JEV is a single stranded positive sense RNA virus wrapped in a nucleo-capsid which is surrounded by a 50 nm glycoprotein containing envelope. The viral RNA has 5′ untranslated region (UTR), a longer 3′ UTR and an open reading frame in between (Chambers et al. 1990). JEV genome RNA encodes three structural proteins—(1) Capsid protein (C), (2) Precursor to membrane protein (prM), (3) Envelope protein (E); and seven nonstructural proteins (NS) NS1, NS2a, NS2b, NS3, NS4a, NS4b and NS5. The E glycoprotein is the most immunogenic protein, composed of 500 amino acids, and the main component of the surface projection of the virion. E protein is responsible for induction of neutralizing antibodies and accounts for the protective response in the host. E protein is also regarded as the cell receptor binding protein and mediates cell fusion and cell entry. The flavivirus enters the cell by endocytosis after attaching to a heparan sulfate receptor. Subsequently the lipid membrane of virus fuses with endosome membrane. The viral RNA enters the cytoplasm of the host cell (Chambers et al. 1990). The virulence of JEV depends on E protein and change in any amino acid may alter its virulence (Cecilia and Gould 1991; Ni and Barrett 1996).

JE is a zoonotic disease and is transmitted between mosquitoes, pigs and water birds (Fig. 2). Humans are accidentally infected by the bite of JEV infected mosquitoes and are dead end host. Humans do not participate in the spread of JEV because of short and low level viremia. Pigs and ardeid birds are the most important host for the maintenance, amplification and spread of JEV. The pigs are the main participants in the transmission cycle with respect to humans. JEV infected animals usually remain asymptomatic though fatal encephalitis has been reported in horses and fetal losses in sows (Burke and Leake 1988). The bird mosquito cycle is thought to be important for maintaining and amplifying JEV in the environment. Culex mosquitoes, especially Culex tritaeniorhynchus, is the most important vector for JEV transmission. C. tritaeniorhynchus breeds in the rice field with shallow water, can fly up to 1.5 km horizontally and up to 1.5 m vertically (Asahina and Noguchi 1968; Scherer et al. 1959).

Following an infected mosquito bite, JEV multiplies in the dermis and then in lymph nodes. Subsequently there is a short viremia during which the virus enters the brain. JEV multiplies in the endothelium of cerebral vessels and thus crosses the blood-brain barrier (Dropulie and Masters 1990). JEV replicates in the neurons. There is perivascular cuffing and infiltration of inflammatory cells, and phagocytosis of neurons (Johnson et al. 1985; Miyake 1964). In fulminant cases, evidence of inflammation may be lacking but viral antigen may be demonstrated in morphologically normal neurons. This may account for normal CSF in some patients. At autopsy, the lesions are mostly restricted to thalamus, basal ganglia, midbrain, cerebral cortex, cerebellum and anterior horn cells of spinal cord. In the acute stage, histopathological examination reveals areas of congestion, small hemorrhages, thrombi formations and neuronophagia. In the sub-acute stage, degeneration, loss of neurons and proliferation of glial cells are more prominent whereas inflammatory cell infiltration is not obvious. In the chronic stage, degeneration or loss of neurons, gliosis, and inflammatory cell infiltration are apparent. In the late stage, there may be calcification of basal ganglia, thalamus and cerebral cortex. The highest concentration of JEV RNA and antigen has been demonstrated in thalamus and brainstem (Srivastava et al. 2012a, b). In the cerebellum, JEV antigen is localized to neurons in the granular and molecular layers, but not to Purkinje cells (Johnson et al. 1985). Co-infection of cysticercosis with JE has been reported in up to 30 % of the patients (Shankar et al. 1983).

Following primary JEV infection, a rapid IgM response occurs in serum within 7 days, and by 1 month, IgM level declines and IgG level increases. Both symptomatic and asymptomatic JEV infections have IgM and IgG response in serum, but only JE patients have this response in the CSF. In the patients who had an earlier flavivirus infection, there is an early rise of IgG and slow rise of IgM. These patients may have milder illness due to neutralization of extracellular viruses and lysis of infected cell through antibody dependent cytotoxicity (Carmenaga et al. 1974). Persistence of JEV in the nervous system has been reported in 5 % of laboratory confirmed cases of JE (Ravi et al. 1993).

The cellular immune response probably restricts the viral replication before it invades the central nervous system (CNS). Immunosuppression by cyclophosphamide results in rapidly progressive encephalitis following JEV infection (Nathanson and Cole 1970). It is therefore likely that cytotoxic lymphocytes help in clearance of JEV. Neuronal injury and host defense in JE have been attributed to a number of pro-inflammatory cytokines and chemokines, which are released by activated microglia and astrocytes in the brain. Cytokines such as tumor necrosis factor (TNF)-α and interferon (IFN)-α/β, -γ activate intracellular antiviral pathways after binding to specific receptors on the surface of infected and uninfected cells. Other cytokines also contribute to antiviral responses (Burke and Morrilnl 1987; Ghoshal et al. 2007). In clinical studies, however, pro-inflammatory cytokines and chemokines were not related to disease severity and mortality (Kalita et al. 2010; (Solomon and Winter 2004). In JE patients with movement disorders, CSF norepinephrine, dopamine, 3,5 dihydroxyphenyl acetic acid, serotonin and homovalinic acid were reduced (Kalita et al. 2007). In an experimental study these neurotransmitters and metabolites were decreased in thalamus, striatum, midbrain and cortex (Misra et al. 2010a). In experimental studies, the maximum damage of thalamus and midbrain in JEV infection was demonstrated by documenting maximum number of JEV RNA copies, JEV antigen labeling and cytokine expression in these areas (Kumar et al. 2009a; Misra et al. 2010a; Srivastava et al. 2009, 2012b).

The incubation period of JEV in humans is 5–15 days. The clinical picture of JEV infection ranges from febrile headache to aseptic meningitis to severe encephalitis. Following 2–4 days of nonspecific fever, headache, gastrointestinal disturbance, the encephalitic illness follows. The encephalitis manifests with fever, behavioral abnormality or altered sensorium. Seizures, focal neurological deficit, decerebration, and tremulous eye movements may be associated. Cranial nerve palsy is rare. Severe cases with JE may develop respiratory paralysis which needs artificial ventilation.

There are two main strategies for prevention of JE

Immunization is the main way of prevention of JE. There are three types of JE vaccines (1) Formalin inactivated (2) Live attenuated and (3) Chimeric. Live attenuated vaccines are safe and effective and efficacy and safety of chimeric vaccine are under evaluation (Table 1).

Human exposure to mosquito bites can be reduced by wearing proper clothes, remaining indoor during dusk and dawn, using mosquito nets and distancing human habitat from rice fields and pigsties.