation and interactions of these two cell types may help mitigate JE progression. This study also provides a technical framework for investigating the pathogenesis of other neurotropic viruses.
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Drug Discovery Landscape
3 orphan drug designations for Japanese encephalitis, including 1 approved therapy.
3 orphan drug designations for Japanese encephalitis, including 1 approved therapy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Japanese encephalitis vaccine, inactivated, adsorbed [IXIARO] | vaccines | FDA | 2012-09-25 | 2013-05-17 | Intercell AG |
Japanese encephalitis vaccine (inactivated, adsorbed) [Ixiaro] | vaccines | EMA | 2006-01-24 | — | [INACTIVE] Intercell AG |
Japanese encephalitis vaccine (live, attenuated) | vaccines | FDA | 1999-05-19 | — | Glovax Co., Ltd. |
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