Japanese Encephalitis

1. Introduction

The culex mosquito is the vector for the Japanese encephalitis virus (JEV), a member of the

flaviviridae family that may infect both animals and humans. The mosquito-borne zoonotic

flavivirus Japanese encephalitis (JE) infects a broad variety of vertebrates in an enzootic

process that particularly involves big waterfowl birds and pigs. Humans and horses play no

role in the transmission of this enzootic cycle and are regarded to be terminal hosts once

infected. In humans, JE infection may range from being benign to causing a moderate febrile

sickness to a potentially fatal central nervous system infection (CNS). The latter is linked to

serious neurological complications and high death rates. (Endy & Nisalak, 2002).

Similar neurotropic flaviviruses may be found on all seven continents: in North America, you

can find the Equine encephalitis virus and the St. Louis encephalitis virus; in Africa and the

Middle East, you'll find West Nile virus; in Australia, you'll find the Murray Valley

encephalitis virus; in South America, you'll find the Roccio virus; and in Russia, you'll find

the Tick transmitted encephalitis virus. (Solomon, 2004). There are significant similarities

between these viral encephalitides on the molecular, epidemiological, and clinical levels.

Molecular evidence suggests that all flaviviruses evolved swiftly to fill ecological niches after

diverging from a common parent about 10,000–20,000 years ago. In East and Southeast Asia,

Japanese encephalitis (JE) is the leading viral cause of encephalitis. Rural regions, in

particular, account for the majority of JE's yearly 50,000 cases and 15,000 fatalities. Nearly

half of JE survivors have cognitive or physical impairments after the disease. (Misra &

Kalita, 2010). The fundamental, clinical, and preventative aspects of JE are the main points of

this review.
 2. Disease Agent

The Japanese encephalitis virus is a nucleocapsid-enclosed, single-stranded positive-sense

RNA virus with a glycoprotein-lined envelope that is 50 nm in diameter. The RNA has one

open reading frame sandwiched between a longer untranslated region (UTR) on 5' and3' ends.

Capsid protein (C), membrane precursor protein (PrM), and envelope protein (E) are the 3

structural proteins encoded, together with 7 nonstructural proteins The nucleocapsid is

formed when the extremely basic C protein joins RNA. (Chambers, Hahn, Galler, & Rice,

1990). By forming a heterodimer with the E protein, PrM is assumed to inhibit the latter's

function as a chaperon, allowing the virus to escape only after it has been released. The PrM

protein is converted to the mature (M) protein form by a furin-like protease just before to

virion release. This promotes the production of active homodimers of the E protein. Having a

length of over 500 amino acids and two putative glycosylation sites, the E protein is a

substantial structural protein. It is the primary focus of the humoral immune response and

plays a crucial role in viral entrance into the host cell. (Stadler, Allison, Schalich, & Heinz,

1997).

Endocytosis is the route through which the virus enters the host cell. Viral RNA enters the

cytoplasm of an afflicted cell when the outer membrane of the virus fuses with the endosome

membrane. When the pH of the endosome decreases, a conformational shift around a putative

hinge area is suggested to facilitate the fusing of the two membranes (domain I and II of the E

protein). As a consequence, the terminal region of domain II is fused to a fusion peptide in

the form of a barrel, which is then inserted into the host cell membrane. There is evidence

that heat shock protein 70 acts as a receptor for the JE virus. (Das, Laxminarayana, Chandra,

Ravi, & Desai, 2009).

Pigs and wading birds are among the intermediary hosts that keep the virus alive and help it

spread. Because humans do not often produce enough virus to infect mosquitoes that feed on

them, they are dubbed "dead-end hosts." Most infections happen in rural locations because

the amplifying hosts are most common in agricultural settings like farms and rice paddies,

where flooded irrigation draws wading birds. While mosquitoes are responsible for the

overwhelming bulk of disease transmission, concerns have been raised that direct contact

with sick pigs (which serve as amplifying hosts) might result in the spread of the virus.

(Simon, Sandhu, & Goyal, 2022). A significant human burden of Japanese encephalitis

persists even in nations with mostly Muslim populations and little pig rearing, such as

Bangladesh. This calls into question the primacy of pigs as amplifying hosts. Unbiased RNA

sequencing in 2017 revealed a whole JEV genome in a patient coinfected and medically

identified with yellow fever in Cunene province, Angola, suggesting that the virus's

distribution was more widespread than previously believed. The experimental description of

non-vector transmission of JEV between pigs through respiratory secretions is intriguing, but

the significance of this mechanism to the natural cycle of the virus is less obvious. (Turtle &

Solomon, 2018).

Humans are a dead-end host for JEV, unlike pigs, since human viraemia is not high enough to

infect the mosquito vector. Most people who are infected with JEV either show no symptoms

at all or have such weak symptoms that they never seek medical attention. The probability of

developing encephalitis after contracting JEV is believed to be between 0.1 and 1%, albeit

this may be an underestimate due to the large population at risk (2–3 billion people

worldwide). Because adults in endemic regions do not show signs of infection after being

exposed to the virus, this suggests that immunity lasts a lifetime. (Turtle & Solomon, 2018)
 3. Environmental Factors

Over the last 70 years, the endemic region for JE has expanded. Encephalitis is difficult to

accurately assess because of regional differences in diagnostic capabilities and reporting.

Japan saw the first known outbreak of JE in the 1930s. The first recorded case of summer

encephalitis in China was in 1935. In the early 1970s, the yearly incidence in China was over

80,000 cases, but now it is between 10,000 and 20,000. In 1938, JE was first documented in

this far eastern Russian republic. There was a major outbreak in South Korea in 1949. The

first reports of JE outbreaks in Northern Vietnam appeared in 1965, and since then the

disease has spread there, with the region now seeing between 1,000 and 3,000 new cases each

year. Northern Thailand's Chiang Mai Valley saw an outbreak of JE in 1969, and now, the

region sees between 1,500 and 2,500 new cases each year. (Vaughn & Hoke, 1992). Until the

1970s, JE in India was only seen in the small city of Vellore in the country's southern region,

where it had first been documented in 1955. In later outbreaks, JE swept throughout the

whole of India, from the coasts to the sub-Himalayan regions to the east. Every year, reports

of large epidemics involving more than 2,000 and 7,000 cases are made public. Reports of JE

began to emerge from Burma, Bangladesh, and Southern Nepal in the late 1970s. About 500

cases of JE are recorded annually in southern Nepal. Sri Lanka saw the first known JE

pandemic in 1985, with 410 cases and 75 fatalities. In addition to India, Pakistan has JE cases

documented. (Misra & Kalita, 2010).

More and more of the world is being affected by JE. It is unclear how JE invades and spreads

to new locations. It has long been hypothesised that the rise in JE cases may be attributable to

changes in land use and agricultural practises that followed deforestation, in particular the

growth of rice producing regions. However, this could not be the main factor in JEV's

expansion into other territories. Wind-borne mosquitoes, avian migration, and the intentional

or unintentional transfer of an infected human host are the three proposed processes. (Misra
& Kalita, 2010). Torres Straits were first exposed to JEV when migrating birds carried the

virus from Indonesia, where the mosquito-pig and mosquito-bird cycles were established.

Cyclonic winds carried infected mosquitoes from the Torres Straits to the northern part of

Australia, where the virus was subsequently spread. Each year, the wind blows infected

Culex tritaeniorhynchus from China and Japan, demonstrating the function of the wind in the

spread of JEV. (Mackenzie, Johansen, Ritchie, van den Hurk, & Hall, 2002)

Many factors may have contributed to the precipitous decline in JE cases in developed

nations like Japan, Taiwan, and South Korea, including widespread childhood immunisation,

vector control, new pig-rearing methods, the physical separation of residential and

agricultural areas, and improved sanitation. Reports of JE in the elderly have emerged from

these regions as a result of successful management of JE in children and a decline in adult

immunity. (Vaughn & Hoke, 1992)

4. Clinical Symptoms of JE

Mosquitoes carrying JEV often infect humans via their bites. The initial symptoms may not

occur for 5 to 15 days after transmission; therefore, little is known about the immediate

aftermath. It has been postulated that a first round of viral amplification occurs in the skin

cells immediately around the mosquito bite, including fibroblasts, endothelial cells, pericytes,

macrophages, and dermal dendritic cells. Newly formed virion particles or migrating infected

immune cells like dendritic cells and T lymphocytes release infectious virions at their

destination, allowing the virus to travel to the brain.

The first symptom of JEV infection is a nonspecific fever. It is unclear what percentage of

JEV infection in humans results in self-limiting disease without involvement of the CNS,

although in certain instances, febrile sickness could be the sole indication of infection, with

no later encephalitis. Three to four days before to the beginning of acute encephalitis
syndrome, which manifests as a distorting of cognition, headache, vomiting, and typically

seizures, nonspecific characteristics such as coryza, diarrhea, or rigors might develop. The

anatomical locations of injury are often reflected in the variability of focal neurological

symptoms. Involvement in the basal ganglia is shown in the characteristics of Parkinson's

disease, such as blank stares and tremors; additional movement problems include lip

smacking, bruxism, choreoathetosis, and hemiballismus. Damage to the spinal cord's anterior

horn cells causes flaccid paralysis, as seen in polio, and cranial nerve symptoms include

facial palsies, ptosis, and aberrant eye movements. Both obvious generalised tonic-clonic

seizures and more subtle motor seizures have been reported, with the latter being more

common in children with advanced illness. Extracranial manifestations such as pulmonary

oedema (which may be neurogenic due to brainstem involvement), hepatomegaly,

splenomegaly, mildly elevated liver enzymes, and thrombocytopenia have also been reported.

Similar symptoms develop in adults with Japanese encephalitis.

There is an intriguing connection between JEV and Zika-related sickness since both may

cause flaccid paralysis in the arms and legs similar to that seen in polio owing to damage to

the anterior horn cells. Electrophysiological signs of demyelination and, rarely, axonal injury,

and inflammatory infiltrates of lymphocytes and monocytes, have all been detected in

patients with JEV-associated GBS, including a fatal case.

The diagnosis of Japanese encephalitis needs laboratory confirmation since JEV is only one

of several causes of an acute encephalitis condition characterised by individuals presenting

with altered mental status. Patients with Japanese encephalitis may have nonspecific

abnormalities on regular peripheral blood tests, including neutrophilia and hyponatraemia.

Lymphocytic pleocytosis is a common finding in cerebrospinal fluid (CSF) analysis, while

acellular CSF is also a possibility. The presence of JEV-specific immunoglobulin M (IgM) in

cerebrospinal fluid (CSF) by ELISA on day 7 of illness is indicative of Japanese encephalitis.

 5. Immune Response

When exposed to JEV for the first time, humans mount an effective adaptive humoral and

cellular immune response. Due to its role in viral binding and subsequent entrance into the

target cell, the envelop (E) protein is an important target for a protective humoral immune

response. (Turtle & Solomon, 2018). Experiments on animals suggest that passive

immunisation with antibodies neutralising the E protein of JEV might be an effective first

line of defence against the virus. To present, 5 genotypes have been characterised, each

characterised by unique epitopes and antibodies that react to 1-5% E protein variants.

Antibodies produced in response to infection or immunisation often cross-react with all JEV

genotypes. Vaccines using live virus or formalin-inactivated virus have been developed

primarily against JEV genotype III because they generate long-lasting immunity and are well

tolerated by youngsters and the elderly. (Kulkarni, et al., 2017).

Support from the adoptive T cell driven immune response is necessary for B cell

development, including the somatic mutation process that optimises antigen binding

characteristics and antibody class switch, which is necessary for the formation of specific

humoral protection against JEV. Since different T cell subpopulations may have different

impacts during JEV infection, it is clear that a targeted T cell response is crucial along the

course of the disease. (Turtle, et al., 2016). Here, JEV-specific CD8+ cytotoxic T cells and T

cells play a vital role in restricting JEV generation and dissemination by targeting and

destroying JEV-infected cells through cytotoxic mechanisms, avoiding infection of the brain

and consequent encephalitis. Immunogenic peptides of the NS proteins presented by MHC

class I have been discovered, and these cytotoxic T cells recognise them. Aiding B cells in

germinal centres is mostly dependent on JEV-specific CD4+ helper T cells that recognise

JEV E protein. On the other hand, CD4+ cells that recognise NS protein epitopes likely aid

the particular cytotoxic immune response, create anti-viral cytokines like interferon-, and
finally regulate and resolve the cellular immune response by giving T cell memory. (Li,

Teleki, & Wang, 2018).

There can be no T cell activation without dendritic cells. They are responsible for processing

and presenting JEV antigens on MHC class I and class II, hence connecting the innate and

acquired immune systems. JEV, however, also effectively infects dendritic cells. Thus, it has

been shown that the attenuated virus may infect dendritic cells. For starters, the innate

immunity systems and cells play a significant role in detecting the JEV infection and

mounting a protective immune response. Pattern recognition receptors known as Toll-like

receptors (TLR), such as TLR7 and TLR8, play a crucial role in detecting JEV components

and activating the immune system. Before acquired immunity kicks in, cytotoxic natural

killer cells (NK) and NK T cells (NKT) do the heavy lifting. (Turtle, et al., 2016). Similarly,

mast cells, which are a component of the innate immune system, contribute to the body's

defence against JEV. However, they may amplify JEV invasion and brain inflammation

rather than aid in resolving the issue. In general, JEV infection substantially stimulates all

established immunological processes and mechanisms, often leading to lifelong immunity.

However, further study is needed to better understand how JEV interacts with immune cells,

particularly in encephalitis instances. (Filgueira & Lannes, 2019).

6. Potential Policy Responses

The Japanese encephalitis virus is resistant to all available antiviral treatments. IV fluids and

antipyretics are all that can be done for treatment except providing comfort. It is possible that

anticonvulsants will be needed to manage the seizures. Neurological damage and persistent

psychological disorders can lead to suboptimal results for survivors, necessitating lifelong

care. Up to 30% will be left with irreversible cognitive, behavioural, or neurological

impairments such as paralysis, chronic seizures, or the inability to communicate or care for

themselves.

Given the lack of an adequate cure, prevention is of paramount importance. It's better to do

this by not being bitten by mosquitoes at all. To prevent bites, wear long sleeves, long pants,

socks, and closed-toe shoes whenever you go outside, no matter how brief your stay may be.

Socks tucked into pant legs provide protection against mosquito bites. The risk of

transmission is lower if one treats clothes with insect repellents containing permethrin,

DEET, or another product approved for use by the Environmental Protection Agency (EPA).

Mosquitoes are more active during the warmer months. Between the hours of dawn and dark,

when mosquitoes are most active, is when most cases of the disease are transmitted. If you're

travelling somewhere warm, it's best to sleep inside where the temperature is controlled, or

use a mosquito net or screen. (Simon, Sandhu, & Goyal, 2022)

There is a short-course immunisation regimen available that is both safe and efficacious.

Vaccine use is really low though. Policy makers should also consider increasing the usage of

vaccines. Current guidelines for the use of the Japanese encephalitis vaccination from the

Centers for Disease Control and Prevention (CDC) are as follows:

Those who are going to stay 30 days or longer in an endemic region during the transmission

season should get the vaccination. Also included are those tourists whose itineraries will see

them predominantly visiting major cities. Short-term (less than a month) tourists who will be

spending significant time outside in rural or agricultural regions, engaging in outdoor

activities, or staying in locations without air conditioning, screens, or bed nets should

seriously consider getting the vaccination. Travelers visiting a location where an epidemic is

known, as well as those whose destinations, activities, and length of trip are unknown, should
also give this some thought. Short-term city visitors are not suggested to get the

immunisation at this time. (Simon, Sandhu, & Goyal, 2022).

7. Conclusion

In the first section, we summarised key epidemiologic data on the emerging JEV, with an

emphasis on the growing global threat posed by this virus to human health, especially in light

of the correlation between climate change and the spread of mosquitoes, which can carry the

virus from place to place. The uncontrollable danger of geographical expansion of JEV was

also explored, with particular focus on the impact of expanded global commerce and the

related international movement of people and animals, as well as the migratory paths of birds

infected with JEV. The next sections focused on human biology and its role in JEV infection

and disease. In doing so, they detailed how viruses move throughout the human body.

Connecting the clinical presentation of JEV infection with fundamental scientific ideas, we

also clarified the connection between JEV and diverse cell types and the immune system.

In South and Southeast Asia, where it is most prevalent among the region's poor, JE remains

a serious public health concern. Until an effective antiviral treatment is developed, patients

with JE must rely on symptomatic and supportive care, as well as preventative measures.

Vector control, environmental modification, and changes in farming methods are among the

most challenging solutions. JE prevention in developed nations may point to the importance

of socioeconomic factors like education and sanitation. Meanwhile, research into more

efficient and less expensive treatments and vaccination methods must continue.
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