**3. Epidemiology**

Encephalitis outbreaks have been recorded since early 19th century from countries like Southeast Asia including Japan, Vietnam, Cambodia, Myanmar, India, Nepal, Malaysia, China, Korea, Taiwan, Thailand and reached to the West including Pakistan and the north‐ east and southwest of India, also the East (New Guinea), the South (Northern Australia Ar‐ chipelago) and it is estimated theoretically to spread further West (Afghanistan). Between 1978 and 1992, 24 imported cases were reported in above regions due to high transmission. Since the 1990s, the JE is variedly transmitting in humans and is reaching new extended re‐ gions encompassing new geographic limits. History tells that a woman in France suffered from JE after she reached Thailand, in 1938. Also JE epidemic was reported in restricted sea‐ coast of the 'USSR' in 1939. Also in 1946 major outbreaks of JE were recorded in Korea, both in civil in 1949 and in American military personnel in 1950.

Sequencing analysis divides JEV into five genotypes (GI–V) rising from ancestor viruses from Indonesia–Malaysia region. These ancestors have evolved into five genotypes; GI, GII, GIII, GIV and GV, out of them GIV and GV are the most divergent. They always remained confined to their origin region of Indonesia–Malaysia. However GI, GII and GIII are the most recent genotypes which have spread across Asia. All phylogenetic characterization and studies done on a large scale highlights GIII as a predominant genotype of JEV in Japan and Korea since 1935 (Schuh et al., 2009). GI was been isolated in Cambodia and then in China in 1979 and GIII was isolated before the 1970s and then in Vietnam and Japan during 1986 and 1990. Later even GI was reported there in 1995 and 2002 proving that all the strains isolated before 1991 were GIII, and after 1994 were GI. The natural cycle of JEV consists of pig-mos‐ quito-pig or bird-mosquito-bird cycles. GIII was the only widely distributed genotype found in India until till when GI JEV strains were detected and isolated from 66 acute encephalitis syndrome (AES) patients along with GIII strains (Fulmali et al., 2011). This detection indi‐ cates their co-circulation and association with humans. In the mid 1990's genetic shift (Nabe‐ shima et al., 2009) had occurred in Japan, Korea and Vietnam that lead to disappearance of GIII and then progressively GI supplanted it (Zhang et al., 2011). In India exact mode of in‐ troduction of GI is not clear, but it is possible that it may have been introduced through mi‐ gratory birds (Huang et al., 2010).

JEV is basically transmitted by *Culex spp* mosquitoes. JEV is distributed in temperate and tropical areas of eastern and southern Asia. Its range has extended from eastern Asia (China, Japan, Korea, maritime Siberia, Taiwan, the Philippines, and Vietnam), to South‐ east Asia and northern Australasia (Cambodia, Indonesia, Laos, Malaysia, Papua New Guinea, Thailand, and the Torres Strait islands of northern Australia), and to southern Asia (Bangladesh, Bhutan, India, Myanmar, Nepal, and Sri Lanka) (Fig. 3). Evidences have also been seen for Pakistan. JE is largely a disease of rural areas, especially associat‐ ed with irrigated rice agriculture. During endemics, no seasonal pattern exists and spora‐ dic cases of encephalitis occur throughout the year, most often in infants and young children. There is a peak in vector density and virus activity during October-December in endemic zones. However, epidemic activity in temperate and subtropical areas occurs most commonly in summer and early autumn (van den et al., 2009).

mission (Mathur et al., 1982). Symptomatic infections are usually present in the form of nonspecific febrile illness, including diarrhoea and rigors followed by headache, vomiting and reduced levels of consciousness and aseptic meningitis or encephalitis. The incubation peri‐ od after JEV exposure varies from 6 to 16 days (Saxena et al., 2009). One in 200/800 infected people develop clinical signs like high fever and nausea. A quarter of patients with symp‐

Encephalitis outbreaks have been recorded since early 19th century from countries like Southeast Asia including Japan, Vietnam, Cambodia, Myanmar, India, Nepal, Malaysia, China, Korea, Taiwan, Thailand and reached to the West including Pakistan and the north‐ east and southwest of India, also the East (New Guinea), the South (Northern Australia Ar‐ chipelago) and it is estimated theoretically to spread further West (Afghanistan). Between 1978 and 1992, 24 imported cases were reported in above regions due to high transmission. Since the 1990s, the JE is variedly transmitting in humans and is reaching new extended re‐ gions encompassing new geographic limits. History tells that a woman in France suffered from JE after she reached Thailand, in 1938. Also JE epidemic was reported in restricted sea‐ coast of the 'USSR' in 1939. Also in 1946 major outbreaks of JE were recorded in Korea, both

Sequencing analysis divides JEV into five genotypes (GI–V) rising from ancestor viruses from Indonesia–Malaysia region. These ancestors have evolved into five genotypes; GI, GII, GIII, GIV and GV, out of them GIV and GV are the most divergent. They always remained confined to their origin region of Indonesia–Malaysia. However GI, GII and GIII are the most recent genotypes which have spread across Asia. All phylogenetic characterization and studies done on a large scale highlights GIII as a predominant genotype of JEV in Japan and Korea since 1935 (Schuh et al., 2009). GI was been isolated in Cambodia and then in China in 1979 and GIII was isolated before the 1970s and then in Vietnam and Japan during 1986 and 1990. Later even GI was reported there in 1995 and 2002 proving that all the strains isolated before 1991 were GIII, and after 1994 were GI. The natural cycle of JEV consists of pig-mos‐ quito-pig or bird-mosquito-bird cycles. GIII was the only widely distributed genotype found in India until till when GI JEV strains were detected and isolated from 66 acute encephalitis syndrome (AES) patients along with GIII strains (Fulmali et al., 2011). This detection indi‐ cates their co-circulation and association with humans. In the mid 1990's genetic shift (Nabe‐ shima et al., 2009) had occurred in Japan, Korea and Vietnam that lead to disappearance of GIII and then progressively GI supplanted it (Zhang et al., 2011). In India exact mode of in‐ troduction of GI is not clear, but it is possible that it may have been introduced through mi‐

JEV is basically transmitted by *Culex spp* mosquitoes. JEV is distributed in temperate and tropical areas of eastern and southern Asia. Its range has extended from eastern Asia (China, Japan, Korea, maritime Siberia, Taiwan, the Philippines, and Vietnam), to South‐

toms die; a third of survivors suffer brain damage.

in civil in 1949 and in American military personnel in 1950.

gratory birds (Huang et al., 2010).

**3. Epidemiology**

164 Encephalitis

**Figure 3.** Epidemiology of JE globally. The areas highlighted in black display the regions under the attack of JEV infec‐ tions and are high infection prone areas.

From past 75 years the major focus of JE coverage was on China and Southeast Asia, but now it has extended its horizons to westward towards India and Pakistan, northern to eastern Russia, eastward towards Philippines and southward to Australia. Occurrence of JE is more closely related to temperature and humidity in the atmosphere (Misra and Kalita, 2010). JEV is also engulfing new geographical regions which are shown by JEV sequencing analysis and results exhibit that JEV is expanding alarmingly to the new re‐ gions of Papua New Guinea and Australia. GI strains are often isolated from Northern Thailand, Cambodia, Korea, China, Japan, Vietnam, Taiwan and Australia between 1967 and the present. GII are isolated from Southern Thailand, Malaysia, Indonesia, Papua New Guinea and Northern Australia. GIII are isolated from temperate regions of Asia. GIV are isolated in Indonesia and GV is isolated in Singapore. Sequence analyses of viral genes are further showing that a "genotype shift" from III to I has occurred in Japan since early 1990s, reasons for which remains unclear (Shimojima et al., 2011). Consider‐ ing India, rapid spread of Japanese encephalitis (JE) towards the newer areas of northern states of India is also reported (Saxena et al., 2006, 2009).

#### **4. JEV: Infectious agents**

The genomic RNA of JEV is ~11 kb in length encoding three structural proteins and sev‐ en non-structural proteins. The RNA genome of the virus is infectious which can spread the horizon of disease. The virus genome contains C proteins complexed with the ge‐ nomic RNA present in a nucleocapsid, and this whole complex is surrounded by envel‐ oped lipid bilayer containing E and prM/M proteins, which is derived from the infected host cells. The prM proteins present in the immature particles, cleave to mature into M proteins. The E protein is the major infectious part which covers the entire surface of the mature virion, and it is the antigen majorly recognized by virus neutralizing antibodies. Further, subviral particles (SVPs), containing prM/M and E proteins enclosed in lipid lay‐ ers but not surrounded by nucleocapsid, are secreted from flavivirus infected cells, prov‐ ing these SVPs to be as excellent immunogens. Along with infective E protein, even NS1 protein is also considered as quite infective which may cause lethal effects to hosts when produced and expressed in large quantities. If antiNS1 immunity steps are taken and cy‐ tolytic antibodies against NS1 are administered, it would contribute in the reduction of the release of progeny viruses from infected cells. Hence a drug with a mixture of antiE and antiNS1 immunity would definitely pose as a potent fighter against flavivirus infec‐ tion (Ishikawa et al., 2011).

#### **5. Transmission of disease**

JE virus undergoes zoonotic cycles which involve mosquitoes and several vertebrate species as hosts and human beings as dead end hosts. *Culex tritaeniorhyncus* and *Culex gelidus* are reported as principal vectors. These vectors breed in rice fields, irrigation canals and water pools filled with stagnant water and in standing puddles, open sewers, fish ponds etc. These infected mosquitoes (~3%) bite domestic animals and birds, but sometimes they may bite a healthy host (human), which are accidental hosts, facilitating the transmission of the virus to man. Pigs and birds serve as reservoirs and amplifying hosts. Man is an incidental host of the JEV (Fig. 4). In humans, after a bite of infected mosquito, initial viral replication occurs in local and regional lymph nodes. Viral invasion of the central nervous system occurs prob‐ ably via blood causing infection and subsequent illness.

**Figure 4.** Life cycle of JEV crossing through important vectors and intermediate hosts and finally to dead end reser‐

Japanese Encephalitis Virus: The Complex Biology of an Emerging Pathogen

http://dx.doi.org/10.5772/54111

167

The majority of human infections with encephalitic flaviviruses are asymptomatic or give rise to only a mild febrile illness. However, in a small percentage of infected individuals the mild infection turns into life-threatening encephalitis. Thus, a key question in the pathogen‐ esis of encephalitic flaviviral disease concerns the conditions that allow virus entry from the blood into the central nervous system (CNS). Hypertension, diabetes mellitus, and coinfec‐ tion with other virus may further deteriorate the infection and can worsen the condition of infected persons by increasing neurological complications which may happen due to facili‐

voirs human hosts.

**6. Pathogenesis and pathology**

**Figure 4.** Life cycle of JEV crossing through important vectors and intermediate hosts and finally to dead end reser‐ voirs human hosts.
