**4.2.4 Heparan sulfate proteoglycans (HSPGs) and HSV**

Heparan sulfate proteoglycans (HSPGs) are secreted and membrane associated proteins covalently attached to unbranched glycosaminoglycan heparan sulfate (HS) molecules which are composed of linear polysaccharide chains (Esko and Selleck, 2002). HS molecules are synthesized on a variety of cell surface proteins but are found consistently on members of two major families of membrane-bound proteoglycans: the transmembrane core proteins syndecans and the GPI-linked glypicans (Bernfield et al., 1999). HS can influence cellenvironment interactions by binding to a heterogeneous group of growth factors, matrix ligands, and cell surface molecules. The possibility that HS could serve as an entry receptor for HSV type 1 and 2 was assessed on HEp-2 cells (WuDunn and Spear, 1989). They found that heparin blocked both virus adsorption. Different adsorption inhibitory agents including, heparin and poly-L-lysine (both bind to anions on the surface of virions and cells) and platelet factor 4 (which has a high affinity for heparin and heparan sulfate) was tested. After the incubation of these agents with HEp-2 cells either immediately before or during exposure with HSV-1 or HSV-2, an inhibition of virions adsorption by heparin was observed. Same results for poly-L-lysine and platelet factor 4 were obtained. A further study investigated the role of cell surface heparan sulfate in HSV infection using heparan sulfatedeficient mutants CHO cells (Shieh et al., 1992). They demonstrated that CHO mutants with defect in heparan sulfate biosynthesis are resistant to HSV infection and have reduced numbers of receptor for HSV.

Virus-Induced Encephalitis and

**5.2 The RIG-I-like receptors (RLRs)** 

Innate Immune Responses – A Focus on Emerging or Re-Emerging Viruses 73

no significant differences where noted in viral growth kinetics or IFN-alpha/beta induction

After the discovery of TLRs, several classes of PRRs, including the RLRs were identified. The RLR family consists of the three RNA helicases members: retinoic inducible gene-I (RIG-I), the melanoma differentiation-associated factor 5 (MDA5 also known as helicard or IFIH1) and the laboratory of genetics and physiology 2 (LGP2) that detect RNA viruses (Yoneyama and Fujita, 2009). RIG-I and MDA5 contain a C-terminal DExD/H box RNA helicase domain that is a characteristic amino acid signature motif of many RNA binding proteins, as well as two N-terminal caspase activation and recruitment domain (CARDs). LGP2 lacks CARD domains and has been proposed to function as a regulator of RIG-I/MDA5 signaling (Nakhaei et al., 2009). RIG-1 and MDA-5 are expressed by microglia and astrocytes, and located mainly in the cytosol and detect both short and long ds and ssRNA respectively (Furr et al., 2008; Hoarau et al., 2011). This interaction activates a series of intracellular signaling pathways using the adaptor molecules such as Interferon promoter stimulator (IPS-1) resulting in the transcription of IFNαβ interleukins and a range of anti-viral proteins. IPS-1 is key in the control of cell infection by several alphaviruses and flaviviruses including CHIKV and WNV, respectively. IPS-1-/- mice was recently shown to exhibit increased susceptibility to WNV infection marked by enhanced viral replication and dissemination with early viral entry into the CNS (Suthar et al., 2010). Moreover, infection of dendritic cells macrophages and primary cortical neurons showed that the IPS-1-dependent RLR signaling was essential for triggering IFN response (Suthar et al., 2010). Unexpectedly, infected KO mice also displayed uncontrolled inflammation that included elevated systemic type I IFN, proinflammatory cytokine and chemokine responses, increased numbers of inflammatory cells, enhanced humoral responses marked by complete loss of virus neutralization activity, and increased numbers of virus-specific CD8+ T cells and non-specific immune cell proliferation in the periphery and in the CNS. This uncontrolled inflammatory response was associated with a lack of regulatory T cell expansion that normally occurs during acute WNV infection. Thus, the enhanced inflammatory response in the absence of IPS-1 was coupled with a failure to protect against WNV infection. This is an important finding which stresses that IPS-1-dependent RLR signaling is equally important in the innate/adaptive immune responses but also in the balance of the immune response to WNV infection. With regards to CHIKV, it has recently been shown that IPS-1 is important at least in the

between wild-type and TLR3 KO fibroblasts, macrophages, and dendritic cells.

periphery to drive a robust anti-viral response (Schilte et al., 2010).

**viral response** 

**5.3 CNS Innate immune system; Interferon type 1 and 2 responses stimulate an anti-**

Mice deficient for the type I IFN receptor (IFNAR) has proved the fundamental importance of the type I IFN in the control of virus replication (Couderc et al., 2008; Muller et al., 1994). Indeed, CNS virus infections are more lethal in mice deficient in IFNAR than the wild type equivalent, emphasizing the importance of IFN/IFNAR pathway for anti-viral defense (Griffin, 2003; Paul et al., 2007). The type 1 interferon response is made by most CNS cells and results in a non-apoptotic anti-viral response by the host cell reducing infection by a replicating RNA virus (Katze et al., 2002). The IFN anti-viral response involves IFN binding to IFNAR on the host cell leading to the activation of Janus kinases (JAK) with phosphorylation of the activators of transcription factors (STAT1 and STAT2). These two

#### **5. Innate immune responses against viral infection in the CNS**

The active and highly regulated control of immune responses in the brain is referred to as "immune privilege". The BBB, which prevents viruses, constituents of the adaptive immune system and antigen presenting cells, gaining accesses to the brain (for a review, see (Savarin and Bergmann, 2008)), is considered to be responsive for this privileged environment of the CNS. The CNS, therefore relies upon glia perivascular and meningeal cells to provide the innate immune response against virus attack (Hauwel et al., 2005). Microglia, astrocytes, ependymal cells, oligodendrocytes and neurons express Pattern Recognition Receptors (PRR)s (Suh et al., 2009) including the highly conserved Toll like receptors (TLR)s and the Retinoic inducible gene like RIG-1 receptors (RLRs) (Fujita et al., 2007) that detect the presence of "non self "as represented by viral nucleic acids.

#### **5.1 TLRs**

The TLRs are PRRs that have unique and essential function in animal immunity. TLRs comprise a family of type I transmembrane receptors, which are characterized by an extracellular leucine-rich repeat (LRR) domain and an intracellular Toll-interleukin-1 receptor (TIR) domain. LRR domains are found in a diverse set of proteins and mediate the recognition of components of foreign pathogens referred to as pathogen-associated molecular patterns (PAMPs) (for a review, see (Alexopoulou et al., 2001)). The cytoplasmic TIR domain of Toll proteins is a conserved protein-protein interaction module that is required for downstream signal transduction. So far, 10 and 12 functional TLRs have been identified in humans and mice, respectively, with TLR1-9 being conserved in both species (Takahashi et al., 2006). Microglia are the resident macrophages in the CNS and also express a wide range of TLRs (TLR1-9). Astrocytes express TLR1, 2, 3, 4, 5 and 9 whereas neurons mainly express TLR3 (Carty and Bowie, 2010). TLRs are located on the cell surface and are also distributed in the endosome so they are strategically placed to detect cytoplasmic viral RNA. TLR9 is activated by DNA rich in CpG motifs, whereas TLR7 and TLR8 recognize RNA viruses and ssRNA. TLR3 is activated by dsRNA formed during replication of viruses. TLRs signal through the adaptor molecules, myeloid differentiation primary response gene 88 (MyD88) and Trif, to initiate intracellular signaling by transcription factors such as and the IFN regulatory factors (IRFs) (Alexopoulou et al., 2001). These IRFs are translocated to the host cell nucleus where they regulate inflammatory cytokine synthesis and stimulate type I interferon synthesis (IFNα-β expression) to produce a protective response (anti-viral state) in adjacent uninfected cells (Paul et al., 2007). A further anti-viral property of the IRF is through its binding to the pro-apoptotic protein Bax and translocation to the mitochondria with activation of the mitochondrial apoptotic pathway, terminating virus replication (Chattopadhyay et al., 2010). Viruses can activate more than one TLR and it is known for example that TLR9 as well as TLR2 in dendritic cells and neuronal cells can respond to HSV to drive a protective IFN- antiviral response (Bereczky-Veress et al., 2010; Sato et al., 2006). RNA viruses such as HIV, Rabies and WNV are more likely to be recognized by TLR3 and/or TLR7 or 8 expressed by microglia and neuronal cells (Prehaud et al., 2005; Szretter et al., 2010; Wang et al., 2004). The absence of TLR3 enhances WNV mortality in mice and increases viral burden in the brain (Daffis et al., 2008). Compared to wild-type controls, TLR3 -/- mice showed relatively little changes in peripheral viral loads. Interestingly, deficiency of TLR3 was associated with enhanced viral replication in primary cortical neuron cultures and greater WNV infection in neurons after intracranial inoculation while no significant differences where noted in viral growth kinetics or IFN-alpha/beta induction between wild-type and TLR3 KO fibroblasts, macrophages, and dendritic cells.

#### **5.2 The RIG-I-like receptors (RLRs)**

72 Non-Flavivirus Encephalitis

The active and highly regulated control of immune responses in the brain is referred to as "immune privilege". The BBB, which prevents viruses, constituents of the adaptive immune system and antigen presenting cells, gaining accesses to the brain (for a review, see (Savarin and Bergmann, 2008)), is considered to be responsive for this privileged environment of the CNS. The CNS, therefore relies upon glia perivascular and meningeal cells to provide the innate immune response against virus attack (Hauwel et al., 2005). Microglia, astrocytes, ependymal cells, oligodendrocytes and neurons express Pattern Recognition Receptors (PRR)s (Suh et al., 2009) including the highly conserved Toll like receptors (TLR)s and the Retinoic inducible gene like RIG-1 receptors (RLRs) (Fujita et al., 2007) that detect the

The TLRs are PRRs that have unique and essential function in animal immunity. TLRs comprise a family of type I transmembrane receptors, which are characterized by an extracellular leucine-rich repeat (LRR) domain and an intracellular Toll-interleukin-1 receptor (TIR) domain. LRR domains are found in a diverse set of proteins and mediate the recognition of components of foreign pathogens referred to as pathogen-associated molecular patterns (PAMPs) (for a review, see (Alexopoulou et al., 2001)). The cytoplasmic TIR domain of Toll proteins is a conserved protein-protein interaction module that is required for downstream signal transduction. So far, 10 and 12 functional TLRs have been identified in humans and mice, respectively, with TLR1-9 being conserved in both species (Takahashi et al., 2006). Microglia are the resident macrophages in the CNS and also express a wide range of TLRs (TLR1-9). Astrocytes express TLR1, 2, 3, 4, 5 and 9 whereas neurons mainly express TLR3 (Carty and Bowie, 2010). TLRs are located on the cell surface and are also distributed in the endosome so they are strategically placed to detect cytoplasmic viral RNA. TLR9 is activated by DNA rich in CpG motifs, whereas TLR7 and TLR8 recognize RNA viruses and ssRNA. TLR3 is activated by dsRNA formed during replication of viruses. TLRs signal through the adaptor molecules, myeloid differentiation primary response gene 88 (MyD88) and Trif, to initiate intracellular signaling by transcription factors such as and the IFN regulatory factors (IRFs) (Alexopoulou et al., 2001). These IRFs are translocated to the host cell nucleus where they regulate inflammatory cytokine synthesis and stimulate type I interferon synthesis (IFNα-β expression) to produce a protective response (anti-viral state) in adjacent uninfected cells (Paul et al., 2007). A further anti-viral property of the IRF is through its binding to the pro-apoptotic protein Bax and translocation to the mitochondria with activation of the mitochondrial apoptotic pathway, terminating virus replication (Chattopadhyay et al., 2010). Viruses can activate more than one TLR and it is known for example that TLR9 as well as TLR2 in dendritic cells and neuronal cells can respond to HSV to drive a protective IFN- antiviral response (Bereczky-Veress et al., 2010; Sato et al., 2006). RNA viruses such as HIV, Rabies and WNV are more likely to be recognized by TLR3 and/or TLR7 or 8 expressed by microglia and neuronal cells (Prehaud et al., 2005; Szretter et al., 2010; Wang et al., 2004). The absence of TLR3 enhances WNV mortality in mice and increases viral burden in the brain (Daffis et al., 2008). Compared to wild-type controls, TLR3 -/- mice showed relatively little changes in peripheral viral loads. Interestingly, deficiency of TLR3 was associated with enhanced viral replication in primary cortical neuron cultures and greater WNV infection in neurons after intracranial inoculation while

**5. Innate immune responses against viral infection in the CNS** 

presence of "non self "as represented by viral nucleic acids.

**5.1 TLRs** 

After the discovery of TLRs, several classes of PRRs, including the RLRs were identified. The RLR family consists of the three RNA helicases members: retinoic inducible gene-I (RIG-I), the melanoma differentiation-associated factor 5 (MDA5 also known as helicard or IFIH1) and the laboratory of genetics and physiology 2 (LGP2) that detect RNA viruses (Yoneyama and Fujita, 2009). RIG-I and MDA5 contain a C-terminal DExD/H box RNA helicase domain that is a characteristic amino acid signature motif of many RNA binding proteins, as well as two N-terminal caspase activation and recruitment domain (CARDs). LGP2 lacks CARD domains and has been proposed to function as a regulator of RIG-I/MDA5 signaling (Nakhaei et al., 2009). RIG-1 and MDA-5 are expressed by microglia and astrocytes, and located mainly in the cytosol and detect both short and long ds and ssRNA respectively (Furr et al., 2008; Hoarau et al., 2011). This interaction activates a series of intracellular signaling pathways using the adaptor molecules such as Interferon promoter stimulator (IPS-1) resulting in the transcription of IFNαβ interleukins and a range of anti-viral proteins. IPS-1 is key in the control of cell infection by several alphaviruses and flaviviruses including CHIKV and WNV, respectively. IPS-1-/- mice was recently shown to exhibit increased susceptibility to WNV infection marked by enhanced viral replication and dissemination with early viral entry into the CNS (Suthar et al., 2010). Moreover, infection of dendritic cells macrophages and primary cortical neurons showed that the IPS-1-dependent RLR signaling was essential for triggering IFN response (Suthar et al., 2010). Unexpectedly, infected KO mice also displayed uncontrolled inflammation that included elevated systemic type I IFN, proinflammatory cytokine and chemokine responses, increased numbers of inflammatory cells, enhanced humoral responses marked by complete loss of virus neutralization activity, and increased numbers of virus-specific CD8+ T cells and non-specific immune cell proliferation in the periphery and in the CNS. This uncontrolled inflammatory response was associated with a lack of regulatory T cell expansion that normally occurs during acute WNV infection. Thus, the enhanced inflammatory response in the absence of IPS-1 was coupled with a failure to protect against WNV infection. This is an important finding which stresses that IPS-1-dependent RLR signaling is equally important in the innate/adaptive immune responses but also in the balance of the immune response to WNV infection. With regards to CHIKV, it has recently been shown that IPS-1 is important at least in the periphery to drive a robust anti-viral response (Schilte et al., 2010).

#### **5.3 CNS Innate immune system; Interferon type 1 and 2 responses stimulate an antiviral response**

Mice deficient for the type I IFN receptor (IFNAR) has proved the fundamental importance of the type I IFN in the control of virus replication (Couderc et al., 2008; Muller et al., 1994). Indeed, CNS virus infections are more lethal in mice deficient in IFNAR than the wild type equivalent, emphasizing the importance of IFN/IFNAR pathway for anti-viral defense (Griffin, 2003; Paul et al., 2007). The type 1 interferon response is made by most CNS cells and results in a non-apoptotic anti-viral response by the host cell reducing infection by a replicating RNA virus (Katze et al., 2002). The IFN anti-viral response involves IFN binding to IFNAR on the host cell leading to the activation of Janus kinases (JAK) with phosphorylation of the activators of transcription factors (STAT1 and STAT2). These two

Virus-Induced Encephalitis and

defence against an emerging neurotropic infection.

Innate Immune Responses – A Focus on Emerging or Re-Emerging Viruses 75

neuronal apoptosis (Liang et al., 1998). The ability of enforced neuronal expression of Beclin 1 to protect against lethal SINV encephalitis suggests a protective role for autophagy in host

Fig. 1. **Interactions between viruses and host cell receptors**: Several receptors are known to interact with viruses and controling subsequent encephalitis. Some are receptors (e.g. CD4, CD46) involved in cell entry and signaling although the pathways which are engaged remain poorly characterized. Others are innate immune receptors such as RIG-I MDA5 and TLR which are expressed by neurons and glial cells (microglia and astrocyte) to initiate welldescribed signaling pathways that converge at the activation of the transcription factors (IRF3/7 and/or nuclear factor-kB (NFkB)). These key events lead to the expression of type-I interferons (IFN-). The innate immune signaling pathways are intimately linked to apoptosis. The intrinsic apoptosis pathway is initiated by the release of cytochrome C from the mitochondria which promotes the formation of the apoptosome, including APAF-1 (apoptotic protease activating factor) and caspase 9 which in turn activates the effector caspase 3. The extrinsic pathway mobilized notably by TNF-, TRAIL or FASL involves death-receptor signaling pathways linked to FADD and caspase 8. Some viruses can escape

apoptosis by inducing the expression of anti-apoptotic proteins such as Bcl2.

proteins enter the nucleus to drive the expression of interferon stimulated genes (ISGs) (Goodbourn et al., 2000) . Host CNS cells in response to IFN stimulation produces a range of anti-viral ISGs, including oligoadenylate synthetase (OAS) and IFN-inducible ds RNA – dependent protein kinase (PKR) that both modulate virus replication; RNAse L and Mx that inhibit viral transcription together with the RNA deaminases (ADAR-1 and APOBEC3G) producing mutations in viral genomes (Goodbourn et al., 2000) (George et al., 2009) (Toth et al., 2009). (IRFs) IRF-7, IRF-9, and ISG54 are all increased following CNS virus infection and one IRF, ISG15, has been found to be significantly increased in astrocytes following their infection with RNA virus (Paul et al., 2007). Type 2 interferon response is due to the interferon again a glycoprotein expressed by activated T cells when TCR binds to their cognate antigen (Goodbourn et al., 2000). Many of the emerging viruses disable the host anti-viral response by targeting the pathways responsible for regulating IFN and anti-viral proteins.

#### **5.4 Phagocytosis and removal of infected cells**

The peculiarity of the CNS is that it is composed by a majority of cells that are nonrenewable. Hence, it is fundamental to rapidly clear the infected cells and limiting bystander effects and to reduce massive neuronal loss. Apoptotic cells must be rapidly cleared from the CNS because they contain neurotoxic proteins and viruses capable of increasing host tissue infection (Griffiths et al., 2009). Apoptotic cells express a range of non-self-molecules termed Apoptotic cell- associated molecular patterns (ACAMPs) on their surface and these molecules include sugars, nucleic acids, ribonucleoproteins and oxidized low density proteins. The best characterized ACAMP is the phosphatidylserine molecule (PS) (Fadok et al., 1998) (Savill et al., 2002). Glia and macrophages express a range of receptors including the phosphatidylserine receptor (PSR), CD14 and the Scavenger receptors (SR) divided into SRA ( SRA-1, SRA-II ) and SR B including CD36 all expressed by microglia (Areschoug and Gordon, 2009; Husemann et al., 2002; Savill et al., 2002) which are all involved in the selective recognition and clearance of apoptotic cells. It should be stressed that these receptors may also contribute in turn to the infection of phagocytic cells.

#### **5.5 Autophagy and control of viral infection**

Autophagy is a fundamental homeostatic process that leads to the degradation and recycling of long-lived cytoplasmic proteins and organelles (Klionsky, 2007) (Yoshimori, 2004). The hallmark of autophagy is the formation of double or multiple membrane-bound vesicles called autophagosomes, which sequester a portion of the cytoplasm and fuse, after maturation, with lysosomes to digest their contents. In the same way, autophagy can also act directly, as an innate immune actor, to engulf and degrade pathogens. There is now some evidence for an antiviral role of autophagy related to viruses that specifically target neurons. The prototype virus studied was SINV, which is a positive-stranded RNA virus in the alphavirus genus. In mice, SINV produces fatal encephalitis that can be prevented by the cellular Bcl-2, an inhibitor of apoptotis (Levine et al., 1993). In a search to understand the mechanism by which Bcl-2 regulates Sindbis virus pathogenesis, a yeast two-hybrid screening was performed of a mouse brain library using Bcl-2 as bait, leading to the identification of a novel Bcl-2-interacting coiled-coil protein, Beclin 1. Beclin 1 is the mammalian homologue of yeast Atg6 and the first identified mammalian autophagy protein. Enforced neuronal expression of Beclin 1 was found to protect mice against fatal SINV encephalitis. In addition, Beclin reduces CNS SINV replication and viral-induced

proteins enter the nucleus to drive the expression of interferon stimulated genes (ISGs) (Goodbourn et al., 2000) . Host CNS cells in response to IFN stimulation produces a range of anti-viral ISGs, including oligoadenylate synthetase (OAS) and IFN-inducible ds RNA – dependent protein kinase (PKR) that both modulate virus replication; RNAse L and Mx that inhibit viral transcription together with the RNA deaminases (ADAR-1 and APOBEC3G) producing mutations in viral genomes (Goodbourn et al., 2000) (George et al., 2009) (Toth et al., 2009). (IRFs) IRF-7, IRF-9, and ISG54 are all increased following CNS virus infection and one IRF, ISG15, has been found to be significantly increased in astrocytes following their infection with RNA virus (Paul et al., 2007). Type 2 interferon response is due to the interferon again a glycoprotein expressed by activated T cells when TCR binds to their cognate antigen (Goodbourn et al., 2000). Many of the emerging viruses disable the host anti-viral response by targeting the pathways responsible for regulating IFN and anti-viral

The peculiarity of the CNS is that it is composed by a majority of cells that are nonrenewable. Hence, it is fundamental to rapidly clear the infected cells and limiting bystander effects and to reduce massive neuronal loss. Apoptotic cells must be rapidly cleared from the CNS because they contain neurotoxic proteins and viruses capable of increasing host tissue infection (Griffiths et al., 2009). Apoptotic cells express a range of non-self-molecules termed Apoptotic cell- associated molecular patterns (ACAMPs) on their surface and these molecules include sugars, nucleic acids, ribonucleoproteins and oxidized low density proteins. The best characterized ACAMP is the phosphatidylserine molecule (PS) (Fadok et al., 1998) (Savill et al., 2002). Glia and macrophages express a range of receptors including the phosphatidylserine receptor (PSR), CD14 and the Scavenger receptors (SR) divided into SRA ( SRA-1, SRA-II ) and SR B including CD36 all expressed by microglia (Areschoug and Gordon, 2009; Husemann et al., 2002; Savill et al., 2002) which are all involved in the selective recognition and clearance of apoptotic cells. It should be stressed that these

Autophagy is a fundamental homeostatic process that leads to the degradation and recycling of long-lived cytoplasmic proteins and organelles (Klionsky, 2007) (Yoshimori, 2004). The hallmark of autophagy is the formation of double or multiple membrane-bound vesicles called autophagosomes, which sequester a portion of the cytoplasm and fuse, after maturation, with lysosomes to digest their contents. In the same way, autophagy can also act directly, as an innate immune actor, to engulf and degrade pathogens. There is now some evidence for an antiviral role of autophagy related to viruses that specifically target neurons. The prototype virus studied was SINV, which is a positive-stranded RNA virus in the alphavirus genus. In mice, SINV produces fatal encephalitis that can be prevented by the cellular Bcl-2, an inhibitor of apoptotis (Levine et al., 1993). In a search to understand the mechanism by which Bcl-2 regulates Sindbis virus pathogenesis, a yeast two-hybrid screening was performed of a mouse brain library using Bcl-2 as bait, leading to the identification of a novel Bcl-2-interacting coiled-coil protein, Beclin 1. Beclin 1 is the mammalian homologue of yeast Atg6 and the first identified mammalian autophagy protein. Enforced neuronal expression of Beclin 1 was found to protect mice against fatal SINV encephalitis. In addition, Beclin reduces CNS SINV replication and viral-induced

receptors may also contribute in turn to the infection of phagocytic cells.

proteins.

**5.4 Phagocytosis and removal of infected cells** 

**5.5 Autophagy and control of viral infection** 

neuronal apoptosis (Liang et al., 1998). The ability of enforced neuronal expression of Beclin 1 to protect against lethal SINV encephalitis suggests a protective role for autophagy in host defence against an emerging neurotropic infection.

Fig. 1. **Interactions between viruses and host cell receptors**: Several receptors are known to interact with viruses and controling subsequent encephalitis. Some are receptors (e.g. CD4, CD46) involved in cell entry and signaling although the pathways which are engaged remain poorly characterized. Others are innate immune receptors such as RIG-I MDA5 and TLR which are expressed by neurons and glial cells (microglia and astrocyte) to initiate welldescribed signaling pathways that converge at the activation of the transcription factors (IRF3/7 and/or nuclear factor-kB (NFkB)). These key events lead to the expression of type-I interferons (IFN-). The innate immune signaling pathways are intimately linked to apoptosis. The intrinsic apoptosis pathway is initiated by the release of cytochrome C from the mitochondria which promotes the formation of the apoptosome, including APAF-1 (apoptotic protease activating factor) and caspase 9 which in turn activates the effector caspase 3. The extrinsic pathway mobilized notably by TNF-, TRAIL or FASL involves death-receptor signaling pathways linked to FADD and caspase 8. Some viruses can escape apoptosis by inducing the expression of anti-apoptotic proteins such as Bcl2.

Virus-Induced Encephalitis and

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