Pathogenesis and Host Immune Response during Japanese Encephalitis Virus Infection

*Swatantra Kumar, Rajni Nyodu, Vimal K. Maurya and Shailendra K. Saxena*

#### **Abstract**

Japanese Encephalitis Virus (JEV) is a mosquito borne flavivirus infection. Transmission of JEV starts with the infected mosquito bite where human dermis layer act as the primary site of infection. Once JEV makes its entry into blood, it infects monocytes wherein the viral replication peaks up without any cell death and results in production of TNF-α. One of the most characteristics pathogenesis of JEV is the breaching of blood brain barrier (BBB). JEV propagation occurs in neurons that results in neuronal cell death as well as dissemination of virus into astrocytes and microglia leading to overexpression of proinflammatory cytokines. JEV infection results in host cells mediated secretion of various types of cytokines including type-1 IFN along with TNF-α and IFN-γ. Molecule like nitrous oxide (NO) exhibits antiviral activities against JEV infection and helps in inhibiting the viral replication by blocking protein synthesis and viral RNA and also in virus infected cells clearance. In addition, the antibody can also acts an opsonizing agent in order to facilitate the phagocytosis of viral particles, which is mediated by Fc or C3 receptor. This chapter focuses on the crucial mechanism of JEV induced pathogenesis including neuropathogenesis viral clearance mechanisms and immune escape strategies.

**Keywords:** Japanese encephalitis virus, Neuropathogenesis, Dendritic cells, Macrophages, Dendritic cells

#### **1. Introduction**

Japanese Encephalitis Virus (JEV) infection is a mosquito-borne zoonotic infection in human which is the most common cause of viral encephalitis in Southeast Asia [1]. The first case of JEV was reported in Japan in the year of 1871. The virus was first isolated in the year 1935 from human brain, which was a fatal case. JEV is responsible for causing a high morbidity and high mortality specifically in the pediatrics age group [2]. Transmission cycle of JEV includes pigs which act as the reservoir/amplifying-host, water bird as carriers and mosquitoes as vector and humans are considered as the dead-end host. JEV is transmitted into human via infected Culex mosquitoes bite and thereby infected individuals develop viremia [3]. Transmission cycle starts mostly post-monsoon where the chance of mosquito breeding increases in paddy fields. JEV is single stranded positive- sense envelope RNA virus and is a member of family *Flaviviridae*. The genome of JEV encodes a

one single open reading frame (ORF) encoding single polyprotein that gets cleaved into three structural proteins namely as Capsid (C), Envelope (E), precursor to membrane protein (prM) and seven non-structural proteins including NS1, NS2A, NS2B, NS3, NS4A, NS4B, NS5 [4]. Based on the genomic variability, JEV has been categorized into five genotypes. The most prevalent genotypes seen in the northern region are I and III and that in southern region are II and IV and also, a putative genotype V [5]. The incubation period of JEV infection is 5–15 days and symptoms includes from febrile illness to a severe disease with patients showing meningoencephalitis, aseptic meningitis or a polio-like acute flaccid paralysis [6].

#### **2. Immune cell targets employed by JEV in peripheral and central nervous system**

Transmission of JEV starts with the infected mosquito bite where human dermis layer act as the primary site of infection. JEV replication occurs in peripheral system including PBMCs wherein the macrophages, dendritic cells (DCs) and monocytes become infected [7]. Such infection in peripheral system gets cleared off due activation of immune system, and that is the reason for low level of viremia in the blood [8]. During any viral infection, antigen presenting cells (APCs) such as dendritic cells (DCs) and macrophages are the first cell types that trigger the cellular immune responses. They produce various cytokines, which includes IL-6 and TNF-α, and many other pro-inflammatory cytokines. Once JEV makes its entry into blood, it infects monocytes wherein the viral replication peaks up without any cell death and results in production of TNF-α [9] that results in the activation and differentiation of monocytes into monocyte-derived dendritic cells (MDDCs) and monocytederived macrophages (MDMs). JEV has developed various immune escape strategies. JEV impairs with the process of DC maturation and where immature human monocyte-derived DCs (im-MDDC) helps in viral replication which takes place by surface expression of co-stimulatory cytokines/chemokine surface receptors [10]. JEV replication has been shown to take place in DCs via reducing the expression of co-stimulatory cytokines, hindering the T-cell activation and by escalating the Treg cells differentiation [11].

During JEV infection, interaction of host-pathogen in the monocyte cell lineage such as monocyte-derived macrophages (MDMs) increases the severity of the disease [12]. Macrophages acts as a hub of viral replication but in case of JEV infection, the productive replication of virus is limited followed by the increase sensitivity to the IFN response [13]. JEV modulates macrophages and DCs in distinguishing pattern. Macrophages get modulated through classical pathway by up regulating co-stimulatory molecules. DCs infected by JEV produce one of the anti-inflammatory cytokine, IL-10 and some of the pro-inflammatory cytokines such as TNF-α, IL-12 and IL-6, whereas macrophages infected by JEV does not produces IL-10 [14]. Such modulation of DCs and macrophages induces an inflammatory environment which then helps in permeability of BBB (blood brain barrier) and hence, the virus tends to spread into central nervous system (CNS). Infection of CNS causes functional damage to DCs including splenic DCs. Since dendritic cells helps in activating naïve T cells, their damage leads to an increase in viral circulation in CNS and hence, reduces the CD4<sup>+</sup> and CD8<sup>+</sup> T-cells response [15]. Although the mechanism of viral entry into the brain is not well understood but once it enters the brain cells, JEV is detected in cerebrospinal fluid (CSF) and in the nervous tissue [16]. One of the most characteristics pathogenesis of JEV is the breaching of BBB [17]. Neuron being the most important target cell during JEV however, when the infection gets into CNS, along with the neuronal cells, astrocytes also gets infected,

**5**

tissue, the CD8+

**Figure 1.**

*proinflammatory cytokine release.*

*Pathogenesis and Host Immune Response during Japanese Encephalitis Virus Infection*

which is a constituent of BBB and an important part of CNS. Astrocytes are also considered to be helping in the transmission of JEV to the cerebrospinal fluid from peripheral tissues. The microglial cell that is considered to be the resident immune cells/macrophage of CNS is also infected by JEV. Microglial cells play a very significant role in CNS during the JEV infection via acting as a virus reservoir [18]. Upon activation microglia produces proinflammatory cytokines like TNF-alpha and IL-6,

*Mechanism of Japanese encephalitis virus infection and involvement of immune cells. In blood JEV primarily infects monocytes and results in TNF-*α *production that results in the activation and differentiation of monocytes into monocyte-derived dendritic cells (MDDCs) and monocyte-derived macrophages (MDMs). These cells are involved in naïve T cell activation, secretion of TNF-*α *and IL-6. JEV can cross the blood brain barrier (BBB) via direct or transmigration of virus harboring monocytes. After entry into the brain, JEV can infect neuronal cells that results in cell death. The transmigrated monocytes differentiate into macrophages which may disseminate the virus to microglia which act as the viral reservoir. Astrocytes are known to disseminate the virus to microglia which results in the activation of microglia leading to over expression of* 

The pathogenesis of JEV needs to be explored at dual phases in human which initiates at the peripheral tissues and then, involvement of central nervous system (CNS). Before entering into CNS, JEV replicates in the langerhans cells (skin dendritic cells), which gets transported into the lymphatic and peripheral tissues which results in increased viremia. During the initial infection in periphery

CNS. Lymphocytes harboring JEV can cross the BBB and via endocytosis process to penetrate the endothelial surface of CNS [20]. However, inability of host to produce antibodies against the infection and the immune evasion strategies of the virus makes this infection lethal. JEV propagation occurs in neurons that results

T cell response prevents the dissemination of the JEV into the

which induce death of neuronal cell (**Figure 1**) [19].

**3. Neuropathogenesis during JEV infection**

*DOI: http://dx.doi.org/10.5772/intechopen.98947*

*Pathogenesis and Host Immune Response during Japanese Encephalitis Virus Infection DOI: http://dx.doi.org/10.5772/intechopen.98947*

#### **Figure 1.**

*Innate Immunity in Health and Disease*

**nervous system**

cells differentiation [11].

CNS and hence, reduces the CD4<sup>+</sup>

one single open reading frame (ORF) encoding single polyprotein that gets cleaved into three structural proteins namely as Capsid (C), Envelope (E), precursor to membrane protein (prM) and seven non-structural proteins including NS1, NS2A, NS2B, NS3, NS4A, NS4B, NS5 [4]. Based on the genomic variability, JEV has been categorized into five genotypes. The most prevalent genotypes seen in the northern region are I and III and that in southern region are II and IV and also, a putative genotype V [5]. The incubation period of JEV infection is 5–15 days and symptoms includes from febrile illness to a severe disease with patients showing meningoen-

cephalitis, aseptic meningitis or a polio-like acute flaccid paralysis [6].

**2. Immune cell targets employed by JEV in peripheral and central** 

Transmission of JEV starts with the infected mosquito bite where human dermis layer act as the primary site of infection. JEV replication occurs in peripheral system including PBMCs wherein the macrophages, dendritic cells (DCs) and monocytes become infected [7]. Such infection in peripheral system gets cleared off due activation of immune system, and that is the reason for low level of viremia in the blood [8]. During any viral infection, antigen presenting cells (APCs) such as dendritic cells (DCs) and macrophages are the first cell types that trigger the cellular immune responses. They produce various cytokines, which includes IL-6 and TNF-α, and many other pro-inflammatory cytokines. Once JEV makes its entry into blood, it infects monocytes wherein the viral replication peaks up without any cell death and results in production of TNF-α [9] that results in the activation and differentiation of monocytes into monocyte-derived dendritic cells (MDDCs) and monocytederived macrophages (MDMs). JEV has developed various immune escape strategies. JEV impairs with the process of DC maturation and where immature human monocyte-derived DCs (im-MDDC) helps in viral replication which takes place by surface expression of co-stimulatory cytokines/chemokine surface receptors [10]. JEV replication has been shown to take place in DCs via reducing the expression of co-stimulatory cytokines, hindering the T-cell activation and by escalating the Treg

During JEV infection, interaction of host-pathogen in the monocyte cell lineage

such as monocyte-derived macrophages (MDMs) increases the severity of the disease [12]. Macrophages acts as a hub of viral replication but in case of JEV infection, the productive replication of virus is limited followed by the increase sensitivity to the IFN response [13]. JEV modulates macrophages and DCs in distinguishing pattern. Macrophages get modulated through classical pathway by up regulating co-stimulatory molecules. DCs infected by JEV produce one of the anti-inflammatory cytokine, IL-10 and some of the pro-inflammatory cytokines such as TNF-α, IL-12 and IL-6, whereas macrophages infected by JEV does not produces IL-10 [14]. Such modulation of DCs and macrophages induces an inflammatory environment which then helps in permeability of BBB (blood brain barrier) and hence, the virus tends to spread into central nervous system (CNS). Infection of CNS causes functional damage to DCs including splenic DCs. Since dendritic cells helps in activating naïve T cells, their damage leads to an increase in viral circulation in

and CD8<sup>+</sup>

mechanism of viral entry into the brain is not well understood but once it enters the brain cells, JEV is detected in cerebrospinal fluid (CSF) and in the nervous tissue [16]. One of the most characteristics pathogenesis of JEV is the breaching of BBB [17]. Neuron being the most important target cell during JEV however, when the infection gets into CNS, along with the neuronal cells, astrocytes also gets infected,

T-cells response [15]. Although the

**4**

*Mechanism of Japanese encephalitis virus infection and involvement of immune cells. In blood JEV primarily infects monocytes and results in TNF-*α *production that results in the activation and differentiation of monocytes into monocyte-derived dendritic cells (MDDCs) and monocyte-derived macrophages (MDMs). These cells are involved in naïve T cell activation, secretion of TNF-*α *and IL-6. JEV can cross the blood brain barrier (BBB) via direct or transmigration of virus harboring monocytes. After entry into the brain, JEV can infect neuronal cells that results in cell death. The transmigrated monocytes differentiate into macrophages which may disseminate the virus to microglia which act as the viral reservoir. Astrocytes are known to disseminate the virus to microglia which results in the activation of microglia leading to over expression of proinflammatory cytokine release.*

which is a constituent of BBB and an important part of CNS. Astrocytes are also considered to be helping in the transmission of JEV to the cerebrospinal fluid from peripheral tissues. The microglial cell that is considered to be the resident immune cells/macrophage of CNS is also infected by JEV. Microglial cells play a very significant role in CNS during the JEV infection via acting as a virus reservoir [18]. Upon activation microglia produces proinflammatory cytokines like TNF-alpha and IL-6, which induce death of neuronal cell (**Figure 1**) [19].

#### **3. Neuropathogenesis during JEV infection**

The pathogenesis of JEV needs to be explored at dual phases in human which initiates at the peripheral tissues and then, involvement of central nervous system (CNS). Before entering into CNS, JEV replicates in the langerhans cells (skin dendritic cells), which gets transported into the lymphatic and peripheral tissues which results in increased viremia. During the initial infection in periphery tissue, the CD8+ T cell response prevents the dissemination of the JEV into the CNS. Lymphocytes harboring JEV can cross the BBB and via endocytosis process to penetrate the endothelial surface of CNS [20]. However, inability of host to produce antibodies against the infection and the immune evasion strategies of the virus makes this infection lethal. JEV propagation occurs in neurons that results

in neuronal cell death. Neuronal cell death occurs via two mechanism; direct and indirect neuronal killing. Direct killing involves the JEV propagation inside the neuronal cells that results in cell death and indirect killing involves aggressive and intense inflammatory responses leading to up-regulation of inflammatory cytokines and reactive oxygen species that causes death of neurons [21]. In addition to cell death, proliferation and growth of neuronal progenitor cells (NPCs) also gets affected which could be the possible reason for the destructive neurological cases in JE survivors [22]. JEV can also cause abnormal neuronal development in fetus via crossing transplacental barrier [23]. In order to prevent the JEV pathogenesis, virus clearance from the peripheral nervous tissues during the initial phase of infection is crucial for designing effective therapy. Clearance of virus-infected cells and recovery during JEV infection relies on the several factors including IgM antibodies, T-lymphocytes and CXCL10 mediated viral clearance by neuronal cells [24].

#### **4. Clearance of JEV by diverse immune cell types**

During JEV infection, viral clearance via immune cells is a multiple step process which involves both innate and adaptive immunity. The initial step focuses on the inhibition or on limiting the spread of virus to any new cells. In addition, already infected cells are then either eliminated or replication of JEV is suppressed permanently. However, mechanism of virus clearance during JEV infection in the CNS tissue requires immense understanding of the level of JEV infection in the CNS tissue. One of the most reliable methods is cytolysis, either immune cytolysis or virusinduced. This method involves complete removal or elimination of virus infected cells or cells where the virus is propagating. The immunological processes that are required for clearance of virus are cell-type specific. However, in case JEV infection, the virus invade the host immune cells by cytolytic mechanism and hence, inhibiting the progression of NCP (neural progenitor cells pool). In order to combat such invasion, the activation of brain macrophages is crucial which gets initiated with the help of nerve cells. These macrophages then mediate non-cytolytic viral clearance by producing IFN-β and by supporting production of T-cells that eventually produces IFN-γ [25]. Further, virus secretes proteins/factors and makes cytokine imbalance and suppresses MHC-I present on the membrane surface.

In response to the JEV infection, several mechanisms of innate immune response get activated. After getting infection, host cells starts producing various types of cytokines including type-1 IFN along with TNF-α and IFN-γ. These cytokines induces inflammatory responses and hence, inhibits the viral replication. Furthermore, the IFN-α and IFN-β binds to the NK cells and initiates the lytic activity and hence, kills the JEV infected cells. This antiviral activity gets initiated by one of the cytokine IL-12 which produced at an early phase of infection. IFN-γ then activates the brain macrophages that expresses MHC-II molecules and subsequently, helps in more cytokine production that result in inhibition of viral replication [26]. Other than the cytokines, molecule like nitrous oxide (NO) also evidently exhibits antiviral activities against JEV infection and helps in inhibiting the viral replication by blocking protein synthesis and viral RNA and also in virus infected cells clearance [27]. Adaptive immune response is highly specific involving antigenic specificity display, self/non-self recognition, and immunologic memory. Generally, during flavivirus infection, the antibodies produced by the host cells along with the complement proteins helps in the destruction of the viral particles [28]. However, in case of JEV infection, the virus tends to evade and slips through the complement mediated mechanism of host cells and by inhibition of classical pathway. Additionally, the receptor present on the macrophages interacts

**7**

*Pathogenesis and Host Immune Response during Japanese Encephalitis Virus Infection*

**5. Cell-mediated immune mechanisms for JEV Clearance**

effector molecules are produced by TH1 cells, CD4+

**6. Humoral immune mechanism for JEV clearance**

structural proteins of virus and host cells interaction.

**7. Complement system against JEV infection**

with the components of the viral antigens and helps in generating soluble proteins, which then triggers adaptive immune responses promoting clearance of virus

In the process of clearance or elimination of JEV infected cells, cell mediated immunity plays a vital role. Cytokines playing the lead in this mechanism is IFN-γ and IL-2 secreted by T-helper (Th) cells or T-cytotoxic (TC) cells. IL-2 helps in the alteration of naïve T cells into virus-specific cytotoxic T lymphocytes (CTL) generation, which then eventually causes killing of virus infected cells [29]. However, in case of JEV or any flaviviral infection, post exposure to the infected cells, the virus controls the release of CTL and other cytokines. The stimulated Th cells generates cytokines which includes IFN-γ, IL-2, IL-6 and TNF-α which tends to disturbs the cellular activities of JEV and hence, protecting the host from viral infection. These

ate anti-viral response in order to initiate cell-mediated immune responses. NO amongst these cytokines, both IFN-γ and TNF-α could possibly help in peripheral virus clearance but not from the CNS. IFN-γ helps in maintaining anti viral properties in host cells and IL-2 then, converts naive T cell (CTL) into effector T cell and hence, activates NK cells which in return eliminates virus infected cells or virions.

During JEV infection, the host cell recruits humoral immune mechanism, which is a very significant mechanism in the process of protection against the infection in human. Once the host cells get infected by the virus, host humoral responses initiates the process by identification of virus with the recruitment of Th cells that responds to the viral antigens. These Th cells then present these viral antigens or proteins to the B cells along with the help of macrophages. Subsequently, the B cells loaded with viral antigen then get converted to plasma cells and post expansion, starts secreting Abs after few days post JE infection. Thus, this is the initiation of the humoral immune response mediated by antibody production [30]. The antibody binds to the epitopes necessary for the fusion of viral envelope with the plasma membrane and thus, blocking the penetration of virus molecules into the host cells. Furthermore, the antibody can also acts an opsonizing agent in order to facilitate the phagocytosis of viral particles, which is mediated by Fc or C3 receptor. Thus, the mechanism of inhibition of virus propagation and reduction of virus generated cytopathic effects is shown by the JE infected neutralizing antibodies. Host immune responses are triggered 4–7 days post infection resulted after structural and non-

Viruses are a kind of pathogen that depends completely upon the host for its survival and its replication. Hence, in order to survive the virus has developed immune escape mechanism from complement system by secreting many inhibitory proteins/cytokines. However, the complement system has an adversary part to play in cases of any *Flavivirus* infection including JE due to it's of multi-component system. This adverse action takes place by either restricting the viral propagation

and CD8+

Tc cells, which medi-

*DOI: http://dx.doi.org/10.5772/intechopen.98947*

infected cells.

with the components of the viral antigens and helps in generating soluble proteins, which then triggers adaptive immune responses promoting clearance of virus infected cells.

#### **5. Cell-mediated immune mechanisms for JEV Clearance**

In the process of clearance or elimination of JEV infected cells, cell mediated immunity plays a vital role. Cytokines playing the lead in this mechanism is IFN-γ and IL-2 secreted by T-helper (Th) cells or T-cytotoxic (TC) cells. IL-2 helps in the alteration of naïve T cells into virus-specific cytotoxic T lymphocytes (CTL) generation, which then eventually causes killing of virus infected cells [29]. However, in case of JEV or any flaviviral infection, post exposure to the infected cells, the virus controls the release of CTL and other cytokines. The stimulated Th cells generates cytokines which includes IFN-γ, IL-2, IL-6 and TNF-α which tends to disturbs the cellular activities of JEV and hence, protecting the host from viral infection. These effector molecules are produced by TH1 cells, CD4+ and CD8+ Tc cells, which mediate anti-viral response in order to initiate cell-mediated immune responses. NO amongst these cytokines, both IFN-γ and TNF-α could possibly help in peripheral virus clearance but not from the CNS. IFN-γ helps in maintaining anti viral properties in host cells and IL-2 then, converts naive T cell (CTL) into effector T cell and hence, activates NK cells which in return eliminates virus infected cells or virions.

#### **6. Humoral immune mechanism for JEV clearance**

During JEV infection, the host cell recruits humoral immune mechanism, which is a very significant mechanism in the process of protection against the infection in human. Once the host cells get infected by the virus, host humoral responses initiates the process by identification of virus with the recruitment of Th cells that responds to the viral antigens. These Th cells then present these viral antigens or proteins to the B cells along with the help of macrophages. Subsequently, the B cells loaded with viral antigen then get converted to plasma cells and post expansion, starts secreting Abs after few days post JE infection. Thus, this is the initiation of the humoral immune response mediated by antibody production [30]. The antibody binds to the epitopes necessary for the fusion of viral envelope with the plasma membrane and thus, blocking the penetration of virus molecules into the host cells. Furthermore, the antibody can also acts an opsonizing agent in order to facilitate the phagocytosis of viral particles, which is mediated by Fc or C3 receptor. Thus, the mechanism of inhibition of virus propagation and reduction of virus generated cytopathic effects is shown by the JE infected neutralizing antibodies. Host immune responses are triggered 4–7 days post infection resulted after structural and nonstructural proteins of virus and host cells interaction.

#### **7. Complement system against JEV infection**

Viruses are a kind of pathogen that depends completely upon the host for its survival and its replication. Hence, in order to survive the virus has developed immune escape mechanism from complement system by secreting many inhibitory proteins/cytokines. However, the complement system has an adversary part to play in cases of any *Flavivirus* infection including JE due to it's of multi-component system. This adverse action takes place by either restricting the viral propagation

*Innate Immunity in Health and Disease*

in neuronal cell death. Neuronal cell death occurs via two mechanism; direct and indirect neuronal killing. Direct killing involves the JEV propagation inside the neuronal cells that results in cell death and indirect killing involves aggressive and intense inflammatory responses leading to up-regulation of inflammatory cytokines and reactive oxygen species that causes death of neurons [21]. In addition to cell death, proliferation and growth of neuronal progenitor cells (NPCs) also gets affected which could be the possible reason for the destructive neurological cases in JE survivors [22]. JEV can also cause abnormal neuronal development in fetus via crossing transplacental barrier [23]. In order to prevent the JEV pathogenesis, virus clearance from the peripheral nervous tissues during the initial phase of infection is crucial for designing effective therapy. Clearance of virus-infected cells and recovery during JEV infection relies on the several factors including IgM antibodies,

T-lymphocytes and CXCL10 mediated viral clearance by neuronal cells [24].

imbalance and suppresses MHC-I present on the membrane surface.

In response to the JEV infection, several mechanisms of innate immune response get activated. After getting infection, host cells starts producing various types of cytokines including type-1 IFN along with TNF-α and IFN-γ. These cytokines induces inflammatory responses and hence, inhibits the viral replication. Furthermore, the IFN-α and IFN-β binds to the NK cells and initiates the lytic activity and hence, kills the JEV infected cells. This antiviral activity gets initiated by one of the cytokine IL-12 which produced at an early phase of infection. IFN-γ then activates the brain macrophages that expresses MHC-II molecules and subsequently, helps in more cytokine production that result in inhibition of viral replication [26]. Other than the cytokines, molecule like nitrous oxide (NO) also evidently exhibits antiviral activities against JEV infection and helps in inhibiting the viral replication by blocking protein synthesis and viral RNA and also in virus infected cells clearance [27]. Adaptive immune response is highly specific involving antigenic specificity display, self/non-self recognition, and immunologic memory. Generally, during flavivirus infection, the antibodies produced by the host cells along with the complement proteins helps in the destruction of the viral particles [28]. However, in case of JEV infection, the virus tends to evade and slips through the complement mediated mechanism of host cells and by inhibition of classical pathway. Additionally, the receptor present on the macrophages interacts

During JEV infection, viral clearance via immune cells is a multiple step process which involves both innate and adaptive immunity. The initial step focuses on the inhibition or on limiting the spread of virus to any new cells. In addition, already infected cells are then either eliminated or replication of JEV is suppressed permanently. However, mechanism of virus clearance during JEV infection in the CNS tissue requires immense understanding of the level of JEV infection in the CNS tissue. One of the most reliable methods is cytolysis, either immune cytolysis or virusinduced. This method involves complete removal or elimination of virus infected cells or cells where the virus is propagating. The immunological processes that are required for clearance of virus are cell-type specific. However, in case JEV infection, the virus invade the host immune cells by cytolytic mechanism and hence, inhibiting the progression of NCP (neural progenitor cells pool). In order to combat such invasion, the activation of brain macrophages is crucial which gets initiated with the help of nerve cells. These macrophages then mediate non-cytolytic viral clearance by producing IFN-β and by supporting production of T-cells that eventually produces IFN-γ [25]. Further, virus secretes proteins/factors and makes cytokine

**4. Clearance of JEV by diverse immune cell types**

**6**

and hence, protecting the host or by triggering an intense inflammatory response, which increases the disease severity. The complement system helps in destruction of the viral particles by complement-dependent lysis of virus, by opsonization, by modulating functions of B-cell and T-cell and also, by phagocytosis [31]. The other pathways in which the viral particles or antigens gets destructed by the complement system is the antibody-dependent and antibody-independent pathways. This action of viral recognition and then its clearance by complement system is carried out by a group of serum proteins along with molecules presented on cell surface. Most of the proteins are presented in an inactive form which then gets activated by three main patterns through which complement system gets activated. These are the classical pathway, alternative pathway and lectin pathway. All the three pathways get started when C3, a proteolytic fragment promotes the cell uptake, which initiates the complement system. The lectin and the alternative pathway get activated by the binding of the mannose-binding lectin (MBL) present on the surface of cell and by the hydrolysis of C3, respectively. These complement system is comprised of four kinds of serum proteins; C3, factor D, factor b and properdin. A more stabilized complex C3b Bb is formed when C3b binds to B (serum protein) with the help of Mg + ions. Also, the unhydrolyzed C3 can possibly produce more of C3b, which gets deposited on the cell surface. Further, C3b Bb 3b complex known to show C5 convertase activity, and eventually, C3b-C5 and 5b component is formed commencing the first step of viral lysis [32]. This complement-mediated pathway to inhibit the contact target chosen by JEV or any flavivirus may help to understand the possible way of combating the infection [33]. The alternative pathway amplifies the activation triggered by the former two pathways and hence, heavily destroys the virus particles. The classical pathway is an antibody dependent process wherein the antibody stimulates the phagocytic cells. The initiation step is the binding of C1q (a polyvalent molecule) with the antigen–antibody complexes, which is present on the surface of a pathogen or by binding directly to the viral protein. Further, C1 complex binds to the cleaved molecules of C4 (C4a and C4b) and furthermore, C2 can complex with C4b and form a new product C4b2b that shows efficient C3 convertase activity, which is essentially required to activate C3 protein. Finally, along with C3, taking into account, C3b and C4b2b with C5 enzyme, a very efficient complex is formed for the destruction of viral particles. Thus, all three pathways converse in a common sequence of events and cause heavy cell lysis of pathogen.

#### **8. Conclusions**

Flaviviruses like JEV has taken the infection strategy into an advanced level by evading the detection machinery of the host-immune mechanism which is in responses to any viral infection to kill the virus- infected cells. This is the point where it has become a necessity of the moment to carry extensive studies on this subject. JEV modulates the host machinery in dual ways that is, by virus-mediated damage and by host- immune responses. JEV alters or inhibit both the innate and adaptive immune responses of the host. Since, no viral antigen is presented by the macrophages which are infected during the early infection phase, no adaptive immune responses is triggered during this phase. Escaping all the immune responses, JEV manages to disseminate into the CNS and causing damage to the CNS is what makes JEV infection more lethal. Any renewal and replenishment of tissues in CNS after infection is challenging. Host responses like CTL activation has been efficient in combating the virus induced MHC molecules. However, JEV comes with a counter viral strategy by activating the non-classical MHC molecules, since, these non -classical MHC molecules inhibits NK cells by binding to its receptors.

**9**

**Author details**

**Acknowledgements**

**Conflict of interest**

Swatantra Kumar†

, Rajni Nyodu†

The authors declare no conflict of interest.

\*Address all correspondence to: shailen@kgmcindia.edu

† These authors contributed equally to this work as first author.

University (KGMU), Lucknow, India

provided the original work is properly cited.

, Vimal K. Maurya and Shailendra K. Saxena\*†

Centre for Advanced Research (CFAR), Faculty of Medicine, King George's Medical

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

*Pathogenesis and Host Immune Response during Japanese Encephalitis Virus Infection*

since; this age group is the mostly effected and has proved to be lethal.

The authors are grateful to the Vice Chancellor, King George's Medical University (KGMU), Lucknow, India for the encouragement for this work. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

NK cells are the crucial cells so as to say, which are efficient to kill the virus infected cells. To get a clear understanding of how to combat the viral immune escape strategy, many viral antigens/proteins are profiled and characterized. Such studies are a new approach towards generating effective vaccines against JEV along with other flaviviruses. Because of all these challenging viral strategies, it has become a necessary research step to reach to a point where viral eradication shall be feasible. In order to reach to this point, basic understanding of the JEV strategy on how JEV manages to trigger imbalance between host's immunopathological and shielding mechanisms is very important. To combat spread of such lethal infection, vaccination against it should be made mandatory in the entire endemic region. Effective surveillance in the endemic region has to be considered especially in pediatric age,

*DOI: http://dx.doi.org/10.5772/intechopen.98947*

*Pathogenesis and Host Immune Response during Japanese Encephalitis Virus Infection DOI: http://dx.doi.org/10.5772/intechopen.98947*

NK cells are the crucial cells so as to say, which are efficient to kill the virus infected cells. To get a clear understanding of how to combat the viral immune escape strategy, many viral antigens/proteins are profiled and characterized. Such studies are a new approach towards generating effective vaccines against JEV along with other flaviviruses. Because of all these challenging viral strategies, it has become a necessary research step to reach to a point where viral eradication shall be feasible. In order to reach to this point, basic understanding of the JEV strategy on how JEV manages to trigger imbalance between host's immunopathological and shielding mechanisms is very important. To combat spread of such lethal infection, vaccination against it should be made mandatory in the entire endemic region. Effective surveillance in the endemic region has to be considered especially in pediatric age, since; this age group is the mostly effected and has proved to be lethal.

#### **Acknowledgements**

*Innate Immunity in Health and Disease*

and hence, protecting the host or by triggering an intense inflammatory response, which increases the disease severity. The complement system helps in destruction of the viral particles by complement-dependent lysis of virus, by opsonization, by modulating functions of B-cell and T-cell and also, by phagocytosis [31]. The other pathways in which the viral particles or antigens gets destructed by the complement system is the antibody-dependent and antibody-independent pathways. This action of viral recognition and then its clearance by complement system is carried out by a group of serum proteins along with molecules presented on cell surface. Most of the proteins are presented in an inactive form which then gets activated by three main patterns through which complement system gets activated. These are the classical pathway, alternative pathway and lectin pathway. All the three pathways get started when C3, a proteolytic fragment promotes the cell uptake, which initiates the complement system. The lectin and the alternative pathway get activated by the binding of the mannose-binding lectin (MBL) present on the surface of cell and by the hydrolysis of C3, respectively. These complement system is comprised of four kinds of serum proteins; C3, factor D, factor b and properdin. A more stabilized complex C3b Bb is formed when C3b binds to B (serum protein) with the help of Mg + ions. Also, the unhydrolyzed C3 can possibly produce more of C3b, which gets deposited on the cell surface. Further, C3b Bb 3b complex known to show C5 convertase activity, and eventually, C3b-C5 and 5b component is formed commencing the first step of viral lysis [32]. This complement-mediated pathway to inhibit the contact target chosen by JEV or any flavivirus may help to understand the possible way of combating the infection [33]. The alternative pathway amplifies the activation triggered by the former two pathways and hence, heavily destroys the virus particles. The classical pathway is an antibody dependent process wherein the antibody stimulates the phagocytic cells. The initiation step is the binding of C1q (a polyvalent molecule) with the antigen–antibody complexes, which is present on the surface of a pathogen or by binding directly to the viral protein. Further, C1 complex binds to the cleaved molecules of C4 (C4a and C4b) and furthermore, C2 can complex with C4b and form a new product C4b2b that shows efficient C3 convertase activity, which is essentially required to activate C3 protein. Finally, along with C3, taking into account, C3b and C4b2b with C5 enzyme, a very efficient complex is formed for the destruction of viral particles. Thus, all three pathways converse in a common sequence of events and cause heavy cell lysis of pathogen.

Flaviviruses like JEV has taken the infection strategy into an advanced level by evading the detection machinery of the host-immune mechanism which is in responses to any viral infection to kill the virus- infected cells. This is the point where it has become a necessity of the moment to carry extensive studies on this subject. JEV modulates the host machinery in dual ways that is, by virus-mediated damage and by host- immune responses. JEV alters or inhibit both the innate and adaptive immune responses of the host. Since, no viral antigen is presented by the macrophages which are infected during the early infection phase, no adaptive immune responses is triggered during this phase. Escaping all the immune responses, JEV manages to disseminate into the CNS and causing damage to the CNS is what makes JEV infection more lethal. Any renewal and replenishment of tissues in CNS after infection is challenging. Host responses like CTL activation has been efficient in combating the virus induced MHC molecules. However, JEV comes with a counter viral strategy by activating the non-classical MHC molecules, since, these non -classical MHC molecules inhibits NK cells by binding to its receptors.

**8**

**8. Conclusions**

The authors are grateful to the Vice Chancellor, King George's Medical University (KGMU), Lucknow, India for the encouragement for this work. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

#### **Conflict of interest**

The authors declare no conflict of interest.

#### **Author details**

Swatantra Kumar† , Rajni Nyodu† , Vimal K. Maurya and Shailendra K. Saxena\*† Centre for Advanced Research (CFAR), Faculty of Medicine, King George's Medical University (KGMU), Lucknow, India

\*Address all correspondence to: shailen@kgmcindia.edu

† These authors contributed equally to this work as first author.

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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[10] Aleyas AG, George JA, Han YW, et al. Functional modulation of dendritic cells and macrophages by Japanese encephalitis virus through MyD88 adaptor molecule-dependent and -independent pathways. J Immunol. 2009;183(4):2462-2474. DOI:10.4049/ jimmunol.0801952

[11] Gupta N, Hegde P, Lecerf M, et al. Japanese encephalitis virus expands regulatory T cells by increasing the expression of PD-L1 on dendritic cells. Eur J Immunol. 2014;44(5):1363-1374. DOI:10.1002/eji.201343701

[12] Sooryanarain H, Sapkal GN, Gore MM. Pathogenic and vaccine strains of Japanese encephalitis virus elicit different levels of human macrophage effector functions. Arch Virol. 2012;157(10):1905-1918. DOI:10.1007/s00705-012-1386-8

[13] Kundu K, Dutta K, Nazmi A, Basu A. Japanese encephalitis virus infection modulates the expression of suppressors of cytokine signaling (SOCS) in macrophages: implications for the hosts' innate immune response. Cell Immunol. 2013;285(1-2):100-110. DOI:10.1016/j.cellimm.2013.09.005

[14] Lannes N, Summerfield A, Filgueira L. Regulation of inflammation in Japanese encephalitis. J Neuroinflammation. 2017;14(1):158. Published 2017 Aug 14. DOI:10.1186/ s12974-017-0931-5

**11**

*Pathogenesis and Host Immune Response during Japanese Encephalitis Virus Infection*

Neurochem. 2008;106(4):1624-1636. DOI:10.1111/j.1471-4159.2008.05511.x

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[24] Pan CH, Chen HW, Huang HW, Tao MH. Protective mechanisms

but not CD8(+) cytotoxic T-cell responses. J Virol. 2001;75(23):11457-

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encephalitis. Eur J Immunol. 2013;43(7): 1789-1798. DOI:10.1002/eji.201243152

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[27] Saxena SK, Singh A, Mathur A. Antiviral effect of nitric oxide during Japanese encephalitis virus infection. Int J Exp Pathol. 2000;81(2):165-172. DOI:10.1046/j.1365-2613.2000.00148.x

[28] Li Y, Counor D, Lu P, Duong V, Yu Y, Deubel V. Protective immunity to Japanese encephalitis virus associated with anti-NS1 antibodies in a mouse model. Virol J. 2012;9:135. Published 2012 Jul 24. DOI:10.1186/1743-

[29] Konishi E, Kurane I, Mason PW, et al. Induction of Japanese encephalitis virus-specific cytotoxic T lymphocytes in humans by poxvirus-based JE vaccine candidates [published correction appears in Vaccine 1999 Feb 5;17(5):I].

11463. DOI:10.1128/JVI.75.23.

help protect against Japanese

11457-11463.2001

09.003

422X-9-135

induced by a Japanese encephalitis virus DNA vaccine: requirement for antibody

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*DOI: http://dx.doi.org/10.5772/intechopen.98947*

[15] Cao S, Li Y, Ye J, et al. Japanese encephalitis Virus wild strain infection suppresses dendritic cells maturation and function, and causes the expansion of regulatory T cells. Virol J. 2011;8:39.

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1128/JVI.00143-15

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[19] Lannes N, Neuhaus V, Scolari B, et al. Interactions of human microglia cells with Japanese encephalitis virus. Virol J. 2017;14(1):8. Published 2017 Jan 14. DOI:10.1186/s12985-016-0675-3

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[22] Das S, Basu A. Japanese encephalitis virus infects neural progenitor cells and

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[15] Cao S, Li Y, Ye J, et al. Japanese encephalitis Virus wild strain infection suppresses dendritic cells maturation and function, and causes the expansion of regulatory T cells. Virol J. 2011;8:39. DOI:10.1186/1743-422X-8-39

[16] Hsieh JT, St John AL. Japanese encephalitis virus and its mechanisms of neuroinvasion. PLoSPathog. 2020; 16(4):e1008260. DOI:10.1371/journal. ppat.1008260

[17] Al-Obaidi MMJ, Bahadoran A, Har LS, et al. Japanese encephalitis virus disrupts blood-brain barrier and modulates apoptosis proteins in THBMEC cells. Virus Res. 2017;233:17- 28. DOI:10.1016/j.virusres.2017.02.012

[18] Chen CJ, Ou YC, Lin SY, et al. Glial activation involvement in neuronal death by Japanese encephalitis virus infection. J Gen Virol. 2010;91(Pt 4):1028-1037. DOI:10.1099/ vir.0.013565-0

[19] Lannes N, Neuhaus V, Scolari B, et al. Interactions of human microglia cells with Japanese encephalitis virus. Virol J. 2017;14(1):8. Published 2017 Jan 14. DOI:10.1186/s12985-016-0675-3

[20] Li F, Wang Y, Yu L, et al. Viral Infection of the Central Nervous System and Neuroinflammation Precede Blood-Brain Barrier Disruption during Japanese Encephalitis Virus Infection. J Virol. 2015;89(10):5602-5614. DOI:10. 1128/JVI.00143-15

[21] Chen SO, Chang TJ, Stone G, Chen CH, Liu JJ. Programmed cell death induced by Japanese encephalitis virus YL vaccine strain or its recombinant envelope protein in varied cultured cells. Intervirology. 2006;49(6):346-351. DOI:10.1159/000095154

[22] Das S, Basu A. Japanese encephalitis virus infects neural progenitor cells and decreases their proliferation. J

Neurochem. 2008;106(4):1624-1636. DOI:10.1111/j.1471-4159.2008.05511.x

[23] Mathur A, Arora KL, Chaturvedi UC. Transplacental Japanese encephalitis virus (JEV) infection in mice during consecutive pregnancies. J Gen Virol. 1982;59(Pt 1):213-217. DOI:10.1099/0022-1317-59-1-213

[24] Pan CH, Chen HW, Huang HW, Tao MH. Protective mechanisms induced by a Japanese encephalitis virus DNA vaccine: requirement for antibody but not CD8(+) cytotoxic T-cell responses. J Virol. 2001;75(23):11457- 11463. DOI:10.1128/JVI.75.23. 11457-11463.2001

[25] Larena M, Regner M, Lobigs M. Cytolytic effector pathways and IFN-γ help protect against Japanese encephalitis. Eur J Immunol. 2013;43(7): 1789-1798. DOI:10.1002/eji.201243152

[26] Chhatbar C, Detje CN, Grabski E, et al. Type I Interferon Receptor Signaling of Neurons and Astrocytes Regulates Microglia Activation during Viral Encephalitis. Cell Rep. 2018;25(1):118- 129.e4. DOI:10.1016/j.celrep.2018. 09.003

[27] Saxena SK, Singh A, Mathur A. Antiviral effect of nitric oxide during Japanese encephalitis virus infection. Int J Exp Pathol. 2000;81(2):165-172. DOI:10.1046/j.1365-2613.2000.00148.x

[28] Li Y, Counor D, Lu P, Duong V, Yu Y, Deubel V. Protective immunity to Japanese encephalitis virus associated with anti-NS1 antibodies in a mouse model. Virol J. 2012;9:135. Published 2012 Jul 24. DOI:10.1186/1743- 422X-9-135

[29] Konishi E, Kurane I, Mason PW, et al. Induction of Japanese encephalitis virus-specific cytotoxic T lymphocytes in humans by poxvirus-based JE vaccine candidates [published correction appears in Vaccine 1999 Feb 5;17(5):I].

**10**

*Innate Immunity in Health and Disease*

**References**

[1] Japanese encephalitis. World Health Organization. (https://www.who.int/ news-room/fact sheets/detail/japanesee ncephalitis#:~:text=Permanent%20 neurologic%20or%20psychiatric%20 sequelae,no%20cure%20for%20the%20 disease) [Accessed on 04 Aril 2021]

Medicine. 2004 351(4):370.DOI:

[9] Sooryanarain H, Ayachit V, Gore M. Activated CD56(+) lymphocytes

in-vitro. Virology. 2012;432(2):250-260.

immunomodulatory and anti-viral effects during Japanese encephalitis virus infection of dendritic cells

DOI:10.1016/j.virol.2012.05.013.

[10] Aleyas AG, George JA, Han YW, et al. Functional modulation of dendritic cells and macrophages by Japanese encephalitis virus through MyD88 adaptor molecule-dependent and -independent pathways. J Immunol. 2009;183(4):2462-2474. DOI:10.4049/

[11] Gupta N, Hegde P, Lecerf M, et al. Japanese encephalitis virus expands regulatory T cells by increasing the expression of PD-L1 on dendritic cells. Eur J Immunol. 2014;44(5):1363-1374.

10.1056/NEJMra030476

(NK+NKT) mediate

jimmunol.0801952

DOI:10.1002/eji.201343701

[12] Sooryanarain H, Sapkal GN, Gore MM. Pathogenic and vaccine strains of Japanese encephalitis virus elicit different levels of human macrophage effector functions. Arch Virol. 2012;157(10):1905-1918. DOI:10.1007/s00705-012-1386-8

[13] Kundu K, Dutta K, Nazmi A, Basu A. Japanese encephalitis virus infection modulates the expression of suppressors of cytokine signaling (SOCS) in macrophages: implications for the hosts' innate immune response. Cell Immunol. 2013;285(1-2):100-110. DOI:10.1016/j.cellimm.2013.09.005

[14] Lannes N, Summerfield A,

in Japanese encephalitis. J

s12974-017-0931-5

Filgueira L. Regulation of inflammation

Neuroinflammation. 2017;14(1):158. Published 2017 Aug 14. DOI:10.1186/

[2] Solomon T, Ni H, Beasley DW, Ekkelenkamp M, Cardosa MJ, Barrett AD. Origin and evolution of Japanese encephalitis virus in southeast Asia. J Virol. 2003;77(5):3091-3098. DOI:10.1128/jvi.77.5.3091-3098.2003

[3] Tu T, Xu K, Xu L, Gao Y, Zhou Y, He Y, Liu Y, Liu Q, Ji H, Tang W. Association between meteorological factors and the prevalence dynamics of Japanese encephalitis. PLoS One. 2021;

Kimura-Kuroda J, et al. Analysis of Japanese encephalitis (JE) virus genome and implications for recombinant JE vaccine. Southeast Asian J Trop Med Public Health. 1990;21(4):663-669.

[5] Gao X, Liu H, Li X, et al. Changing Geographic Distribution of Japanese Encephalitis Virus Genotypes, 1935-2017. Vector Borne Zoonotic Dis. 2019;19(1):35-

[6] Saxena SK, Kumar S, Maurya VK. Pathogen-associated acute encephalitis

44. DOI:10.1089/vbz.2018.2291

syndrome: therapeutics and management. Future Microbiol. 2019;14:259-262. DOI:10.2217/

[7] Nikitina E, Larionova I, Choinzonov E, Kzhyshkowska J. Monocytes and Macrophages as Viral Targets and Reservoirs. Int J Mol Sci. 2018;19(9):2821. Published 2018 Sep 18.

DOI:10.3390/ijms19092821

[8] Solomon, Tom. Flavivirus

Encephalitis. New England Journal of

fmb-2018-0334

16(3):e0247980.

[4] Yasui K, Miyamoto M,

Vaccine. 1998;16(8):842-849. DOI:10.1016/s0264-410x(97)00265-x

[30] Ochsenbein AF, Pinschewer DD, Odermatt B, Carroll MC, Hengartner H, Zinkernagel RM. Protective T cellindependent antiviral antibody responses are dependent on complement. J Exp Med. 1999;190(8): 1165-1174. DOI:10.1084/jem.190.8.1165

[31] Thielens NM, Tacnet-Delorme P, Arlaud GJ. Interaction of C1q and mannan-binding lectin with viruses. Immunobiology. 2002;205(4-5):563-574. DOI:10.1078/0171-2985-00155

[32] Agrawal P, Nawadkar R, Ojha H, Kumar J, Sahu A. Complement Evasion Strategies of Viruses: An Overview. Front Microbiol. 2017;8:1117. DOI:10.3389/fmicb.2017.01117

[33] Avirutnan P, Mehlhop E, Diamond MS. Complement and its role in protection and pathogenesis of flavivirus infections. Vaccine. 2008;26(Suppl 8):I100-I107. DOI:10.1016/j.vaccine.2008.11.061

**13**

**Chapter 2**

**Abstract**

**1. Introduction**

Function

How Human Herpesviruses

*Linda Popella and Alexander Steinkasserer*

implications of DC subversion regarding T lymphocyte activation.

them targeting dendritic cell (DCs) as described below [3, 5, 9–12].

**Keywords:** dendritic cells, HSV-1, HSV-2, VZV, HCMV, CD83, CYTIP, adhesion, migration, lamins, autophagy, H-particles, L-particles, T lymphocyte activation

*Herpesviridae* constitute an extremely successful virus family, evident from the considerable prevalence among the world's population [1]. During co-evolution of herpesviruses with its human host, not only the host's immune system was compelled to mount efficient antiviral defense mechanisms but also the virus has evolved a multitude of sophisticated strategies to dampen those immune responses [2–6]. Thus, herpesviral infections of men represent a tug of war, in which the host's antiviral responses are faced with the virus-mediated immune evasion mechanisms. The probably most intriguing strategy of herpesviral immune subversion is the establishment of latency in immune-privileged niches in the host, leading to lifelong persistent infections accompanied by episodes of viral reactivation [7, 8]. An additional cornerstone contributing to the success of human herpesviruses is the potent infection of a plethora of distinct cell types *in vitro* and *in vivo*, including the manipulation of vital functions of nonimmune as well as immune cells, many of

Subvert Dendritic Cell Biology and

In the last decades, a multitude of distinct herpesvirus-mediated immune evasion mechanisms targeting dendritic cell (DC) biology were uncovered. Within this chapter, we summarize the current knowledge how herpesviruses, especially the α-herpesviruses HSV-1, HSV-2, varicella-zoster virus (VZV), and the β-herpesvirus HCMV, shape and exploit the function of myeloid DCs in order to hamper the induction of potent antiviral immune responses. In particular, the main topics covering herpesvirus-mediated immune evasion will involve: (i) the modulation of immature DC (iDC) phenotype, (ii) modulation of iDC apoptosis, (iii) the inhibition of DC maturation, (iv) degradation of the immune-modulatory molecule CD83 in mature DCs (mDCs), (v) interference with the negative regulator of β2 integrin activity, cytohesin-1 interaction partner (CYTIP), (vi) resulting in modulation of adhesion and migration of mDCs, (vii) autophagic degradation of lamins to support productive HSV-1 replication in iDCs, (viii) the release of uninfectious L-particles with immune-modulatory potential from HSV-1-infected mDCs, and (ix) the

#### **Chapter 2**

*Innate Immunity in Health and Disease*

Vaccine. 1998;16(8):842-849.

DOI:10.1016/s0264-410x(97)00265-x

[30] Ochsenbein AF, Pinschewer DD, Odermatt B, Carroll MC, Hengartner H, Zinkernagel RM. Protective T cellindependent antiviral antibody responses are dependent on

complement. J Exp Med. 1999;190(8): 1165-1174. DOI:10.1084/jem.190.8.1165

[31] Thielens NM, Tacnet-Delorme P, Arlaud GJ. Interaction of C1q and mannan-binding lectin with viruses. Immunobiology. 2002;205(4-5):563-574.

[32] Agrawal P, Nawadkar R, Ojha H, Kumar J, Sahu A. Complement Evasion Strategies of Viruses: An Overview. Front Microbiol. 2017;8:1117. DOI:10.3389/fmicb.2017.01117

Diamond MS. Complement and its role in protection and pathogenesis of flavivirus infections. Vaccine. 2008;26(Suppl 8):I100-I107. DOI:10.1016/j.vaccine.2008.11.061

DOI:10.1078/0171-2985-00155

[33] Avirutnan P, Mehlhop E,

**12**
