**8. Host immune responses**

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

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‐

The pathogenesis of the neurotropic flaviviruses like JEV, involves both virus-mediated damage and the host immune responses. After the mosquito bite, when the virus is inoculat‐ ed in the host, it replicates in skin dendritic cells, and then is transported to lymph nodes, from where it spreads to peripheral organs, enhancing the viremia. Entry into CNS is an im‐ portant event which aids viral encephalitis [9]. Roles of both the innate and adaptive im‐ mune responses in controlling flaviviral infection are important. IgM and IgG are involved in preventing viral dissemination to the CNS, however CD8+ T cells are important for recov‐

Infection with flavivirus triggers the host's innate immunity, resulting in signalling path‐ ways and production of interferons (IFN) which are secretory cytokines produced as a re‐ sponse against viral infection. When these IFN bind to the cell-surface receptors, Jak–Stat signaling pathway is activated which in turn induces the transcription of interferon-stimu‐ lated genes (ISGs), and the resulting products have potent antiviral, antitumor, and immu‐ nomodulatory effects. To win against the IFN defence system, viruses encode viral proteins which are potent enough to block IFN signaling, via various mechanisms (Sen 2001, Weber et al., 2004) like blocking IFN action by preventing Tyk-2 phosphorylation by the production

transmission cycle (Müllbacher et al., 2003).

168 Encephalitis

mune cells such as spleen and kupffer cells respectively.

ery and immunopathological phases of viral infection.

of NS5 protein of JEV (Lin et al., 2004; Lin et al., 2006;Liang et al., 2009).

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

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 adaptive immune response.
