Innate immune response to viral infection Cytokine - sepeap

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ARTICLE IN PRESS 2 S. Koyama et al. / Cytokine xxx (2008) xxx–xxx virus infection. TLR3 is expressed more widely, but is mainly expressed on conventional DCs (cDCs) [5]. The function of TLR8 is not clearly known yet. Recently endoplasmic reticulum (ER) protein UNC93B1 turned out to be essential for trafficking of TLR7 and TLR9 from ER to endosome [6], but what triggers this TLR-trafficking from ER to endosome before viral recognition by TLRs remains to be elucidated. A recent report suggests that TLR-sorting to the ligand may utilize autophagy, which is a cellular process for recycling cytosolic compartments and, in the case of pDC, eliminating exogenous pathogen. Although cytoplasmic vesicular somatitis viruses (VSV) in pDC are thought to be trapped by autophagosome expressing ATG5 and detected by TLR7 in lysosomes for a type I IFN response [7], in non-immune cells ATG5 suppresses the type I IFN response by interaction with caspase recruitment domains (CARDs) presented by RIG-I and IFN-b promoter stimulator-1 (IPS-1) [8] (Fig. 1). 2.2. Endosomal recognition of viral RNA by TLRs TLR7 recognizes several kinds of RNA viruses, including orthomyxoviruses in pDCs. TLR7 signals through a TIR domaincontaining adapter, myeloid differentiation factor 88 (MyD88). Upon exposure to its ligand, MyD88 forms a complex with interleukin-1-receptor (IL-1R)-associated kinase-4 (IRAK-4), IRAK-1, tumor necrosis factor-receptor associated factor 3 (TRAF3), TRAF6, Ikka and IRF-7 [9–11]. Following the formation of this signaling complex, IRF7 and nuclear factor-kappa B (NF-jB) are activated, which results in the production of type I IFNs and cytokines (Fig. 1). TLR3 recognizes double-stranded (ds)RNA and triggers a signaling pathway via a TIR domain-containing adapter inducing IFN-b (TRIF) (also known as TICAM-1) [12,13]. TRIF associates with TRAF3 and TRAF6 via TRAF-binding motifs which exist in its N-terminal portion and also with receptor interacting protein (RIP) 1 and RIP3 via RIP homotypic interaction motif (RHIM) [14,15]. TRAF6 and RIP1 activate NF-jB while TRAF3 activates TRAF family member-associated NK-jB activator (TANK)-binding kinase 1 (TBK1) and inducible IjB kinase (IKK-i). Activation of these pathways triggers antiviral responses (Fig. 1). TLR3 also activates the phosphatidylinositol-3 kinase (PI3K) pathway [16]. Tyrosine phosphorylation of TLR3 induces PI3K recruitment to the receptor and subsequent activation of Akt leads to activation of IRF-3. TLR3 plays an important role in the pathogenesis of RNA virus infections in vivo. For example, TLR3 deficient mice are resistant to infection Fig. 1. RNA sensing in virus infection. TLR3 recognizes dsRNA and triggers a signaling pathway via a TRIF. TRIF associates with TRAF3, TRAF6 and RIP1. TRAF6 and RIP1 activate NF-kB and AP-1 while TRAF3 activates TBK1/IKK-i and is followed by a type I IFN response. Both RIG-I and MDA5 associate with an adapter protein IPS-1. IPS-1 localizes on the outer mitochondrial membrane and the CARD of it interacts with that of RIG-I or MDA5. IPS-1 associates with TRAF3 which induces the production of type I IFNs and FADD which induces activation of NF-kB. TLR7 signals through MyD88. MyD88 forms a complex with IRAK-4, IRAK-1, TRAF3, TRAF6, Ikka and IRF-7 and this complex is recruited to the TLR by ligand stimulation. Downstream of this signaling complex, IRF7 and NF-kB are activated and this is followed by the production of type I IFNs and cytokines. ER protein UNC93B1 plays a key role in trafficking of TLR7 from ER to endosome, but the triggers are unknown. In the case of VSV recognition in pDC, the virus is trapped by autophagosome expressing ATG5 and detected by TLR7 in the lysosome for production of a type I IFN response. Moreover in non-immune cells ATG5 suppresses the type I IFN response via RIG-I or IPS-1 inhibition. Yellow rectangles (TIR, CARD) indicate protein–protein interaction regions for downstream signaling. Please cite this article in press as: Koyama S et al., Innate immune response to viral infection, Cytokine (2008), doi:10.1016/ j.cyto.2008.07.009
ARTICLE IN PRESS S. Koyama et al. / Cytokine xxx (2008) xxx–xxx 3 with West Nile virus [17] and influenza virus [18]. In both cases inflammatory responses are decreased in TLR3 deficient mice, which suggests that an excess production of cytokines is rather harmful for the survival of mice. 2.3. Intracellular recognition of viral RNA by RLRs Recently, three homologous DExD/H box RNA helicases, RIG-I, melanoma differentiation-associated gene 5 (MDA5) and LGP2, were identified as cytoplasmic sensors of virus RNA, named here as RIG-like receptors (RLRs). RIG-I and MDA5 play a major role in recognition of RNA viruses in cDCs, macrophages and fibroblasts. RIG-I and MDA5 share two N-terminal CARDs followed by an RNA helicase domain [19] while LGP2 lacks a CARD. RIG-I binds 5 0 -triphosphorylated single-stranded (ss)RNA [20] and short dsRNA [21] and stimulates production of type I IFNs. By contrast, MDA5 preferentially recognizes longer-dsRNA, including synthetic poly-IC [22]. RIG-I recognizes a variety of RNA viruses including influenza virus, VSV and Japanese encephalitis virus (JEV) while MDA5 recognizes picorna family such as encephalomyocarditis virus (EMCV), Theiler’s virus and Mengo virus [22]. Therefore, RIG-I and MDA5 deficient mice are highly susceptible to VSV and EMCV, respectively. In addition it was indicated that the antiviral protein RNase L, which can cleave and turn a singlestranded portion of not only viral but also self RNA into preferentially double-stranded form RNA, is a ligand for RIG-I and MDA5 [23]. The CARDs of RIG-I and MDA5 are responsible for initiating the signaling pathway. Both RIG-I and MDA5 associate with an adapter protein IPS-1 also known as MAVS, VISA or CARDIF, which also contains an N-terminal CARD [24–27]. IPS-1 localizes on the outer mitochondrial membrane. The IPS-1 CARD interacts with that of RIG-I or MDA5. IPS-1 then associates with TRAF3, followed by activation of TBK1 and Ikk-i. These kinases phosphorylate IRF3 and IRF7 and induce type I IFN production [28,29]. IPS-1 also interacts with Fas-associated death domain-containing protein (FADD) and leads to activation of NF-jB through cleavage of caspase-8/-10 [30] (Fig. 1). 2.4. Differential role of TLR and RLR in antiviral responses Occasionally both TLR and RLR are engaged for sensing the same dsRNA or ssRNA. Normally dsRNA does not exist in host cells but in virus infection it is detected as not only a viral structure but also as a byproduct of viral replication. dsRNA activates macrophages and dendritic cells via TLR3 to secrete pro-inflammatory cytokines, especially IL-12. However, type-I IFNs are produced by virus-infected cells such as fibroblasts by TLR3 independently. MDA5 recognizes synthetic dsRNA, poly-IC, and the ssRNA virus, EMCV, which generates dsRNA during replication, and induces the type-I IFN response [22,31]. Poly-IC is neither capable of inducing an innate immune response nor of working as an adjuvant in TRIF/ IPS-1 double knockout mice [32]. In contrast to dsRNA, ssRNA abundantly exists not only in pathogens but also in host cells. ssRNA is recognized by TLR7 (or TLR8 in humans) and RIG-I in a cell-type specific manner. Although TLR7 and TLR8 recognize GU of AU rich sequences of ssRNA viruses such as influenza virus and HIV, through TLR7 expressing cells such as pDC, or TLR8 expressing cells such as myeloid DC or monocytes, it is unclear whether its sequence specificity is dependent on the receptor or the cell [33]. In contrast to TLR7, RIG-I is expressed in most cell types. As described previously, RIG-I recognizes 5 0 -triphosphorylated ssRNA [20]. In the case of influenza A virus infection, its negative-sense ssRNA genome is recognized by TLR7 expressed in pDCs and a signal is transmitted through its adaptor protein MyD88 [34]. On the other hand, it is recognized by RIG-I ubiquitously expressed in most cell types, such as fibroblasts or cDCs in vitro [35], and probably by the alveolar macrophage in vivo [36], via its adaptor protein IPS-1. In mouse lungs after intranasal infection of influenza virus both TLR7/MyD88 and RIG-I/IPS-1 pathways concurrently control the type-I IFN response [37]. 2.5. Endosomal and intracellular recognition of viral DNA TLR9 recognizes unmethylated DNA with a CpG motif (CpG- DNA) and DNA viruses, including herpes simplex virus (HSV)-1, HSV-2 and cytomegalovirus (CMV) in pDCs. TLR9 shares the adapter protein MyD88 and the downstream signaling pathway with TLR7. cDCs and macrophages also respond to CpG-DNA and produce small amounts of IFN-b through IRF-1 activation rather than IRF-3 or IRF-7 activation [38]. Recently, it was reported that genomic DNA of viruses, such as adenovirus, vaccinia virus and HSV [39–41], could be also recognized in a TLR9-independent manner, using an as yet unknown recognition mechanism in the cytoplasm [42,43]. In this case, DNA which has entered the cytoplasm activates the infected cells via TBK1 and IRF3 [44]. Actually the source of DNA is not restricted to viruses; but it can also come from bacteria and damaged host cells. The activity of this DNA is more potent in ds right-hand B- form DNA than in left-handed Z-form DNA, while ssDNA displays no activity [40,44,45] (Fig. 2). In addition DAI (also known as ZBP1 or DLM1) which contains two Z-DNA binding domains, was shown to be a potential cytoplasmic DNA sensor [46]. However, DAI KO mice induced a normal type I IFN response in vitro and in vivo after B-DNA stimulation and also indicated DNA-vaccine-induced adaptive immune responses, suggesting its role is redundant [47]. Potential cytoplasmic DNA sensors still remain to be elucidated. 2.6. The recognition of viral components at the cell surface In addition to the endosomal TLRs, TLR2 and TLR4 have also been suggested to be involved in recognition of viruses. TLR2 has been shown to detect components of measles virus, HSV and hepatitis C virus (HCV) [48–50], while TLR4 produces a response to retrovirus and respiratory syncytial virus (RSV) [51,52]. While viral proteins recognized by these surface TLRs trigger pro-inflammatory responses, their contribution to either protective or pathological immune responses largely depends on the type of virus, route of infection, and other host factors [53]. 2.7. NLRs mediates innate immune activation by intracellular viral nucleic acids NLR proteins are comprised three motifs, C-terminal LRRs, central nucleotide-binding domain and N-terminal signaling domaincontaining CARDs, and Pyrin domain or baculovirus IAP repeats [54]. Cryopyrin/NALP3 was shown to recognize both ssRNA and dsRNA of viral origin or their synthetic versions and to induce caspase-1 activation via apoptosis-associated speck-like protein containing a caspase-activating and recruitment domain (ASC) [55,56]. In addition, some NLRs participate in nucleic acid-mediated innate immune activation through caspase-1 activation [56,57], and NF-jB activation towards IFN-I production via a synergistic pathway activated by NOD2 [58]. 3. Discrimination between self and viral nucleic acids The innate immune systems for virus sensing described above miraculously detect the invasion of pathogens such as viruses, Please cite this article in press as: Koyama S et al., Innate immune response to viral infection, Cytokine (2008), doi:10.1016/ j.cyto.2008.07.009
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