**3. Viral replication and morphogenesis**

**2. Epidemiological features**

4 Trends in Infectious Diseases

JE is believed to be originated in Indonesia and Malaysia long back in mid 1500s [Weaver *et al*., 1999; Sinniah *et al*., 1989]. JEV leads to major outbreaks in both temperate regions of Asia like China, Japan, Korea, Philippines, Taiwan and tropical regions like Bangladesh, India, Sri Lanka and Nepal [Bista *et al*., 2005]. The cases of JE are also reported in newer geographical regions in the Torres Strait islands of Australia and in Papua New Guinea [Fig. 1]. The reason for this wide spread of JE is unknown but it may be due to population shift or variations in agricultural practices, animal husbandry, climate, ecology or migratory birds patterns. In India the first case of JE was seen in 1955. JE is reported to be endemic in many parts such as Assam,

Bihar, Madhya Pradesh, Tamil Nadu, Uttar Pradesh and West Bengal.

**Figure 1.** Epidemiology of JE globally. The areas highlighted in red display the endemic regions affected by JE.

JEV virion comprises of a single strand of positive-sense RNA of around 11kb, enclosed in a nucleocapsid and surrounded by envelope made up of glycoproteins [Agrawal *et al*., 2013; Ye *et al*., 2012]. The RNA consists of a short 5' untranslated region (UTR), a longer 3' UTR and a single open reading frame between them. It encodes 3432 aminoacid polyprotein, which is translationally and post translationally cleaved by viral and host proteases into three structural proteins (core-C, pre-membrane-PrM and envelope-E) and seven nonstructural (NS) proteins (NS1,NS2A,NS2B,NS3,NS4A,NS4B and NS5) [Fig 2][Yang *et al*., 2013].

**Figure 2.** Organization of the JEV genome

The C protein of 12-14 kDa in size is highly basic and fuses with the RNA to form the nucleo‐ capsid. The PrM is in close proximity with the E protein, forming a heterodimer and is believed to act as a 'chaperone' to it, hindering its function until after virion release. Just before the virion release, the PrM protein is cleaved by a protease to its mature M protein form. This alteration contributes for the formation and activation of E protein homodimers. Researchers suggested that the extremely conserved N glycosylation motif N15-X16-T17 in JEV PrM and its N-glycan substituents are essential for several stages of JEV biology: PrM biogenesis, virus release and pathogenesis. The E protein is the largest structural protein, comprising of approximately 500 aminoacids, with up to two potential glycosylation sites. It is the main target for the humoral immune response and is believed to play a vital role in viral entry into host cells [Solomon *et al*., 2003]. The xlink protein is involved in virus replication and regulation of the innate immune response [Li *et al*., 2012; Zhang *et al*., 2012]. The functions of NS3 and NS4 are prominent, they code for serine protease and RNA dependent RNA polymerase (RdRp) [Lu *et al*., 2013]. There is a high rate of mutation in JEV because RdRp is expected to have some error which leads to vast alterations in genomic sequences of JEV worldwide [Saxena *et al*., 2008]. Since all flaviviral NS proteins are essential for viral replication, any one of them can be selected as target for selective inhibitors of viral replication for therapeutic intervention [Anantpadma *et al*., 2011; Mastrangelo *et al*., 2012].

are involved in inducing neuronal death that complements JE. Neuronal death by secreted TNF is mediated by the TNF receptor-associated death domain protein (TRADD), which there upon regulates a downstream apoptotic cascade, in neurons [Swarup *et al*., 2007]. During JEV infection, nitric oxide (NO) is released by macrophages and plays a significant role in inflam‐ mation, even though NO itself is a strong antimicrobial agent, researchers have suggested that it strongly inhibits synthesis of viral RNA, protein accumulation and virus release from infected cells. NO production is higher in the JEV infected brain, and plays a crucial role in the innate immunity of the host and its ability to restrict the initial stages of JEV infection in the

Japanese Encephalitis: A Neglected Viral Disease and Its Impact on Global Health

http://dx.doi.org/10.5772/58529

7

In addition to neuronal and microglial cells, astrocytes are also infected by JEV. Astrocytes are known to maintain homeostasis in the CNS and support the survival and information processing function of neurons. They respond fast to CNS infection and help regulate neuro‐ inflammation. JEV infection results in astrocyte activation, but the infection overpowers the capacity of activated astrocytes to maintain metabolic homeostasis, resulting in an over accumulation of toxic byproducts of metabolism that are injurious to neuronal viability. However JEV infection triggers metabolic reprogramming by upregulating the expression of many proteins such as IP-10, ceruloplasmin and glutamine synthase by astrocytes, involved in the metabolic pathways vital for maintaining neuronal health. This increase is deficient to meet the increased demand that accompanies JEV infection. Astrocytes help in the transmis‐

Prodromal stage 1-6 days Fever, muscle pain, headache along with vomiting. In children

JE usually develops in patients after an incubation period of 5-15 days [Table 1]. In humans, most JEV infections are asymptomatic, with about 1 in 300 JEV infections resulting in symp‐ toms ranging from non-specific mild fever to severe meningoencephalitis categorized by fever, lessened consciousness, seizures and focal neurological signs. At later stages, poliomyelitislike flaccid paralysis and parkinsonian syndrome develop, which exhibit the standard description of JE like dull, flat and mask-like face with wide, unblinking eyes, tremor, wide‐

abdominal pain may be prominent.

14-15 day onwards Fever subsides, neurological signs may improve, and eventually

condition may persist, if patient survives.

7-13 days Photophobia, hyperexcitability, focal and neurological signs,

gastrointestinal symptoms like nausea, vomiting, diarrhea and

muscular rigidity, dull, mask like face with wide unblinking eyes, tremor, widespread hyertonia, cogwheel rigidity, other

irregularities in movement, upper motor neuron signs, cerebellar signs and cranial nerve paralysis sometimes leading to coma

either death may occur, or a long term psychoneurological

sion of JEV from peripheral tissues to the cerebrospinal fluid.

**Disease course Incubation period Signs and symptoms**

**Table 1.** Duration, signs and symptoms of Japanese encephalitis

CNS [Saxena *et al*., 2000].

Acute encephalitic

Late convalescent

stage

stage
