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:
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.
2026-08-13 | 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.
2026-08-05 | 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
2026-08-13 | 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.
2026-08-13 | 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.
2026-08-05 | 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
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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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