Japanese B Encephalitis
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Japanese encephalitis (JE) is an infection of the
brain The brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head (cephalization), usually near organs for ...
caused by the Japanese encephalitis virus (JEV). While most infections result in little or no symptoms, occasional inflammation of the brain occurs. In these cases, symptoms may include headache, vomiting, fever, confusion and
seizure A seizure is a sudden, brief disruption of brain activity caused by abnormal, excessive, or synchronous neuronal firing. Depending on the regions of the brain involved, seizures can lead to changes in movement, sensation, behavior, awareness, o ...
s. This occurs about 5 to 15 days after infection. JEV is generally spread by
mosquito Mosquitoes, the Culicidae, are a Family (biology), family of small Diptera, flies consisting of 3,600 species. The word ''mosquito'' (formed by ''Musca (fly), mosca'' and diminutive ''-ito'') is Spanish and Portuguese for ''little fly''. Mos ...
es, specifically those of the ''
Culex ''Culex'' or typical mosquitoes are a genus of mosquitoes, several species of which serve as vectors of one or more important diseases of birds, humans, and other animals. The diseases they vector include arbovirus infections such as West Nil ...
'' type.
Pigs The pig (''Sus domesticus''), also called swine (: swine) or hog, is an omnivorous, domesticated, even-toed, hoofed mammal. It is named the domestic pig when distinguishing it from other members of the genus '' Sus''. Some authorities cons ...
and wild birds serve as a reservoir for the virus. The disease occurs mostly outside of cities. Diagnosis is based on blood or
cerebrospinal fluid Cerebrospinal fluid (CSF) is a clear, colorless Extracellular fluid#Transcellular fluid, transcellular body fluid found within the meninges, meningeal tissue that surrounds the vertebrate brain and spinal cord, and in the ventricular system, ven ...
testing. Prevention is generally achieved with the
Japanese encephalitis vaccine Japanese encephalitis vaccine is a vaccine that protects against Japanese encephalitis. The vaccines are more than 90% effective. The duration of protection with the vaccine is not clear but its effectiveness appears to decrease over time. Doses ...
, which is both safe and effective. Other measures include avoiding mosquito bites. Once infected, there is no specific treatment, with care being supportive. This is generally carried out in a hospital. Permanent problems occur in up to half of people who recover from JE. The disease primarily occurs in
East East is one of the four cardinal directions or points of the compass. It is the opposite direction from west and is the direction from which the Sun rises on the Earth. Etymology As in other languages, the word is formed from the fact that ea ...
and
Southeast Asia Southeast Asia is the geographical United Nations geoscheme for Asia#South-eastern Asia, southeastern region of Asia, consisting of the regions that are situated south of China, east of the Indian subcontinent, and northwest of the Mainland Au ...
as well as the Western Pacific. About 3 billion people live in areas where the disease occurs. About 68,000 symptomatic cases occur a year, with about 17,000 deaths. Often, cases occur in
outbreak In epidemiology, an outbreak is a sudden increase in occurrences of a disease when cases are in excess of normal expectancy for the location or season. It may affect a small and localized group or impact upon thousands of people across an entire ...
s. The disease was first described in
Japan Japan is an island country in East Asia. Located in the Pacific Ocean off the northeast coast of the Asia, Asian mainland, it is bordered on the west by the Sea of Japan and extends from the Sea of Okhotsk in the north to the East China Sea ...
in
1871 Events January–March * January 3 – Franco-Prussian War: Battle of Bapaume – Prussians win a strategic victory. * January 18 – Proclamation of the German Empire: The member states of the North German Confederation and the sout ...
.


Signs and symptoms

The Japanese encephalitis virus (JEV) has an
incubation period Incubation period (also known as the latent period or latency period) is the time elapsed between exposure to a pathogenic organism, a chemical, or ionizing radiation, radiation, and when symptoms and signs are first apparent. In a typical infect ...
of 2 to 26 days. The vast majority of infections are
asymptomatic Asymptomatic (or clinically silent) is an adjective categorising the medical conditions (i.e., injuries or diseases) that patients carry but without experiencing their symptoms, despite an explicit diagnosis (e.g., a positive medical test). P ...
. Only 1 in 250 infections develop into encephalitis. Severe rigors may mark the onset of this disease in humans. Fever, headache, and
malaise In medicine, malaise is a feeling of general discomfort, uneasiness or lack of wellbeing and often the first sign of an infection or other disease. It is considered a vague termdescribing the state of simply not feeling well. The word has exist ...
are other
non-specific symptom Signs and symptoms are diagnostic indications of an illness, injury, or condition. Signs are objective and externally observable; symptoms are a person's reported subjective experiences. A sign for example may be a higher or lower temperature ...
s of this disease which may last for a period of between 1 and 6 days. Signs that develop during the acute encephalitic stage include neck rigidity,
cachexia Cachexia () is a syndrome that happens when people have certain illnesses, causing muscle loss that cannot be fully reversed with improved nutrition. It is most common in diseases like cancer, Heart failure, congestive heart failure, chronic o ...
,
hemiparesis Hemiparesis, also called unilateral paresis, is the weakness of one entire side of the body (''wikt:hemi-#Prefix, hemi-'' means "half"). Hemiplegia, in its most severe form, is the complete paralysis of one entire side of the body. Either hemipar ...
, convulsions, and a raised body temperature between . The mortality rate of the disease is around 25% and is generally higher in children under five, the immuno-suppressed, and the elderly. Transplacental spread has been noted.
Neurological disorder Neurological disorders represent a complex array of medical conditions that fundamentally disrupt the functioning of the nervous system. These disorders affect the brain, spinal cord, and nerve networks, presenting unique diagnosis, treatment, and ...
s develop in 40% of those who survive with lifelong neurological defects such as deafness, emotional lability and
hemiparesis Hemiparesis, also called unilateral paresis, is the weakness of one entire side of the body (''wikt:hemi-#Prefix, hemi-'' means "half"). Hemiplegia, in its most severe form, is the complete paralysis of one entire side of the body. Either hemipar ...
occurring in those who had
central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...
involvement. Increased microglial activation following Japanese encephalitis infection has been found to influence the outcome of viral pathogenesis. Microglia are the resident
immune cell White blood cells (scientific name leukocytes), also called immune cells or immunocytes, are cell (biology), cells of the immune system that are involved in protecting the body against both infectious disease and foreign entities. White blood c ...
s of the central nervous system (CNS) and have a critical role in host defense against invading microorganisms. Activated microglia secrete cytokines, such as interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-α), which can cause toxic effects in the brain. Additionally, other soluble factors such as
neurotoxins Neurotoxins are toxins that are destructive to nerve tissue (causing neurotoxicity). Neurotoxins are an extensive class of exogenous chemical neurological insultsSpencer 2000 that can adversely affect function in both developing and mature n ...
, excitatory neurotransmitters,
prostaglandin Prostaglandins (PG) are a group of physiology, physiologically active lipid compounds called eicosanoids that have diverse hormone-like effects in animals. Prostaglandins have been found in almost every Tissue (biology), tissue in humans and ot ...
,
reactive oxygen In chemistry and biology, reactive oxygen species (ROS) are highly reactive chemicals formed from diatomic oxygen (), water, and hydrogen peroxide. Some prominent ROS are hydroperoxide (H2O2), superoxide (O2−), hydroxyl radical (OH.), and sing ...
, and nitrogen species are secreted by activated microglia. In a
murine The Old World rats and mice, part of the subfamily Murinae in the family Muridae, comprise at least 519 species. Members of this subfamily are called murines. In terms of species richness, this subfamily is larger than all mammal families excep ...
model of JE, it was found that in the
hippocampus The hippocampus (: hippocampi; via Latin from Ancient Greek, Greek , 'seahorse'), also hippocampus proper, is a major component of the brain of humans and many other vertebrates. In the human brain the hippocampus, the dentate gyrus, and the ...
and the
striatum The striatum (: striata) or corpus striatum is a cluster of interconnected nuclei that make up the largest structure of the subcortical basal ganglia. The striatum is a critical component of the motor and reward systems; receives glutamat ...
, the number of activated microglia was more than anywhere else in the brain, closely followed by that in the
thalamus The thalamus (: thalami; from Greek language, Greek Wikt:θάλαμος, θάλαμος, "chamber") is a large mass of gray matter on the lateral wall of the third ventricle forming the wikt:dorsal, dorsal part of the diencephalon (a division of ...
. In the cortex, the number of activated microglia was significantly less when compared to other regions of the
mouse brain A mouse (: mice) is a small rodent. Characteristically, mice are known to have a pointed snout, small rounded ears, a body-length scaly tail, and a high breeding rate. The best known mouse species is the common house mouse (''Mus musculus'' ...
. An overall induction of differential expression of proinflammatory cytokines and
chemokines Chemokines (), or chemotactic cytokines, are a family of small cytokines or signaling proteins secreted by cells that induce directional movement of leukocytes, as well as other cell types, including endothelial and epithelial cells. In addit ...
from different brain regions during a progressive Japanese encephalitis infection was also observed. Although the net effect of the proinflammatory mediators is to kill infectious organisms and infected cells as well as to stimulate the production of molecules that amplify the mounting response to damage, it is also evident that in a non-regenerating organ such as the brain, a dysregulated innate immune response would be deleterious. In JE the tight regulation of microglial activation appears to be disturbed, resulting in an autotoxic loop of microglial activation that possibly leads to bystander neuronal damage. In animals, key signs include infertility and abortion in pigs, neurological disease in horses, and systemic signs including fever, lethargy and anorexia.Japanese Encephalitis Virus
reviewed and published by
WikiVet WikiVet is a wiki of veterinary content based on the MediaWiki platform. The website is a collaborative initiative between various veterinary schools, and its content covers the entire veterinary curriculum. WikiVet is part of the WikiVet Educatio ...
, accessed 11 October 2011.


Cause

It is a disease caused by the
mosquito Mosquitoes, the Culicidae, are a Family (biology), family of small Diptera, flies consisting of 3,600 species. The word ''mosquito'' (formed by ''Musca (fly), mosca'' and diminutive ''-ito'') is Spanish and Portuguese for ''little fly''. Mos ...
-borne
Japanese encephalitis virus Japanese encephalitis (JE) is an infection of the brain caused by the Japanese encephalitis virus (JEV). While most infections result in little or no symptoms, occasional inflammation of the brain occurs. In these cases, symptoms may include he ...
(JEV).


Virology

JEV is a virus from the family ''
Flaviviridae ''Flaviviridae'' is a family of Viral envelope, enveloped positive-strand RNA viruses which mainly infect mammals and birds. They are primarily spread through arthropod vector (epidemiology), vectors (mainly ticks and mosquitoes). The family gets ...
'', part of the Japanese encephalitis serocomplex of nine genetically and
antigen In immunology, an antigen (Ag) is a molecule, moiety, foreign particulate matter, or an allergen, such as pollen, that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response. ...
ically related viruses, some of which are particularly severe in
horses The horse (''Equus ferus caballus'') is a domesticated, one-toed, hoofed mammal. It belongs to the taxonomic family Equidae and is one of two extant subspecies of ''Equus ferus''. The horse has evolved over the past 45 to 55 milli ...
, and four of which, including
West Nile virus West Nile virus (WNV) is a single-stranded RNA virus that causes West Nile fever. It is a member of the family ''Flaviviridae'', from the genus ''Flavivirus'', which also contains the Zika virus, dengue virus, and yellow fever virus. The virus ...
, are known to infect humans. The enveloped virus is closely related to the
West Nile virus West Nile virus (WNV) is a single-stranded RNA virus that causes West Nile fever. It is a member of the family ''Flaviviridae'', from the genus ''Flavivirus'', which also contains the Zika virus, dengue virus, and yellow fever virus. The virus ...
and the St. Louis encephalitis virus. The positive sense single-stranded
RNA Ribonucleic acid (RNA) is a polymeric molecule that is essential for most biological functions, either by performing the function itself (non-coding RNA) or by forming a template for the production of proteins (messenger RNA). RNA and deoxyrib ...
genome is packaged in the
capsid A capsid is the protein shell of a virus, enclosing its genetic material. It consists of several oligomeric (repeating) structural subunits made of protein called protomers. The observable 3-dimensional morphological subunits, which may or m ...
which is formed by the capsid protein. The outer envelope is formed by envelope protein and is the protective antigen. It aids in the entry of the virus into the cell. The genome also encodes several nonstructural proteins (NS1, NS2a, NS2b, NS3, N4a, NS4b, NS5). NS1 is also produced as a secretory form. NS3 is a putative
helicase Helicases are a class of enzymes that are vital to all organisms. Their main function is to unpack an organism's genetic material. Helicases are motor proteins that move directionally along a nucleic double helix, separating the two hybridized ...
, and NS5 is the viral
polymerase In biochemistry, a polymerase is an enzyme (Enzyme Commission number, EC 2.7.7.6/7/19/48/49) that synthesizes long chains of polymers or nucleic acids. DNA polymerase and RNA polymerase are used to assemble DNA and RNA molecules, respectively, by ...
. It has been noted that Japanese encephalitis infects the lumen of the
endoplasmic reticulum The endoplasmic reticulum (ER) is a part of a transportation system of the eukaryote, eukaryotic cell, and has many other important functions such as protein folding. The word endoplasmic means "within the cytoplasm", and reticulum is Latin for ...
(ER) and rapidly accumulates substantial amounts of viral proteins. Based on the envelope gene, there are five genotypes (I–V). The Muar strain, isolated from a patient in
Malaya Malaya refers to a number of historical and current political entities related to what is currently Peninsular Malaysia in Southeast Asia: Political entities * British Malaya (1826–1957), a loose collection of the British colony of the Straits ...
in 1952, is the prototype strain of genotype V. Genotype V is the earliest recognized ancestral strain. The first clinical reports date from 1870, but the virus appears to have evolved in the mid-16th century. Complete genomes of 372 strains of this virus have been sequenced as of 2024.


Diagnosis

Japanese encephalitis is diagnosed by commercially available tests detecting JE virus-specific IgM antibodies in serum and/or
cerebrospinal fluid Cerebrospinal fluid (CSF) is a clear, colorless Extracellular fluid#Transcellular fluid, transcellular body fluid found within the meninges, meningeal tissue that surrounds the vertebrate brain and spinal cord, and in the ventricular system, ven ...
, for example by IgM capture
ELISA The enzyme-linked immunosorbent assay (ELISA) (, ) is a commonly used analytical biochemistry assay, first described by Eva Engvall and Peter Perlmann in 1971. The assay is a solid-phase type of enzyme immunoassay (EIA) to detect the presence of ...
. 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. Patients with JE virus IgM antibodies should have confirmatory neutralizing antibody testing. Confirmatory testing in the US is available only at the CDC and a few specialized reference laboratories. In fatal cases, nucleic acid amplification and virus culture of autopsy tissues can be useful. Viral antigens can be shown in tissues by indirect fluorescent antibody staining.


Prevention

Infection with Japanese encephalitis confers lifelong
immunity Immunity may refer to: Medicine * Immunity (medical), resistance of an organism to infection or disease * ''Immunity'' (journal), a scientific journal published by Cell Press Biology * Immune system Engineering * Radiofrequence immunity ...
. There are currently three
vaccines A vaccine is a biological preparation that provides active acquired immunity to a particular infectious or malignant disease. The safety and effectiveness of vaccines has been widely studied and verified. A vaccine typically contains an ag ...
available: SA14-14-2, IXIARO (IC51, also marketed in Australia, New Zealand as JESPECT and India as JEEV) and ChimeriVax-JE (marketed as IMOJEV). All current vaccines are based on the genotype III virus. A
formalin Formaldehyde ( , ) (systematic name methanal) is an organic compound with the chemical formula and structure , more precisely . The compound is a pungent, colourless gas that polymerises spontaneously into paraformaldehyde. It is stored as ...
-inactivated mouse-brain-derived vaccine was first produced in Japan in the 1930s and validated for use in Taiwan in the 1960s and Thailand in the 1980s. The widespread use of vaccines and
urbanization Urbanization (or urbanisation in British English) is the population shift from Rural area, rural to urban areas, the corresponding decrease in the proportion of people living in rural areas, and the ways in which societies adapt to this change. ...
has led to control of the disease in Japan and Singapore. The high cost of this vaccine, which is grown in live mice, means that poorer countries could not afford to give it as part of a routine immunization program. The most common adverse effects are redness and pain at the injection site. Uncommonly, an
urticarial Hives, also known as urticaria, is a kind of skin rash with red or flesh-colored, raised, itchy bumps. Hives may burn or sting. The patches of rash may appear on different body parts, with variable duration from minutes to days, and typically ...
reaction can develop about four days after injection. Vaccines produced from mouse brain have a risk of
autoimmune In immunology, autoimmunity is the system of immune responses of an organism against its own healthy cells, tissues and other normal body constituents. Any disease resulting from this type of immune response is termed an " autoimmune disease" ...
neurological complications of around 1 per million vaccinations. However where the vaccine is not produced in mouse brains but
in vitro ''In vitro'' (meaning ''in glass'', or ''in the glass'') Research, studies are performed with Cell (biology), cells or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in ...
using
cell culture Cell culture or tissue culture is the process by which cell (biology), cells are grown under controlled conditions, generally outside of their natural environment. After cells of interest have been Cell isolation, isolated from living tissue, ...
there are few adverse effects compared to
placebo A placebo ( ) can be roughly defined as a sham medical treatment. Common placebos include inert tablets (like sugar pills), inert injections (like saline), sham surgery, and other procedures. Placebos are used in randomized clinical trials ...
, the main side effects being headache and
myalgia Myalgia or muscle pain is a painful sensation evolving from muscle tissue. It is a symptom of many diseases. The most common cause of acute myalgia is the overuse of a muscle or group of muscles; another likely cause is viral infection, espec ...
. The neutralizing
antibody An antibody (Ab) or immunoglobulin (Ig) is a large, Y-shaped protein belonging to the immunoglobulin superfamily which is used by the immune system to identify and neutralize antigens such as pathogenic bacteria, bacteria and viruses, includin ...
persists in the circulation for at least two to three years, and perhaps longer. The total duration of protection is unknown, but because there is no firm evidence for protection beyond three years, boosters are recommended every 11 months for people who remain at risk. Some data are available regarding the interchangeability of other JE vaccines and IXIARO.


Treatment

There is no specific treatment for Japanese encephalitis and treatment is supportive, with assistance given for
feeding Eating (also known as consuming) is the ingestion of food. In biology, this is typically done to provide a heterotrophic organism with energy and nutrients and to allow for growth. Animals and other heterotrophs must eat in order to survive – ...
,
breathing Breathing (spiration or ventilation) is the rhythmical process of moving air into ( inhalation) and out of ( exhalation) the lungs to facilitate gas exchange with the internal environment, mostly to flush out carbon dioxide and bring in oxy ...
or
seizure A seizure is a sudden, brief disruption of brain activity caused by abnormal, excessive, or synchronous neuronal firing. Depending on the regions of the brain involved, seizures can lead to changes in movement, sensation, behavior, awareness, o ...
control as required. Raised
intracranial pressure Intracranial pressure (ICP) is the pressure exerted by fluids such as cerebrospinal fluid (CSF) inside the skull and on the brain tissue. ICP is measured in millimeters of mercury ( mmHg) and at rest, is normally 7–15 mmHg for a supine adu ...
may be managed with
mannitol Mannitol is a type of sugar alcohol used as a sweetener and medication. It is used as a low calorie sweetener as it is poorly absorbed by the intestines. As a medication, it is used to decrease pressure in the eyes, as in glaucoma, and to l ...
. There is no
transmission Transmission or transmit may refer to: Science and technology * Power transmission ** Electric power transmission ** Transmission (mechanical device), technology that allows controlled application of power *** Automatic transmission *** Manual tra ...
from person to person and therefore patients do not need to be isolated. A breakthrough in the field of Japanese encephalitis therapeutics is the identification of
macrophage Macrophages (; abbreviated MPhi, φ, MΦ or MP) are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris and foreign substances, which do not have proteins that ...
receptor involvement in the disease severity. A recent report of an Indian group demonstrates the involvement of
monocyte Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and monocyte-derived dendritic cells. As a part of the vertebrate innate immune system monocytes also ...
and
macrophage Macrophages (; abbreviated MPhi, φ, MΦ or MP) are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris and foreign substances, which do not have proteins that ...
receptor
CLEC5A C-type lectin domain family 5 member A (CLEC5A), also known as C-type lectin superfamily member 5 (CLECSF5) and myeloid DAP12-associating lectin 1 (MDL-1) is a C-type lectin that in humans is encoded by the ''CLEC5A'' gene. Structurally MDL-1 is ...
in severe inflammatory response in Japanese encephalitis infection of the brain. This transcriptomic study provides a hypothesis of
neuroinflammation Neuroinflammation is inflammation of the nervous tissue. It may be initiated in response to a variety of cues, including infection, traumatic brain injury,Ebert SE, Jensen P, Ozenne B, Armand S, Svarer C, Stenbaek DS ''et al.'' Molecular imaging of ...
and a new lead in development of appropriate therapies for Japanese encephalitis. The effectiveness of
intravenous immunoglobulin Immunoglobulin therapy is the use of a mixture of antibodies (normal human immunoglobulin) to treat several health conditions. These conditions include primary immunodeficiency, immune thrombocytopenic purpura, chronic inflammatory demyelinat ...
for Japanese encephalitis is unclear due to a paucity of evidence. Intravenous immunoglobulin for Japanese encephalitis appeared to have no benefit.


Epidemiology

Japanese encephalitis (JE) is the leading cause of viral encephalitis in
Asia Asia ( , ) is the largest continent in the world by both land area and population. It covers an area of more than 44 million square kilometres, about 30% of Earth's total land area and 8% of Earth's total surface area. The continent, which ...
, with up to 70,000 cases reported annually. Of those with symptoms case-fatality rates range from 20% to 30%. Rare outbreaks in U.S. territories in the Western Pacific have also occurred. Residents of rural areas in endemic locations are at highest risk; Japanese encephalitis does not usually occur in urban areas. Countries that have had major epidemics in the past, but which have controlled the disease primarily by vaccination, include
China China, officially the People's Republic of China (PRC), is a country in East Asia. With population of China, a population exceeding 1.4 billion, it is the list of countries by population (United Nations), second-most populous country after ...
,
South Korea South Korea, officially the Republic of Korea (ROK), is a country in East Asia. It constitutes the southern half of the Korea, Korean Peninsula and borders North Korea along the Korean Demilitarized Zone, with the Yellow Sea to the west and t ...
,
Singapore Singapore, officially the Republic of Singapore, is an island country and city-state in Southeast Asia. The country's territory comprises one main island, 63 satellite islands and islets, and one outlying islet. It is about one degree ...
,
Japan Japan is an island country in East Asia. Located in the Pacific Ocean off the northeast coast of the Asia, Asian mainland, it is bordered on the west by the Sea of Japan and extends from the Sea of Okhotsk in the north to the East China Sea ...
,
Taiwan Taiwan, officially the Republic of China (ROC), is a country in East Asia. The main geography of Taiwan, island of Taiwan, also known as ''Formosa'', lies between the East China Sea, East and South China Seas in the northwestern Pacific Ocea ...
and
Thailand Thailand, officially the Kingdom of Thailand and historically known as Siam (the official name until 1939), is a country in Southeast Asia on the Mainland Southeast Asia, Indochinese Peninsula. With a population of almost 66 million, it spa ...
. Other countries that still have periodic epidemics include
Vietnam Vietnam, officially the Socialist Republic of Vietnam (SRV), is a country at the eastern edge of mainland Southeast Asia, with an area of about and a population of over 100 million, making it the world's List of countries and depende ...
,
Cambodia Cambodia, officially the Kingdom of Cambodia, is a country in Southeast Asia on the Mainland Southeast Asia, Indochinese Peninsula. It is bordered by Thailand to the northwest, Laos to the north, and Vietnam to the east, and has a coastline ...
,
Myanmar Myanmar, officially the Republic of the Union of Myanmar; and also referred to as Burma (the official English name until 1989), is a country in northwest Southeast Asia. It is the largest country by area in Mainland Southeast Asia and has ...
,
India India, officially the Republic of India, is a country in South Asia. It is the List of countries and dependencies by area, seventh-largest country by area; the List of countries by population (United Nations), most populous country since ...
,
Nepal Nepal, officially the Federal Democratic Republic of Nepal, is a landlocked country in South Asia. It is mainly situated in the Himalayas, but also includes parts of the Indo-Gangetic Plain. It borders the Tibet Autonomous Region of China Ch ...
, and
Malaysia Malaysia is a country in Southeast Asia. Featuring the Tanjung Piai, southernmost point of continental Eurasia, it is a federation, federal constitutional monarchy consisting of States and federal territories of Malaysia, 13 states and thre ...
. Japanese encephalitis has been reported in the
Torres Strait Islands The Torres Strait Islands are an archipelago of at least 274 small islands in the Torres Strait, a waterway separating far northern continental Australia's Cape York Peninsula and the island of New Guinea. They span an area of , but their tot ...
, and two fatal cases were reported in mainland northern
Australia Australia, officially the Commonwealth of Australia, is a country comprising mainland Australia, the mainland of the Australia (continent), Australian continent, the island of Tasmania and list of islands of Australia, numerous smaller isl ...
in 1998. There were reported cases in
Kachin State Kachin State (; Jingpho language, Kachin: ) is the northernmost administrative divisions of Myanmar, state of Myanmar. It is bordered by China to the north and east (Tibet Autonomous Region, Tibet and Yunnan, respectively), Shan State to the sou ...
, Myanmar in 2013. There were 116 deaths reported in Odisha's Malkangiri district of India in 2016. In 2022, the notable increase in the distribution of the virus in Australia due to
climate change Present-day climate change includes both global warming—the ongoing increase in Global surface temperature, global average temperature—and its wider effects on Earth's climate system. Climate variability and change, Climate change in ...
became a concern to health officials as the population has limited immunity to the disease and the presence of large numbers of farmed and feral pigs could act as reservoirs for the virus. In February 2022, Japanese encephalitis was detected and confirmed in piggeries in Victoria, Queensland and New South Wales. On 4 March, cases were detected in South Australia. By October 2022, the outbreak in eastern mainland Australia had caused 42 symptomatic human cases of the disease, resulting in seven deaths. In 2025, further cases and a fatality were recorded in south-eastern Australia. Humans, cattle, and horses are dead-end hosts as the disease manifests as fatal encephalitis. Pigs act as amplifying hosts and have a vital role in the epidemiology of the disease. Infection in swine is asymptomatic, except in pregnant sows when abortion and fetal abnormalities are common sequelae. The most important vector is ''
Culex tritaeniorhynchus ''Culex (Culex) tritaeniorhynchus'' is a species of mosquito and is the main vector of the disease Japanese encephalitis. This mosquito is a native of northern Asia, and parts of Africa (northeast and sub-Saharan). Females target large animal ...
'', which feeds on cattle in preference to humans. The natural hosts of the Japanese encephalitis virus are birds, not humans, and many believe the virus will never be eliminated. In November 2011, the Japanese encephalitis virus was reported in '' Culex bitaeniorhynchus'' in
South Korea South Korea, officially the Republic of Korea (ROK), is a country in East Asia. It constitutes the southern half of the Korea, Korean Peninsula and borders North Korea along the Korean Demilitarized Zone, with the Yellow Sea to the west and t ...
. Recently, whole genome
microarray A microarray is a multiplex (assay), multiplex lab-on-a-chip. Its purpose is to simultaneously detect the expression of thousands of biological interactions. It is a two-dimensional array on a Substrate (materials science), solid substrate—usu ...
research of
neurons A neuron (American English), neurone (British English), or nerve cell, is an membrane potential#Cell excitability, excitable cell (biology), cell that fires electric signals called action potentials across a neural network (biology), neural net ...
infected with the Japanese encephalitis virus has shown that neurons play an important role in their own defense against Japanese encephalitis infection. Although this challenges the long-held belief that neurons are immunologically quiescent, an improved understanding of the proinflammatory effects responsible for immune-mediated control of viral infection and neuronal injury during Japanese encephalitis infection is an essential step for developing strategies for limiting the severity of CNS disease. A number of drugs have been investigated to either reduce viral replication or provide neuroprotection in cell lines or studies in mice. None are currently advocated in treating human patients. * The use of
rosmarinic acid Rosmarinic acid, named after rosemary (''Salvia rosmarinus'' Spenn.), is a polyphenol constituent of many culinary herbs, including rosemary (''Salvia rosmarinus'' L.), perilla (''Perilla frutescens'' L.), sage (''Salvia officinalis'' L.), min ...
,
arctigenin Arctigenin is a lignan found in certain plants of the Asteraceae, including the greater burdock (''Arctium lappa'') and ''Saussurea heteromalla''. It has shown antiviral and anticancer effects in vitro. It is the aglycone of arctiin. The use of ...
, and
oligosaccharides An oligosaccharide (; ) is a saccharide polymer containing a small number (typically three to ten) of monosaccharides (simple sugars). Oligosaccharides can have many functions including cell recognition and cell adhesion. They are normally presen ...
with
degree of polymerization The degree of polymerization, or DP, is the number of structural unit, monomeric units in a macromolecule or polymer or oligomer molecule. For a homopolymer, there is only one type of monomeric unit and the ''number-average'' degree of polymeriza ...
6 from ''
Gracilaria ''Gracilaria'', also known as irish moss or ogonori, is a genus of red algae in the family Gracilariaceae. It is notable for its economic importance as an agarophyte meaning that it is used to make agar, as well as its use as a food for humans ...
'' sp. or ''
Monostroma ''Monostroma'' is a genus of marine green algae (seaweed) in the family Monostromataceae. As the name suggests, algae of this genus are monostromatic (single cell layered). '' Monostroma kuroshiense'', an algae of this genus, is commercially cu ...
'' ''nitidum'' is effective in a mouse model of Japanese encephalitis. *
Curcumin Curcumin is a bright yellow chemical produced by plants of the ''Curcuma longa'' species. It is the principal curcuminoid of turmeric (''Curcuma longa''), a member of the ginger family, Zingiberaceae. It is sold as a herbal supplement, cosmetic ...
has been shown to impart neuroprotection against Japanese encephalitis infection in an in vitro study. Curcumin possibly acts by decreasing cellular reactive oxygen species levels, restoration of cellular
membrane integrity The cell membrane (also known as the plasma membrane or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of a cell from the outside environment (the extrac ...
, decreasing
pro-apoptotic Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...
signaling molecules, and modulating cellular levels of stress-related proteins. It has also been shown that the production of infective viral particles from previously infected
neuroblastoma Neuroblastoma (NB) is a type of cancer that forms in certain types of nerve tissue. It most frequently starts from one of the adrenal glands but can also develop in the head, neck, chest, abdomen, or Vertebral column, spine. Symptoms may include ...
cells is reduced, which is achieved by inhibition of the
ubiquitin-proteasome system Proteasomes are essential protein complexes responsible for the degradation of proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that help such reactions are called proteases. Proteasomes are found inside all e ...
. *
Minocycline Minocycline, sold under the brand name Minocin among others, is a tetracycline antibiotic medication used to treat a number of bacterial infections such as some occurring in certain forms of pneumonia. It is generally (but not always) less pre ...
in mice resulted in marked decreases in the levels of several markers, viral titer, and the level of proinflammatory mediators and also prevented
blood–brain barrier The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that regulates the transfer of solutes and chemicals between the circulatory system and the central nervous system ...
damage.


Evolution

It is theorized that the virus may have originated from an ancestral virus in the mid-1500s in the
Malay Archipelago The Malay Archipelago is the archipelago between Mainland Southeast Asia and Australia, and is also called Insulindia or the Indo-Australian Archipelago. The name was taken from the 19th-century European concept of a Malay race, later based ...
region and evolved there into five different genotypes that spread across Asia. The mean evolutionary rate has been estimated to be 4.35 (range: 3.49 to 5.30) nucleotide substitutions per site per year.


Outbreak history

The clinical recognition and recording of Japanese encephalitis (JE) trace back to the 19th century when recurring encephalitis outbreaks were noted during Japan’s summer months. The first clinical case of JE was documented in 1871 in Japan. However, it wasn’t until 1924, during a major outbreak involving over 6,000 cases, that JE’s severity and potential for widespread impact became apparent. Subsequent outbreaks in Japan were recorded in 1927, 1934, and 1935, each contributing to a deeper understanding of the disease and its transmission patterns. The spread of JE extended beyond Japan over the following decades, impacting numerous countries across Asia. On the Korean Peninsula, the first JE cases were reported in 1933, and mainland China documented its initial cases in 1940. The virus reached the Philippines in the early 1950s and continued its westward spread, with Pakistan recording cases in 1983, marking JE’s furthest westward extension. By 1995, JE cases had reached Papua New Guinea and northern Australia (specifically the Torres Strait), representing the virus's southernmost range. According to the World Health Organization (WHO), JE is also endemic to the Western Pacific Islands, but cases are rare, possibly due to an enzootic cycle that does not sustain continuous viral transmission. Epidemics in these islands likely occur only when the virus is introduced from other JE-endemic regions. In the early 2020s, JE had become endemic in the southern parts of Australia with locally contracted human fatalities from the disease being recorded in these areas for the first time.


References


External links

* * * * * Erratum in: MMWR Morb Mortal Wkly Rep. 2017 Jun 23;66(24):653. * {{DEFAULTSORT:Japanese Encephalitis Swine diseases Tropical diseases Viral encephalitis Wikipedia medicine articles ready to translate Vaccine-preventable diseases