Japanese encephalitis virus

Japanese Encephalitis Virus (JE)
Scientific classification
Phylum: Flaviviridae Genus: Flavivirus Species: Japanese encephalitis virus

General information and Symptoms

Originally named Japanese B encephalitis virus in order to aid in distinguishing this species of encephalitis with an agent causing Von Economo's type A encephalitis species, it has since been modified to a more simple name without the B. Japanese encephalitis (JE) is a virus that infects the central nervous system, which consists of the brain and spinal cord. It may range from mild to acute infection. Mild Symptoms include flu-like illness that may include:

• Headaches
• Agitation
• Fatigue
• Nausea
• Vomiting
• Chills
• Fever

A severe infection symptoms may include mild symptoms as well as:

• Rapid onset
• Stupor
• Disorientation
• Coma
• Tremors
• Occasional convulsions (occurs more often in infants)
• Spastic paralysis
• Flaccid paralysis (occurs in rare instances)

As the infection progresses without treatment it may reach an acute level. When such a high level of infection occurs, there are serious side affects which include moderate brain damage, varying degrees of paralysis, as well as seizures and death.

Transmission and Epidemiology

Japanese encephalitis virus is an arthropod-borne virus called an arbovirus. The vector that spreads this arbovirus is a mosquito.

The Culicine mosquito from the genus Culex are responsible for many diseases such as Dengue fever, Yellow fever, Venezuelan equine encephalitis, as well as Japanese encephalitis. Their eggs are laid in still water that is either clean water or contaminated with organic waste. These eggs are also resistant to desiccation for several months. The first reported suspicion of JE was within the last century and first documented in horses as well as humans in Japan, which explains the origin of its name. In 1924 it was first isolated in rabbits from human brain tissue. The specific species of Culex mosquitos linked to the JE virus is the C. tritaeniorhynchus. Infection into a healthy human begins with an infected mosquito. This mosquito lands on a human's skin and bites the victim. This process transmits the virus into the bloodstream and is able to cause viraemia. The initial spread of the virus from the bite site allows it access to the rest of the body through the circulatory system.

The mosquito can be infected with the virus by feeding on infected humans, horses, and cattle. These are all hosts that are dead-end resulting in high rates of fatality. These hosts do not transmit the disease as readily, however, swine are largely asymptomatic hosts. The only exception is the high abnormalities and abortions of fetal swine in pregnant sows. Because of pigs' lack of symptoms mosquitos are more likely to feed on a seemingly healthy pig. This causes the mosquito to become a vector. The cochlea, a part of the ear, is the primary site of infection in humans. The species that is most significant in the transmission of the JE virus, C. tritaeniorhynchus, typically feeds on bovine animals. Despite suggestions of the spraying of pesticides to kill mosquito vectors and moving swine herds to more rural areas away from humans there is a belief among many that Japanese encephalitis will not be eliminated. The reason is because birds are the unaccounted for natural host for the virus. JE is the most prevalent of viral encephalitis in Asia with 30,000-50,000 cases reported each year; of those cases, fatalities fall between 0.3-60%. There is a high risk of contracting this virus in rural areas that are endemic to the virus. Some cities have had success in conquering major epidemic outbreaks of JE, such as Japan, Korea, Thailand, Taiwan, and China. They have done this with vaccinations. While these countries, to a certain extent, have successfully contained this virus, other endemic regions continue to have periodic outbreaks. The countries that fall into this category are Malaysia, Myanmar, India, Nepal, Cambodia, and Vietnam. Despite JE occurring mostly in Asia, 1998 had the first case report of 2 fatalities of JE on the mainland of northern Australia.

Pathology

Japanese Encephalitis is antigenically linked to several other flaviviruses and belongs to the family Flaviviridae." An Antigen is a substance that causes the body to illicit an immune response such as the production of antibody through the introduction of a foreign substance such as a virus or bacteria into the body. In the autopsies performed on 20 persons who died in the 1924 encephalitis epidemic of Tokyo, Nagano, and Shikoku districts of Japan there were 9 acute, 8 subacute, and 3 chronic. An acute case typically lasts between 1 and 2 weeks, subacute would continue for 2 or more weeks while chronic cases are several months to several years with some permanent sequelae. In this studyboth qualitative and quantitative approaches were used. The focus of this study was the inflammatory changes of the central nervous system (CNS). In acute cases there were areas of degenerative tissue, severe damage of the nerve cells, neuronophagia which is the phagocytosis of infected neurons, perivascular cuffing, and injury to the parenchyma. The grey matter of the brain is where all these changes occur. Lesions are usually found in the diencephalon and mesencephalon, with the next highest frequency found in the brain stem, cerebral cortex and the cerebellum. There may also be slight changes seen in the leptomeninges of the spinal cord. In subacute cases, changes are found to be less than that of acute cases. Inflammation is still found in the mesencephalon, diencephalon and brain stem but, is rarely found in the cerebral cortex, cerebellum, meninges, and spinal cord. The most dominant changes in this stage are degeneration of nerve cells, even to the point of loss, and proliferation of glial cells. Lesions also are more localized in subacute cases. Hylalin thrombus formation, a blood clot, may be found in both acute and subacute stages. Chronic stages exhibit localized necrosis or softening seen in the mesencephalon, diencephalon, and brain stem but is most often in the substantia nigra. There is also degeneration of nervous tissue that may lead to complete loss, fibrous thickening of the vascular walls, and marked post-inflammatory organization. Overall, there are cellular changes in the reticulo-endothelial system of the visceral organs. Studies have shown that the cells seem to be undergoing karyolysis (dissolution of chromatin by DNAase in a dying cell or autolysis (cell suicide). Karyolysis is the chromatin matter dissolution by DNAase by a dying cell. Autolysis and karyolysis are most often seen in acute cases.

Ecology

Japanese encephalitis is a disease that is the major cause of viral encephalitis in southeast Asia, with the number of infected cases greater than 50,000 annually In Malaysia, JE is endemic, with the first case reported during World War II and published in 1951. The number of cases reported was 273 from 1985-1993, although this number does not take into account undocumented cases. JE is also an endemic disease in Japan. The Japanese climate, where the first case of JE was reported, is temperate allowing for variations as you travel north to south. It is a country of over three thousand islands that is home to one of the most densely populated people in the world. The estimated population is 127.3 million people with the most dominant ethnic group being the Yamato people. Due to steep elevations , climate and earthquakes about 70-80% of the country is forested, mountainous and not ideal for agricultural use, living, or industrial use. The earthquakes result from Japan's positioning on the Pacific Ring of Fire, which lie at the juncture of three tectonic plates. It is known that Ardeid wading birds are the primary maintenance hosts, swine are the main amplifying hosts, and the Culex mosquitos are the primary vectors. in 1995 was the first record of JE virus in northern Australia and by late 1998 the swine, which previously lived in pen's located in close proximity to the house, were linked to an early 1998 outbreak that was widespread on the Bandu island. The mosquito responsible as the vector of JE virus in this area is the Cx.sitiens subgroup. There are also a percentage of mosquitos from the Culex genus that feed on birds such as viremic egrets and herons which are found on the Badu island. Culex moquitoes tend to breed in ground pools such as flooded rice fields during dusk. This is perfect for Asia that experiences a rainy season that increases the risk of JE infection because of the heavy rainfall and irrigation.

Structure and Metabolism

JE is an enveloped virus that has positive sense single stranded RNA genome (+ssRNA). The outer envelope aids in the viral entry to cell through its composition, it is composed of (E) protein which is a protective polypeptide. The structure is packaged in a capsid formed by the capsid protein. The genome encodes several structural proteins:

• NS1
• NS2 a and b
• NS3(a putative helicase)
• N4a
• NS4b
• NS5(a viral polymerase)

This type of the encephalitis virus causes rapid and significant build up of viral proteins. Incubation period is between 5 to 15 days with most cases expressing no symptoms, only 1 in 250 infected individuals developing encephalitis.

Current Research

In 1995 an emergence of JE virus was seen in northern Australia. A study was done to see how removing domesticated pigs further from heavily populated areas on Badu Island in the Torres straight would affect the mosquito infection rates. The reason why this area was chosen was due to its being the most infected area for humans, swine and other animals. A link was found between intense transmission and the domesticated pigs that were housed in close proximity on the same grounds as where their human owner's dwelling place. In 1998 there was a widespread outbreak that led to an approximately 2.5 km move of all domesticated pigs to a piggery. This immediately led to a reduction in the Culex mosquitos (specifically the Cx.sitiens) to feed on the infected or potentially infected pigs. The conclusion to this study indicated that despite moving the infected pigs away from the immediate areas where the mosquito vectors could be infected by biting those pigs it did not negate JE viral risk for humans. This is because the pigs that were removed from that area could be bitten by the same mosquito vectors from other areas and travel to populated areas. The mean flight distance for a Culex mosquito is 4.4km, which is further than the 2.5 km the pigs were moved for this study, the greatest distance a female mosquito of this genus can travel is up to 12 km. The recommendation in this case is to move domesticated infected pigs further than 5 km away from any human inhabitant. Also an important aspect of this study is that 23% of blood meals for the Culex mosquito are birds such as the herons and egrets. Both populations reside on Badu Island.

In King George's Medical College located in Lucknow, India scientists used the high correlation between those who recovered or were infected with JE and Parkinson's disease. A clinical study was performed on patients with lesions predominantly in the substantia nigra due to JE infections. The patients were from areas where JE is considered an endemic and 5 patients of the 52 were selected because of the lesions that were found only in the substantia nigra on MRI. This is unique because lesions are usually in a wide range of areas within the brain and brain stem. Before this study there was no reported isolation of lesions in this area of the brain. After extensive testing and observation, it was shown that features of Parkinson's were present. Some of them included mask-like face, tremors, bradykinesia, postural instability when walking, and glabellar tap sign. Of the 5 patients only 3 exhibited mutism that was reversible, during the acute phase of JE. The normal symptoms of JE viral infection also accompany the Parkinsonian features from this study. Over time the symptoms of Parkinson's were either completely recovered from, which was found in 3 patients who were followed for over a year, while the other 2 made substantial recovery within 2 months of regaining consciousness. The conclusion to this study stated that there was a link for some patients who suffer from acute encephalic illness from Japanese encephalitis, where lesions are mostly found in the subtantia nigra of the brain. This study is also significant in that despite some viral infections being directly linked to Parkinson's disease, this is the first to be linked to the lesions that are found in a specific region causing Parkinsonian features.

Previously the JE-VAX vaccine was used to reduce symptomatic infections, which are rare, by 80-90%. This vaccine requires three 1.0 ml subcutaneous injections on specific days, for infants 1-2 years of age the dose is reduced to 0.5 ml. The days that are suggested for the 3 injections are 0, 7, 3 and the immunization is required at least 10 days before departure. About 20% of these people have mild allergic reactions that range from discomfort at the site of injection , muscle aches, to vomiting, and dizziness. A very small percentage, about 0.6%, develop severe allergic reactions such as angioedema, respiratory distress and anaphylaxis. This may occur up to a week after the injection has been administered. A high correlation between those with a history of hives and severe allergic reactions to JE-VAX have been found. These reactions may occur after any of the three dose course and there is no recommendation on boosters other than waiting after 3 years to do so. In the United States, summer 2009 a new alternative is taking the place of JE-VAX, which is no longer being produced. IXIARO, despite not having any official recommendations at this time, in March 2009 was approved by the Food and Drug Administration and seems to be more tolerable than JE-VAX. It also only requires 2 injections versus the 3 that was prescribed for JE-VAX.