Japanese encephalitis virus: Associated immune response and recent progress in vaccine development.

Japanese encephalitis (JE) has emerged as one of the most important form of viral encephalitis, which accounts for an estimated 70,000 cases each year with approximately 10,000 fatalities. The clinical presentations and outcome of the infection is dependent upon both virulence of viral determinants and host immune responses. The causative pathogen of JE is a virus known as Japanese encephalitis virus (JEV), which penetrates into the CNS from blood and triggers rapid humoral and cell-mediated immune response. Humoral response is crucial for the control of dissemination of JEV infection and the cytokines produced by cell-mediated immunity during JEV infections serve as potent immune mediators. Till date, JE is only vaccine preventable and no complete antiviral treatment is available so far. Further, vaccine-mediated prevention also has certain limitations. Therefore, an understanding of the pathogenesis of JEV infection can enable the researchers to presume the depth of treatment regime. This review highlights the importance of understanding of the immune mechanisms that are operated in the host during JEV infection and would be helpful in improving future vaccination strategy against JEV.

mosGCTL-7, a C-Type Lectin Protein, Mediates Japanese Encephalitis Virus Infection in Mosquitoes.

Japanese encephalitis virus (JEV) is an arthropod-borne flavivirus prevalent in Asia and the Western Pacific and is the leading cause of viral encephalitis. JEV is maintained in a transmission cycle between mosquitoes and vertebrate hosts, but the molecular mechanisms by which the mosquito vector participates in transmission are unclear. We investigated the expression of all C-type lectins during JEV infection in Aedes aegypti The C-type lectin mosquito galactose-specific C-type lectin 7 (mosGCTL-7) (VectorBase accession no. AAEL002524) was significantly upregulated by JEV infection and facilitated infection in vivo and in vitro mosGCTL-7 bound to the N-glycan at N154 on the JEV envelope protein. This recognition of viral N-glycan by mosGCTL-7 is required for JEV infection, and we found that this interaction was Ca2+ dependent. After mosGCTL-7 bound to the glycan, mosPTP-1 bound to mosGCTL-7, promoting JEV entry. The viral burden in vivo and in vitro was significantly decreased by mosPTP-1 double-stranded RNA (dsRNA) treatment, and infection was abolished by anti-mosGCTL-7 antibodies. Our results indicate that the mosGCTL-7/mosPTP-1 pathway plays a key role in JEV infection in mosquitoes. An improved understanding of the mechanisms underlying flavivirus infection in mosquitoes will provide further opportunities for developing new strategies to control viral dissemination in nature.IMPORTANCE Japanese encephalitis virus is a mosquito-borne flavivirus and is the primary cause of viral encephalitis in the Asia-Pacific region. Twenty-four countries in the WHO Southeast Asia and Western Pacific regions have endemic JEV transmission, which exposes >3 billion people to the risks of infection, although JEV primarily affects children. C-type lectins are host factors that play a role in flavivirus infection in humans, swine, and other mammals. In this study, we investigated C-type lectin functions in JEV-infected Aedes aegypti and Culex pipiens pallens mosquitoes and cultured cells. JEV infection changed the expression of almost all C-type lectins in vivo and in vitro, and mosGCTL-7 bound to the JEV envelope protein via an N-glycan at N154. Cell surface mosPTP-1 interacted with the mosGCTL-7-JEV complex to facilitate virus infection in vivo and in vitro Our findings provide further opportunities for developing new strategies to control arbovirus dissemination in nature.

Bacillus Calmette-Guérin Confers Neuroprotection in a Murine Model of Japanese Encephalitis.

OBJECTIVE: Japanese encephalitis (JE) is a debilitating disease caused by infection with the JE virus (JEV; family: Flaviviridae), which leaves neurological sequelae in survivors but more often leads to mortality. Neurodegeneration caused by inflammation is the primary pathology behind the clinical manifestation of encephalitis caused by JEV. Bacillus Calmette-Guérin (BCG) has been used in immunoprophylaxis for tuberculosis and in the adjuvant therapy of many malignancies, and has exhibited neuroprotective activities in experimental models of Parkinson and Alzheimer disease. This study aimed at assessing the neuroprotective role of BCG in a murine model of JE. METHODS: Suckling mice were inoculated with 106 CFU of BCG and at 18 days postinoculation were challenged with 100 LD50 of JEV. PBS-inoculated mice were used as controls. Mice were sacrificed on days 2, 4, 6, and 8. Brain tissue was homogenized for RNA extraction. One-step real-time RT-PCR was performed to assess the relative gene expressions of TNF-α, IL-6, and iNOS. RESULTS: The BCG-inoculated (BCG+JEV) group exhibited a significant delay in the presentation of neuropathological symptoms, longer survival, and a downregulation in the expression of TNF-α, IL-6, and iNOS on days 2, 4, and 6 post-JEV challenge compared to the JEV group. CONCLUSION: These findings indicate that the administration of BCG offers neuroprotection in the murine model of JE. BCG should therefore be further investigated as an adjuvant in the management of JE. BCG is an accepted vaccine for tuberculosis in many countries that are endemic for JEV. This approach may have a significant impact on the public health burden in these countries.

Constant up-regulation of BiP/GRP78 expression prevents virus-induced apoptosis in BHK-21 cells with Japanese encephalitis virus persistent infection.

BACKGROUND: Persistent infection of the Japanese Encephalitis Virus (JEV) has been reported in clinical cases, experimental animals, and various cell culture systems. We previously reported the establishment of spontaneous JEV persistent infection, assisted by defective interfering particle accumulation and/or attenuated helper viruses, in BHK-21 cells devoid of virus-induced apoptosis, cBS6-2 and cBS6-3. However, cell-specific factors may play important roles in controlling JEV replication and have never been assessed for this specific phenomenon. Recent evidence suggests that viruses have evolved various mechanisms to cope with endoplasmic reticulum stress signaling pathways for their efficient amplification and transmission, including the unfolded protein response (UPR). RESULTS: To identify the host cell factors that affect JEV persistence, we investigated the expression of essential UPR factors in cBS6-2 and cBS6-3 cells. Of the selected UPR factors tested, the most noticeable deviations from those of the normal BHK-21 cells with JEV acute infection were as follows: the suppression of C/EBP homologous binding protein (CHOP) and the constant up-regulation of immunoglobulin binding protein (BiP) expression in cBS6-2 and cBS6-3 cells. In JEV acute infection on normal BHK-21 cells, silencing CHOP expression through specific siRNA blocked cell death almost completely. Meanwhile, depletion of BiP by specific siRNA unlocked CHOP expression in cBS6-2 and cBS6-3 cells, resulting in massive cell death. Fulminant apoptotic cell death for both cell clones on tunicamycin treatment revealed that the JEV persistently infected cells still contained functional arms for cell fate decisions. CONCLUSIONS: BHK-21 cells with JEV persistent infection strive against virus-induced apoptosis through constant up-regulation of BiP expression, resulting in the complete depletion of CHOP even with apparent virus amplification in the cells. Accordingly, the attenuation of virus replication as well as the modifications to cell metabolism could be additional factors contributing to the development of JEV persistent infection in mammalian cells.

Japanese encephalitis in a French traveler to Nepal.

Japanese encephalitis is frequent in Asia, with a severe prognosis, but rare in travelers. Culex mosquitoes transmit Japanese encephalitis virus. Risk factors are destination, duration of stay, summer and fall seasons, outdoor activities, and type of accommodation. We report the case of a French traveler to Nepal with neutralization-based serological confirmed Japanese encephalitis. He presented classical clinical (viral syndrome before an encephalitis status with behavioral disorder, global hypotonia, mutism, movement disorders, seizure, and coma), radiological (lesions of thalami, cortico-spinal tracts, and brainstem) and biological features (lymphocytic meningitis). Nowadays, the presence of Japanese encephalitis virus in Nepal, including mountain areas, is established but Japanese encephalitis remains rare in travelers returning from this area and neurologist physicians need to become familiar with this. We recommend vaccination for travelers spending a long period of time in Nepal and having at-risk outdoor activities.

Flaviviruses, an expanding threat in public health: focus on dengue, West Nile, and Japanese encephalitis virus.

The flaviviruses dengue, West Nile, and Japanese encephalitis represent three major mosquito-borne viruses worldwide. These pathogens impact the lives of millions of individuals and potentially could affect non-endemic areas already colonized by mosquito vectors. Unintentional transport of infected vectors (Aedes and Culex spp.), traveling within endemic areas, rapid adaptation of the insects into new geographic locations, climate change, and lack of medical surveillance have greatly contributed to the increase in flaviviral infections worldwide. The mechanisms by which flaviviruses alter the immune and the central nervous system have only recently been examined despite the alarming number of infections, related deaths, and increasing global distribution. In this review, we will discuss the expansion of the geographic areas affected by flaviviruses, the potential threats to previously unaffected countries, the mechanisms of pathogenesis, and the potential therapeutic interventions to limit the devastating consequences of these viruses.

Hospital-based surveillance of Japanese encephalitis at a tertiary hospital in Manila.

Japanese encephalitis virus (JEV) is endemic in the Philippines but the incidence and burden of disease are not well established. We conducted a prospective hospital-based study at San Lazaro Hospital, a tertiary level hospital in Manila, from September 2005 to December 2006. Cases were determined using an in-house dengue and Japanese encephalitis (JE) enzyme-linked immunosorbent assay in order to detect the proportion of JE cases among the acute encephalitis syndrome (AES) cases admitted to our hospital. Fifteen patients were found to have AES, of whom 6 (40%) had confirmed JE. Of the JE cases, 4 were females and 2 were males with an age range of 3-14 years. Three of the 6 JE cases occurred during July. The most common signs and symptoms on admission among JE cases were: fever, headache, loss of appetite, neck rigidity and altered sensorium. JE likely comprises a significant proportion of hospitalized AES cases among children from Manila and nearby provinces. Further studies on the nation-wide prevalence and distribution of JE in the Philippines are needed to guide health authorities in disease control and prevention strategies.

Japanese encephalitis - prevention in travellers.

This article is the fourth in a series providing a summary of prevention strategies and vaccination for infections that may be acquired by travellers. The series aims to provide practical strategies to assist general practitioners in giving travel advice, as a synthesis of multiple information sources which must otherwise be consulted. Japanese encephalitis (JE) is a potentially fatal arboviral infection prevalent in large parts of Asia, as well as Papua New Guinea and the outer Torres Strait Islands. It is the commonest cause of encephalitis worldwide. Although it seldom affects travellers, its serious consequences and at times unpredictable epidemiology make its prevention an important part of the pre-travel consultation. The phasing out of the previously used mouse brain derived inactivated JE vaccine, and the availability of new, safer vaccines now and in the near future, have prompted a reassessment of vaccination recommendations internationally to include a greater number of travellers.

Cognitive impairment in encephalitis: P3 and MRI correlation.

OBJECTIVE: In view of paucity of studies on P3 in encephalitis, we report clinical, MRI and P3 changes in encephalitis patients. DESIGN: The diagnosis of encephalitis was based on clinical, MRI, ELISA and/or PCR and categorized into Japanese encephalitis (JE), dengue, herpes (HSE) and nonspecific group. Cognitive functions were evaluated 1 month after the illness when patient was able to cooperate for Mini Mental State examination (MMSE). P3 was carried out by odd ball auditory paradigm recording from Cz, Fz and Pz referred to linked mastoids. RESULTS: 30 encephalitis patients including 16 JE, 2 HSE and 12 nonspecific whose median age was 24 (13-53) years were prospectively evaluated. P3 was studied after a median duration of 3 months. MMSE was abnormal in 19 patients. CzP3 was abnormal in 6; 5 of whom had abnormal MMSE. MRI was abnormal in 18 showing thalamic lesion in 13, basal ganglia in 3 and cortical in 7 patients. MMSE was abnormal in all the patients with HSE, 81% with JE and 33% with nonspecific encephalitis. P3 was more frequently abnormal in patients with abnormal MMSE and MRI. CONCLUSION: Cognitive impairment is common in HSE and JE; abnormal MMSE and MRI are associated with P3 abnormality.

Recent advances in understanding Japanese encephalitis.

Japanese encephalitis (JE) is a clinical manifestation of the brain inflammation caused by JE virus (JEV). This virus imparts permanent neurological damage, thus imposing a heavy burden on public health and society. Neuro-inflammation is the hallmark of JEV infection. The prolonged pro-inflammatory response is due primarily to microglial activation, which eventually leads to severe encephalitis. A continual effort is going on in the scientific community toward an understanding of cellular and molecular factors that are involved in JEV neuro-invasion and inflammatory processes. This review not only gives a comprehensive update on the recent advances on understanding virus structure and mechanisms of pathogenesis but also briefly discusses crucial unresolved issues. We also highlight challenging areas of research that might open new avenues for controlling virus-induced neuro-inflammation.

Clinical analysis of psychiatric symptoms of Japanese encephalitis during the convalescent Period: A single center study in Chongqing, China.

BACKGROUND: This study aimed to analyze clinical and imaging features of children with severe Japanese encephalitis (JE), and to analyze causes and solutions for psychiatric symptoms of JE during the convalescent period. METHODS: We analyzed clinical information for 78 children with severe JE at the Department of Neurology, Department of Infection, and Department of Rehabilitation in our hospital during 2014-2016. Seventy-eight cases of severe JE were divided into patients with psychiatric symptoms and no psychiatric symptoms groups. We focused on analysis of the patients with psychiatric symptoms group. RESULTS: The incidence of psychiatric symptoms during the convalescent period was 46.15% (36/78). Antipsychotic drugs can effectively control psychiatric symptoms and shorten duration of symptoms. Seventy-one patients underwent reexamination with a head MRI. Of these, 8 cases (8/36 = 22.22%) in patients with psychiatric symptoms group showed new lesions in the basal ganglia, insula, and hippocampus. During the 12-month follow-up, two cases showed reappearance of psychiatric symptoms that had been relieved previously. CONCLUSION: This study found that severe JE cases revealed a considerable proportion with psychiatric symptoms during the convalescent period.

Longitudinal magnetic resonance imaging changes in Japanese encephalitis.

BACKGROUND: Japanese encephalitis is a flavivirus that can cause pandemic encephalitis, and is prevalent in Southeast Asia and Australia. Brain images of patients with Japanese encephalitis are characterized by thalamic lesions, distinct from those seen in viral encephalopathies caused by the herpes simplex virus and West Nile virus. AIM: Herein, we describe for the first time a time-dependent magnetic resonance imaging pattern in Japanese encephalitis in a 10-month-old Japanese boy. CASE: The patient was a previously healthy 10-month-old Japanese boy, who exhibited acute-onset flaccid tetraplegia and loss of tendon reflexes. RESULTS: Brain MRI showed characteristic thalamic changes on diffusion weighted images from spotty to uniform and from the left to the right side, associated with low apparent diffusion coefficient maps. These images suggest that the Japanese encephalitis virus may first affect the unilateral thalamus, possibly expanding to the other side, with characteristic patterns changing from spotty to uniform in a manner consistent with the presentation of cytotoxic edema. CONCLUSION: This report first showed longitudinal magnetic resonance changes in Japanese encephalitis, which may help in accurate diagnosis and in discrimination from other etiologies.

Japanese Encephalitis Virus infection induces inflammation of swine testis through RIG-I-NF-ĸB signaling pathway.

Japanese Encephalitis Virus (JEV) is an important zoonotic flavivirus transmitted by mosquitos. JEV infection in sows primarily manifests as a reproductive disease such as abortion and transient infertility while in infected boars, it can cause orchitis. Previous studies mainly focused on the pathogenesis of human encephalitis caused by JEV infection, while few concentrations have been made to unveil the potential mechanism of reproductive dysfunction in JEV-infected pigs. In this study, histopathological analysis and immunohistochemistry staining was performed on testis of JEV-infected boars, indicating that JEV could infect testicular cells and cause inflammatory changes in testis. In vitro assays reveal that primary swine testicular cells and swine testis (ST) cells are highly permissive to JEV and significant inflammatory response was shown during JEV infection. Mechanically, we found that JEV infection increases the expression of retinoic acid-inducible gene I (RIG-I) and activates transcription factor NF-κB. Production of pro-inflammatory cytokines was greatly reduced in JEV infected testicular cells after knockout of RIG-I or treatment with the NF-κB specific inhibitor. In addition, activation of NF-κB was also significantly suppressed upon RIG-I knockout. Taken together, our results reveal that JEV could infect boar testicles, and RIG-I-NF-κB signaling pathway is involved in JEV-induced inflammation in swine testicular cells.

Chronic post-encephalitic epilepsy following Japanese encephalitis: Clinical features, neuroimaging data, and outcomes.

PURPOSE: Japanese encephalitis (JE), the main cause of viral encephalitis in Asia, usually presents with acute symptomatic seizures; however, there have been very few systematic reports regarding late unprovoked seizures and epilepsy. We aimed to describe the clinical features and outcomes of post-encephalitic epilepsy following JE. METHODS: Patients with epilepsy with a previous confirmed diagnosis of JE visiting West China Hospital from 2013 to 2019 were enrolled in the observational case-controlled study. Patients with epilepsy with a history of other non-specific viral encephalitis were enrolled as controls. For all enrolled subjects, disease related information was recorded. RESULTS: Forty-eight patients with JE (20 males; median age, 21.0 years; average epilepsy duration, 8.55 years) were identified. The median duration from JE to the first unprovoked seizure was 7.73 years, which significantly differed from that of the controls (7.73 vs. 2.69 years, respectively; p = 4.59 × 10-6). Most patients had focal epilepsy, and 29 (78.38%) were drug resistant. Among 45 patients with available neuroimaging data, three in fourth had no obvious abnormality, and the temporal lobe and hippocampus (22.22%) were the most affected brain regions. Six patients had surgery, and three achieved class-one seizure-free status. CONCLUSION: The latency to the first unprovoked seizure was longer in patients with JE than controls. Regarding chronic epilepsy, three in four had structural abnormalities, and the long-term outcomes of post-encephalitic epilepsy following JE were poor. Surgery remains an option for drug-resistant epilepsy.

Evaluation of cholinergic functions in patients with Japanese encephalitis and Herpes simplex encephalitis.

Cognitive and memory impairment are related to cholinergic dysfunction and are important complications of viral encephalitis, In view of paucity of studies on cholinergic dysfunction in encephalitis, this study has been undertaken. We report acetyl choline esterase (AChE) and muscurinic 2 (M2) receptor levels in herpes simplex encephalitis (HSE) and Japanese encephalitis (JE) patients, and correlate these with cognitive functions and MRI findings. Patients with JE and HSE were evaluated for consciousness, neurological and MRI findings, plasma AChE and M2 receptor levels on admission and after one year. Twenty-nine patients with JE and 23 with HSE were included. Admission AChE levels in JE (48.32 ±â€¯5.36 nmol/min/ml) and HSE (41.92 ±â€¯5.12 nmol/min/ml) were significantly lower compared with controls (70.50 ±â€¯8.30 nmol/min/ml). M2 receptor levels were also low in JE (4.52 ±â€¯0.56 ng/ml) and HSE (4.35 ±â€¯0.57 ng/ml) compared with controls (7.95 ±â€¯0.41 ng/ml). In JE, AChE activity (r = 0.43, p = 0.02) and M2 receptor levels (r = 0.43, p = 0.02) correlated with caudate involvement, and AChE activity (r = 0.76, p = 0.03) with Mini Mental State Examination ( MMSE) score. In HSE, M2 receptor levels (r = 0.53, p = 0.03) correlated with MMSE. The levels of AChE and M2 receptors increased at one year compared to the baseline, which was greater in JE than in HSE. Both AChE and M2 receptors were reduced in JE and HSE and correlated with cognition at one year. Recovery of these biomarkers was more in JE than HSE.

The epidemiology, clinical features, and long-term prognosis of Japanese encephalitis in central sarawak, malaysia, 1997-2005.

BACKGROUND: Japanese encephalitis is a major public health problem in Asia. However, there is little data on the long-term outcome of Japanese encephalitis survivors. METHODS: We prospectively evaluated children with serologically confirmed Japanese encephalitis over an 8.3-year period. The patients were assessed and their outcomes were graded with a functional outcome score at hospital discharge and at follow-up appointments. We examined how patient outcome at hospital discharge compared with that at long-term follow-up visits, when changes in outcome occurred, and the prognostic indicators of the eventual outcome. RESULTS: One hundred and eighteen patients were recruited into the study, and 10 (8%) died during the acute phase of illness. At hospital discharge, 44 (41%) of the 108 patients who survived had apparent full recovery; 3 (3%) had mild, 28 (26%) had moderate, and 33 (31%) had severe neurological sequelae. Eighty six of the 108 patients were followed up for a median duration of 52.9 months (range, 0.9-114.9 months). During follow-up, 31 patients experienced improvement, but 15 patients experienced deterioration in their outcome grade. In most cases, assessment during the first 3-6 months after hospital discharge was predictive of the long-term outcome. More than one-half of the patients continued to experience neuropsychological sequelae and behavioral disorders. A combination of poor perfusion, Glasgow coma score < or =8, and > or =2 witnessed seizures predicted a poor long-term outcome with 65% sensitivity and 92% specificity. CONCLUSIONS: Neurological assessment of Japanese encephalitis survivors at hospital discharge does not predict long-term outcome. Seizures and shock are treatable risk factors for a poor outcome at hospital discharge and at long-term follow-up visits.

A cohort study to assess the new WHO Japanese encephalitis surveillance standards.

OBJECTIVE: To assess the field-test version of the new WHO Japanese encephalitis (JE) surveillance standards. METHODS: We applied the clinical case definition of acute encephalitis syndrome (AES), laboratory diagnostic criteria and case classifications to patients with suspected central nervous system (CNS) infections in southern Viet Nam. FINDINGS: Of the 380 patients (149 children) recruited with suspected CNS infections, 296 (96 children) met the AES case definition. 54 children were infected with JE virus (JEV), of whom 35 (65%) had AES, giving a sensitivity of 65% (95% CI: 56-73) and specificity of 39% (95% CI: 30-48). Nine adults with JEV presented with AES. 19 JEV-infected children missed by surveillance included 10 with acute flaccid paralysis, two with flaccid hemiparesis and six with meningism only. Altering the case definition to include limb paralysis and meningism improved sensitivity to 89% (95% CI: 83-95), while reducing specificity to 23% (95% CI: 15-30). Six children that did not have AES on admission had reduced consciousness after admission. Cerebrospinal fluid (CSF) analysis diagnosed seven patients negative on serum analysis. Five patients with neurological manifestations of dengue infection had JEV antibodies in serum and would have been misdiagnosed had we not tested for dengue antibodies in parallel. CONCLUSION: Children infected with JEV that presented with acute limb paralysis or neck stiffness only were missed by the surveillance standards, although some of them subsequently became encephalopathic. A footnote in the surveillance standards drawing attention to these presentations would be helpful. An acute CSF sample is more sensitive and specific than an acute serum sample.

Japanese encephalitis virus differentially modulates the induction of multiple pro-inflammatory mediators in human astrocytoma and astroglioma cell-lines.

Astrocytes become activated in response to many CNS pathologies. The process of astrocyte activation remains rather enigmatic and results in so-called reactive gliosis, a reaction with specific structural and functional characteristics. Astrocytes play a vital role in regulating aspects of inflammation and in the homeostatic maintenance of the CNS. However, the responses of different human astroglial cell-lines in viral encephalitis mediated inflammation are not well documented. We have shown that Japanese encephalitis virus (JEV) infection causes morphological and functional changes in astrocytic cell-lines. We have demonstrated that besides reactive oxygen species (ROS) JEV infection differentially regulated the induction pattern of IL-6, IL-1 beta and IL-8. IP-10, MCP-1, MIG and RANTES secretions in different astroglial cell-lines. The expression of different proteins such as astrocyte-specific glial fibrillary acidic protein (GFAP), the glutamate aspartate transporter/essential amino acid transporter-1 (GLAST/EAAT-1), glutamate transporter-1/essential amino acid transporter-2 (GLT-1/EAAT-2), Ceruloplasmin and Thioredoxin (TRX) expression level also differ in different human astrocyte cell-lines following infection.

Japanese encephalitis - the prospects for new treatments.

Japanese encephalitis is a mosquito-borne disease that occurs in Asia and is caused by Japanese encephalitis virus (JEV), a member of the genus Flavivirus. Although many flaviviruses can cause encephalitis, JEV causes particularly severe neurological manifestations. The virus causes loss of more disability-adjusted life years than any other arthropod-borne virus owing to the frequent neurological sequelae of the condition. Despite substantial advances in our understanding of Japanese encephalitis from in vitro studies and animal models, studies of pathogenesis and treatment in humans are lagging behind. Few mechanistic studies have been conducted in humans, and only four clinical trials of therapies for Japanese encephalitis have taken place in the past 10 years despite an estimated incidence of 69,000 cases per year. Previous trials for Japanese encephalitis might have been too small to detect important benefits of potential treatments. Many potential treatment targets exist for Japanese encephalitis, and pathogenesis and virological studies have uncovered mechanisms by which these drugs could work. In this Review, we summarize the epidemiology, clinical features, prevention and treatment of Japanese encephalitis and focus on potential new therapeutic strategies, based on repurposing existing compounds that are already suitable for human use and could be trialled without delay. We use our newly improved understanding of Japanese encephalitis pathogenesis to posit potential treatments and outline some of the many challenges that remain in tackling the disease in humans.