Japanese encephalitis virus (JEV) is the leading cause of viral encephalitis worldwide; with an estimated 35,000 to 50,000 cases and 10,000 deaths annually. Approximately 25% of encephalitis patients die while about 50% of the survivors develop permanent neurologic and/or psychiatric sequelae, including memory loss, impaired cognition, behavioral disturbances, convulsions, motor weakness or paralysis, and abnormalities of tone and coordination. The virus is a member of the JE serogroup of the genus Flavivirus, family Flaviviridae, and is transmitted between vertebrate hosts by mosquitoes, principally by Culex tritaeniorhynchus. Flaviviruses are known to cause many diseases in humans. Japanese encephalitis virus (JEV), West Nile Virus (WNV), Dengue Virus (DENV), Yellow Fever Virus (YFV) and Zika Virus (ZIKV) are the most common flaviviral infections.
Japanese encephalitis was recognized in horses and humans as early as 1871. In 1924 a severe epidemic was reported from Japan. In 1934, Hyashi reproduced the disease in monkey by intra-cerebral inoculation. In 1935, JE virus was isolated from human brain in Tokyo, Japan, and its virological and serological prototype, Nakayama strain, was established. Five genotypes of JEV are known at present. Different genotypes of JEV (associated with different virulence patterns) thrive in a particular climatic condition: genotypes IV (the oldest) and V are isolated in the tropical endemic region of Indonesia–Malaysia, whereas genotypes III and I are found in the epidemic region.
2. Signs and Symptoms
Most JEV infections are mild (fever and headache) or without apparent symptoms, but approximately 1 in 250 infections results in severe clinical illness. Severe disease is characterized by rapid onset of high fever, headache, neck stiffness, disorientation, coma, seizures, spastic paralysis and ultimately death (Figure 1). The case-fatality rate can be as high as 30% among those with disease symptoms. Of those who survive, 20%–30% suffer permanent intellectual, behavioural or neurological problems such as paralysis, recurrent seizures or the inability to speak.
Figure 1. Common symptoms of Japanese encephalitis.
The incubation period of JEV is about 10-15 days. Most of the infected patients have no symptom or mild symptom, only a few with central nervous system symptoms, such as high fever, headache, cachexia, disturbance of consciousness and convulsions, etc. The manifestation can be divided into four levels according to the severity of the disease:
|a.||Mild symptoms. Patients remain conscious, but with cachexia in different degrees. Usually with no convulsions except several child patient caused by high fever. The temperature of the patient could between 38~39℃. Most mild symptom patient recovery within one week. The infection usually need CSF or serological test to confirm.|
|b.||Common symptoms. Patients with conscious disturbance such as lethargy or mild coma, abdominal reflex and cremasteric reflex disappearing, may have sort term convulsion. The temperature of the patient could be about 40℃ last for 10 day, no sequela.|
|c.||Severe symptom. The temperature keep above 40℃, patients become unconscious and with repeated or continuous convulsion. Usually have localizing symptom and sign. Central respiratory failure could also appear. The progress could last for more than two weeks. Patients could have mental disorder and paralysis among recovery phase, some would have sequela after recovery.|
|d.||Burst symptom. The temperature rising quickly, patient become high or over fever, and with repeated or continuous strong convulsion. Could be die due to the respiratory failure if not rescue in time. Survival usually suffer serious sequela.|
3. Viral Structure
JEV is an enveloped virus about 50 nm in diameter with a single stranded (ss), plus sense, RNA genome of ~11 kb in length. The genome is organized into a capsid formed by multiple copies of capsid C protein; which is covered by a host derived lipid bilayer. The genome has one open reading frame (ORF) encoding for a single polyprotein, which is cleaved into 3 structural proteins e capsid C, precursor to membrane (prM), envelope E and 7 non-structural proteins: NS1, NS2A, NS2B, NS3, NS4A, NS4B, NS5, by viral proteases and host signalases, post translationally.
C protein has w120 amino acids and forms homodimers. It is involved in packaging of the viral genome and formation of the nucleocapsid. prM (~165 aa) and E (~495 aa) are glycoproteins having two transmembrane helices. They are released from the nascent polyprotein following co-translational cleavage by signal peptidases. In the immature virions, prM protein might serve as a chaperone for folding and assembly of the E protein. The prM gets cleaved by cellular furin-like protease to form M (~75 aa) and the protein peptide during the maturation of the flaviviruses in the Golgi complex. Ninety homodimers of E protein present in the host derived lipid bilayer form the major mature virion component. The E protein is the main target of neutralizing antibodies and contains a cellular receptor-binding site(s) and a fusion peptide.
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Figure 2. Viral structure of Japanese encephalitis virus. The viral particle (A), the E protein structure (B) and the cross-section profile of JEV (C).
4. Diagnosis, Treatment and Prevention
Individuals who live in or have travelled to a JE-endemic area and experience encephalitis are considered a suspected JE case. To confirm JEV infection and to rule out other causes of encephalitis requires a laboratory testing of serum or, preferentially, cerebrospinal fluid. Surveillance of the disease is mostly syndromic for acute encephalitis. Laboratory diagnosis of JE is generally accomplished by testing of serum or cerebrospinal fluid (CSF) to detect virus-specific IgM antibodies. JE virus IgM antibodies are usually detectable 3 to 8 days after onset of illness and persist for 30 to 90 days, but longer persistence has been documented. Therefore, positive IgM antibodies occasionally may reflect a past infection or vaccination. Serum collected within 10 days of illness onset may not have detectable IgM, and the test should be repeated on a convalescent sample. For patients with JE virus IgM antibodies, confirmatory neutralizing antibody testing should be performed. In fatal cases, nucleic acid amplification, histopathology with immunohistochemistry, and virus culture of autopsy tissues can also be useful.
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There is no antiviral treatment for patients with JE. Treatment is supportive to relieve symptoms and stabilize the patient.
Safe and effective JE vaccines are available to prevent disease. There are 4 main types of JE vaccines currently in use: inactivated mouse brain-derived vaccines, inactivated Vero cell-derived vaccines, live attenuated vaccines, and live recombinant vaccines. Over the past years, the live attenuated SA14-14-2 vaccine manufactured in China has become the most widely used vaccine in endemic countries, and it was prequalified by WHO in October 2013. All travelers to Japanese encephalitis-endemic areas should take precautions to avoid mosquito bites to reduce the risk for JE. Personal preventive measures include the use of repellents, long-sleeved clothes, coils and vaporizers. Travelers spending extensive time in JE endemic areas are recommended to get vaccinated.
|1.||Misra U K, Kalita J. Overview: japanese encephalitis[J]. Progress in neurobiology, 2010, 91(2): 108-120.|
|2.||Johri; Sunit K. Singh S. Japanese encephalitis virus: from genome to infectome[J]. Microbes and Infection, 2011 (4).|
|3.||Solomon T, Ni H, Beasley D W C, et al. Origin and evolution of Japanese encephalitis virus in southeast Asia[J]. Journal of virology, 2003, 77(5): 3091-3098.|
|4.||Luca V C, AbiMansour J, Nelson C A, et al. Crystal structure of the Japanese encephalitis virus envelope protein[J]. Journal of virology, 2012, 86(4): 2337-2346.|
|5.||Ghosh D, Basu A. Japanese encephalitis—a pathological and clinical perspective[J]. PLoS negl trop dis, 2009, 3(9): e437.|