**6. Pathogenesis and pathology**

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

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‐

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‐

states of India is also reported (Saxena et al., 2006, 2009).

**4. JEV: Infectious agents**

166 Encephalitis

tion (Ishikawa et al., 2011).

**5. Transmission of disease**

ably via blood causing infection and subsequent illness.

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‐ tation of virus across the blood–brain barrier (Singh et al., 2009). Histological examination shows that virus can affect neurons present in thalamus and brain. Viral antigen is later gets cleared from there due to the induction of adaptive immune. A strong virus-specific anti‐ body response, in CNS may act for recovery from encephalitic infection. Clinical infections with the mosquito-borne encephalitic flaviviruses in humans mostly occur in the absence of detectable viremia consistent with the notion that humans are dead-end hosts in the natural transmission cycle (Müllbacher et al., 2003).

**8. Host immune responses**

adaptive immune response.

**9. Adaptive immune response**

The virus enters the neuro-parenchyma by crossing capillary walls in the brain and distrib‐ utes itself in various parts of brain. Initially JE virus is partially destroyed at its site of entry and the remaining virus is disseminated by local and systemic extra neural replication lead‐ ing to viremia. After primary infection with JEV, presence of IgM antibodies and T-lympho‐ cytes are seen until 2 weeks approximately. But antibodies alone are neither capable of terminating the viremia nor preventing the subsequent infection. Pregnancy is known to cause immunosuppression and persistent maternal infection or pregnancy induced reactiva‐ tion of the virus which causes foetal infection. Isolation of JEV from human placenta and foetuses has been reported. JEV can establish latency within different organs despite the presence of antiviral antibodies. A significant decrease in serum iron levels, a frequent fea‐ ture of microbial invasion is observed during JE infection. An early influx of macrophages followed by neutrophils at the site of injury in different organs of humans and mice has been reported, which is correlated with the production of a neutrophil chemotactic macro‐ phage derived factor MDF, with development of hypoglycemia. This chemotactic protein (MDF) has been shown to play a protective role in the host defense against JEV, through production of reactive oxygen intermediates in neutrophils and reactive nitrogen oxide spe‐

Japanese Encephalitis Virus: The Complex Biology of an Emerging Pathogen

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

169

The earliest host response to viral infection is the induction of IFN. Type I IFNs, IFN-α and β are produced by leukocytes and fibroblasts, respectively, in response to infection and activate the transcription of a host of IFN inducible genes that leads to the induction of antiviral pathways. IFN-α has important immunoregulatory functions including the activation of monocytes, enhancement of chemokine expression and MHC class I and II induction. Most of the antiviral activity of IFN-α is mediated by NO radicals synthesized by monocytic phagocytes, mortality in JEV-infected mice increased when the activity of NO synthase was inhibited (Saxena et al., 2000, 2001) as NO blocks mechanism of viral RNA and protein synthesis (Müllbacher et al., 2003). Also natural killer (NK) cells are important part of the innate immune response which is activated at the viral invasion which helps in early defence as NK cells synthesize and regulate cytokines, necessary for

The importance of humoral response in recovery from encephalitis is demonstrated by several studies showing that administration of antibody during early infection can pro‐ tect against JE. Studies of the entry process of JEV using electron and confocal microsco‐ py techniques showed that neutralizing mAb strongly inhibits JEV-induced fusion and internalization into cells, but not binding of virus to cells. T cells are of crucial impor‐ tance for the recovery from most virus infections and individuals deficient in T cells are unable to control virus infections. T cells are necessary for recovery and protection after

cies degrading the virus protein and RNA (Tiwari et al., 2012).

Japanese encephalitis (JE) is now the foremost cause of viral CNS infection. JEV pathogene‐ sis is still unclear (Yang *et al.,* 2011). Since the variation exists in neuro-virulence and periph‐ eral pathogenicity among JE virus strains. After the infected mosquito bite, the virus enters into the reticulo-endothelial system and invades the central nervous system after the transi‐ ent period of viremia. It distributes itself in hypothalamus, hippocampus, substantia nigra and medulla oblongata regions of brain via vascular endothelial cells by the mechanism of endocytosis which involves cholesterol and clathrin mediated pathways, referred to as lipid rafts acting as portals for virus entry (Das et al., 2010). The virus replicates in neurons and matures in the neuronal secretary system. Nearly 33% of JE infected patients die due to neu‐ rocysticercosis (NCC), suggesting that it may somehow predispose to JE (Desai et al., 1997). During acute stages congestion, edema, hemorrhagic symptoms are found in brain. Patho‐ logical changes in the neural tissues have also been reported in lymphoid organs and im‐ mune cells such as spleen and kupffer cells respectively.
