Japanese encephalitis | |
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Other names | Japanese B encephalitis |
The geographic distribution of Japanese encephalitis (dark green) | |
Specialty | Infectious disease |
Symptoms | Headache, fever, vomiting, confusion, seizures [1] |
Usual onset | 5 to 15 days after infection [1] |
Causes | Japanese encephalitis virus (spread by mosquitoes) |
Diagnostic method | Blood or cerebrospinal fluid testing [2] |
Prevention | Japanese encephalitis vaccine, avoiding mosquito bites [2] |
Treatment | Supportive care [1] |
Prognosis | Permanent neurological problems occur in up to half of survivors [2] |
Frequency | 68,000 [2] |
Deaths | 17,000 [2] |
Japanese encephalitis (JE) is an infection of the brain caused by the Japanese encephalitis virus (JEV). [3] While most infections result in little or no symptoms, occasional inflammation of the brain occurs. [3] In these cases, symptoms may include headache, vomiting, fever, confusion and seizures. [1] This occurs about 5 to 15 days after infection. [1]
JEV is generally spread by mosquitoes, specifically those of the Culex type. [2] Pigs and wild birds serve as a reservoir for the virus. [2] The disease occurs mostly outside of cities. [2] Diagnosis is based on blood or cerebrospinal fluid testing. [2]
Prevention is generally achieved with the Japanese encephalitis vaccine, which is both safe and effective. [2] Other measures include avoiding mosquito bites. [2] Once infected, there is no specific treatment, with care being supportive. [1] This is generally carried out in a hospital. [1] Permanent problems occur in up to half of people who recover from JE. [2]
The disease primarily occurs in East and Southeast Asia as well as the Western Pacific. [2] About 3 billion people live in areas where the disease occurs. [2] About 68,000 symptomatic cases occur a year, with about 17,000 deaths. [2] Often, cases occur in outbreaks. [2] The disease was first described in Japan in 1871. [2] [4]
The Japanese encephalitis virus (JEV) has an incubation period of 2 to 26 days. [5] The vast majority of infections are asymptomatic: only 1 in 250 infections develop into encephalitis. [6]
Severe rigors may mark the onset of this disease in humans. Fever, headache and malaise are other non-specific symptoms of this disease which may last for a period of between 1 and 6 days. Signs which develop during the acute encephalitic stage include neck rigidity, cachexia, hemiparesis, convulsions and a raised body temperature between 38–41 °C (100.4–105.8 °F). 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 disorders develop in 40% of those who survive with lifelong neurological defects such as deafness, emotional lability and hemiparesis occurring in those who had central nervous system involvement. [7]
Increased microglial activation following Japanese encephalitis infection has been found to influence the outcome of viral pathogenesis. Microglia are the resident immune cells 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, excitatory neurotransmitters, prostaglandin, reactive oxygen, and nitrogen species are secreted by activated microglia.[ citation needed ]
In a murine model of JE, it was found that in the hippocampus and the striatum, the number of activated microglia was more than anywhere else in the brain, closely followed by that in the thalamus. In the cortex, the number of activated microglia was significantly less when compared to other regions of the mouse brain. An overall induction of differential expression of proinflammatory cytokines and chemokines from different brain regions during a progressive Japanese encephalitis infection was also observed.[ citation needed ]
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 nonregenerating 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. [8] In animals, key signs include infertility and abortion in pigs, neurological disease in horses, and systemic signs including fever, lethargy and anorexia. [9]
It is a disease caused by the mosquito-borne Japanese encephalitis virus (JEV). [10]
Japanese encephalitis virus | |
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Flavivirus structure and genome | |
Virus classification | |
(unranked): | Virus |
Realm: | Riboviria |
Kingdom: | Orthornavirae |
Phylum: | Kitrinoviricota |
Class: | Flasuviricetes |
Order: | Amarillovirales |
Family: | Flaviviridae |
Genus: | Flavivirus |
Species: | Japanese encephalitis virus |
JEV is a virus from the family Flaviviridae , part of the Japanese encephalitis serocomplex of 9 genetically and antigenically related viruses, some which are particularly severe in horses, and four known to infect humans including West Nile virus. [11] The enveloped virus is closely related to the West Nile virus and the St. Louis encephalitis virus. The positive sense single-stranded RNA genome is packaged in the capsid which is formed by the capsid protein. The outer envelope is formed by envelope protein and is the protective antigen. It aids in entry of the virus into the cell. The genome also encodes several nonstructural proteins (NS1, NS2a, NS2b, NS3, N4a, NS4b, NS5). NS1 is produced as a secretory form also. NS3 is a putative helicase, and NS5 is the viral polymerase. It has been noted that Japanese encephalitis infects the lumen of the endoplasmic reticulum (ER) [12] [13] 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 in 1952, is the prototype strain of genotype V. Genotype V is the earliest recognized ancestral strain. [14] The first clinical reports date from 1870, but the virus appears to have evolved in the mid-16th century. Over sixty complete genomes of this virus had been sequenced by 2010.[ citation needed ]
Japanese encephalitis is diagnosed by commercially available tests detecting JE virus-specific IgM antibodies in serum and/or cerebrospinal fluid, for example by IgM capture ELISA. [15]
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. [16] 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 antigen can be shown in tissues by indirect fluorescent antibody staining. [9]
Infection with Japanese encephalitis confers lifelong immunity. There are currently three vaccines available: SA14-14-2, IXIARO (IC51, also marketed in Australia, New Zealand as JESPECT and India as JEEV [17] ) and ChimeriVax-JE (marketed as IMOJEV). [18] All current vaccines are based on the genotype III virus.[ citation needed ]
A formalin-inactivated mouse-brain-derived vaccine was first produced in Japan in the 1930s and was validated for use in Taiwan in the 1960s and in Thailand in the 1980s. The widespread use of vaccine and urbanization 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 have not been able to afford to give it as part of a routine immunization program. [10]
The most common adverse effects are redness and pain at the injection site. Uncommonly, an urticarial reaction can develop about four days after injection. Vaccines produced from mouse brain have a risk of autoimmune neurological complications of around 1 per million vaccinations. [19] However where the vaccine is not produced in mouse brains but in vitro using cell culture there are few adverse effects compared to placebo, the main side effects being headache and myalgia. [20]
The neutralizing antibody persists in the circulation for at least two to three years, and perhaps longer. [21] [22] The total duration of protection is unknown, but because there is no firm evidence for protection beyond three years, boosters are recommended every three years for people who remain at risk. [23] Furthermore, there are no data available regarding the interchangeability of other JE vaccines and IXIARO.[ citation needed ]
There is no specific treatment for Japanese encephalitis and treatment is supportive, [24] with assistance given for feeding, breathing or seizure control as required. Raised intracranial pressure may be managed with mannitol. [25] There is no transmission from person to person and therefore patients do not need to be isolated.[ citation needed ]
A breakthrough in the field of Japanese encephalitis therapeutics is the identification of macrophage receptor involvement in the disease severity. A recent report of an Indian group demonstrates the involvement of monocyte and macrophage receptor CLEC5A in severe inflammatory response in Japanese encephalitis infection of the brain. This transcriptomic study provides a hypothesis of neuroinflammation and a new lead in development of appropriate therapies for Japanese encephalitis. [26] [27]
The effectiveness of intravenous immunoglobulin for the management of encephalitis is unclear due to a lack of evidence. [28] Intravenous immunoglobulin for Japanese encephalitis appeared to have no benefit. [28]
Japanese encephalitis (JE) is the leading cause of viral encephalitis in Asia, with up to 70,000 cases reported annually. [29] Case-fatality rates range from 0.3% to 60% and depend on the population and age. 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.[ citation needed ]
Countries which have had major epidemics in the past, but which have controlled the disease primarily by vaccination, include China, South Korea, Singapore, Japan, Taiwan and Thailand. Other countries that still have periodic epidemics include Vietnam, Cambodia, Myanmar, India, Nepal, and Malaysia. Japanese encephalitis has been reported in the Torres Strait Islands, and two fatal cases were reported in mainland northern Australia in 1998. There were reported cases in Kachin State, Myanmar in 2013. There were 116 deaths reported in Odisha's Malkangiri district of India in 2016.[ citation needed ]
In 2022, the notable increase in distribution of the virus in Australia due to climate change 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. [7] 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. [30] [31]
Humans, cattle, and horses are dead-end hosts as the disease manifests as fatal encephalitis. Pigs act as an amplifying host and have a very important 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 , 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 therefore never be eliminated. [32] In November 2011, the Japanese encephalitis virus was reported in Culex bitaeniorhynchus in South Korea. [33]
Recently, whole genome microarray research of neurons 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. [34]
A number of drugs have been investigated to either reduce viral replication or provide neuroprotection in cell lines or studies upon mice. None are currently advocated in treating human patients.
It is theorized that the virus may have originated from an ancestral virus in the mid-1500s in the Malay Archipelago region and evolved there into five different genotypes which spread across Asia. [41] The mean evolutionary rate has been estimated to be 4.35×10−4 (range: 3.49×10−4 to 5.30×10−4) nucleotide substitutions per site per year. [41]
Dengue fever is a mosquito-borne tropical disease caused by the dengue virus. Symptoms typically begin 3 to 14 days after infection. These may include a high fever, headache, vomiting, muscle and joint pains, and a characteristic skin itching and skin rash. Recovery generally takes two to seven days. In a small proportion of cases, the disease develops into a more severe dengue hemorrhagic fever, resulting in bleeding, low levels of blood platelets and blood plasma leakage, or into dengue shock syndrome, where dangerously low blood pressure occurs.
Mumps is a viral disease caused by the mumps virus. Initial symptoms of mumps are non-specific and include fever, headache, malaise, muscle pain, and loss of appetite. These symptoms are usually followed by painful swelling of the parotid glands, called parotitis, which is the most common symptom of a mumps infection. Symptoms typically occur 16 to 18 days after exposure to the virus and resolve within two weeks. About one third of infections are asymptomatic.
Rotaviruses are the most common cause of diarrhoeal disease among infants and young children. Nearly every child in the world is infected with a rotavirus at least once by the age of five. Immunity develops with each infection, so subsequent infections are less severe. Adults are rarely affected. Rotavirus is a genus of double-stranded RNA viruses in the family Reoviridae.There are nine species of the genus, referred to as A, B, C, D, F, G, H, I and J. Rotavirus A, the most common species, causes more than 90% of rotavirus infections in humans.
Erythema infectiosum, fifth disease, or slapped cheek syndrome is one of several possible manifestations of infection by parvovirus B19. Fifth disease typically presents as a rash and is more common in children. While parvovirus B19 can affect humans of all ages, only two out of ten individuals will present with physical symptoms.
Hepatitis A is an infectious disease of the liver caused by Hepatovirus A (HAV); it is a type of viral hepatitis. Many cases have few or no symptoms, especially in the young. The time between infection and symptoms, in those who develop them, is 2–6 weeks. When symptoms occur, they typically last 8 weeks and may include nausea, vomiting, diarrhea, jaundice, fever, and abdominal pain. Around 10–15% of people experience a recurrence of symptoms during the 6 months after the initial infection. Acute liver failure may rarely occur, with this being more common in the elderly.
Hepatitis E is inflammation of the liver caused by infection with the hepatitis E virus (HEV); it is a type of viral hepatitis. Hepatitis E has mainly a fecal-oral transmission route that is similar to hepatitis A, although the viruses are unrelated. In retrospect, the earliest known epidemic of hepatitis E occurred in 1955 in New Delhi, but the virus was not isolated until 1983 by Russian scientists investigating an outbreak in Afghanistan. HEV is a positive-sense, single-stranded, nonenveloped, RNA icosahedral virus and one of five known human hepatitis viruses: A, B, C, D, and E.
Flavivirus, renamed Orthoflavivirus in 2023, is a genus of positive-strand RNA viruses in the family Flaviviridae. The genus includes the West Nile virus, dengue virus, tick-borne encephalitis virus, yellow fever virus, Zika virus and several other viruses which may cause encephalitis, as well as insect-specific flaviviruses (ISFs) such as cell fusing agent virus (CFAV), Palm Creek virus (PCV), and Parramatta River virus (PaRV). While dual-host flaviviruses can infect vertebrates as well as arthropods, insect-specific flaviviruses are restricted to their competent arthropods. The means by which flaviviruses establish persistent infection in their competent vectors and cause disease in humans depends upon several virus-host interactions, including the intricate interplay between flavivirus-encoded immune antagonists and the host antiviral innate immune effector molecules.
Dengue virus (DENV) is the cause of dengue fever. It is a mosquito-borne, single positive-stranded RNA virus of the family Flaviviridae; genus Flavivirus. Four serotypes of the virus have been found, and a reported fifth has yet to be confirmed, all of which can cause the full spectrum of disease. Nevertheless, scientists' understanding of dengue virus may be simplistic as, rather than distinct antigenic groups, a continuum appears to exist. This same study identified 47 strains of dengue virus. Additionally, coinfection with and lack of rapid tests for Zika virus and chikungunya complicate matters in real-world infections.
Microglia are a type of neuroglia located throughout the brain and spinal cord. Microglia account for about 10-15% of cells found within the brain. As the resident macrophage cells, they act as the first and main form of active immune defense in the central nervous system (CNS). Microglia originate in the yolk sac under a tightly regulated molecular process. These cells are distributed in large non-overlapping regions throughout the CNS. Microglia are key cells in overall brain maintenance—they are constantly scavenging the CNS for plaques, damaged or unnecessary neurons and synapses, and infectious agents. Since these processes must be efficient to prevent potentially fatal damage, microglia are extremely sensitive to even small pathological changes in the CNS. This sensitivity is achieved in part by the presence of unique potassium channels that respond to even small changes in extracellular potassium. Recent evidence shows that microglia are also key players in the sustainment of normal brain functions under healthy conditions. Microglia also constantly monitor neuronal functions through direct somatic contacts and exert neuroprotective effects when needed.
Tick-borne encephalitis virus (TBEV) is a positive-strand RNA virus associated with tick-borne encephalitis in the genus Flavivirus.
Envelope glycoprotein GP120 is a glycoprotein exposed on the surface of the HIV envelope. It was discovered by Professors Tun-Hou Lee and Myron "Max" Essex of the Harvard School of Public Health in 1984. The 120 in its name comes from its molecular weight of 120 kDa. Gp120 is essential for virus entry into cells as it plays a vital role in attachment to specific cell surface receptors. These receptors are DC-SIGN, Heparan Sulfate Proteoglycan and a specific interaction with the CD4 receptor, particularly on helper T-cells. Binding to CD4 induces the start of a cascade of conformational changes in gp120 and gp41 that lead to the fusion of the viral membrane with the host cell membrane. Binding to CD4 is mainly electrostatic although there are van der Waals interactions and hydrogen bonds.
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Antibody-dependent cellular cytotoxicity (ADCC), also referred to as antibody-dependent cell-mediated cytotoxicity, is a mechanism of cell-mediated immune defense whereby an effector cell of the immune system kills a target cell, whose membrane-surface antigens have been bound by specific antibodies. It is one of the mechanisms through which antibodies, as part of the humoral immune response, can act to limit and contain infection.
Human betaherpesvirus 5, also called human cytomegalovirus (HCMV), is species of virus in the genus Cytomegalovirus, which in turn is a member of the viral family known as Herpesviridae or herpesviruses. It is also commonly called CMV. Within Herpesviridae, HCMV belongs to the Betaherpesvirinae subfamily, which also includes cytomegaloviruses from other mammals. CMV is a double-stranded DNA virus.
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Hepatitis B is an infectious disease caused by the Hepatitis B virus (HBV) that affects the liver; it is a type of viral hepatitis. It can cause both acute and chronic infection.
A neutralizing antibody (NAb) is an antibody that defends a cell from a pathogen or infectious particle by neutralizing any effect it has biologically. Neutralization renders the particle no longer infectious or pathogenic. Neutralizing antibodies are part of the humoral response of the adaptive immune system against viruses, intracellular bacteria and microbial toxin. By binding specifically to surface structures (antigen) on an infectious particle, neutralizing antibodies prevent the particle from interacting with its host cells it might infect and destroy.
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.
Anirban Basu is an Indian neurobiologist, who is primarily interested in neurovirology, a senior scientist at the National Brain Research Centre, a deemed to be university, located in Manesar, Gurgaon, Haryana. He is internationally known for his studies on Japanese encephalitis. Basu is an elected fellow of all the three major Indian science Academies namely the Indian Academy of Sciences, the Indian National Science Academy and the National Academy of Sciences, India as well as of the West Bengal Academy of Science and Technology. The Department of Biotechnology of the Government of India awarded him the National Bioscience Award for Career Development, one of the prominent Indian science awards, for his contributions to biosciences and biotechnology, in 2010.
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