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Cytokine
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Review Article

Innate immune response to viral infection


Shohei Koyama a,b, Ken J. Ishii a,c, Cevayir Coban a,b, Shizuo Akira a,b,*
a b c

Laboratory of Host Defense, WPI Immunology Frontier Research Center, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan Department of Host Defense, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan Department of Molecular Protozoology, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan

a r t i c l e

i n f o

a b s t r a c t
In viral infections the host innate immune system is meant to act as a rst line defense to prevent viral invasion or replication before more specic protection by the adaptive immune system is generated. In the innate immune response, pattern recognition receptors (PRRs) are engaged to detect specic viral components such as viral RNA or DNA or viral intermediate products and to induce type I interferons (IFNs) and other pro-inammatory cytokines in the infected cells and other immune cells. Recently these innate immune receptors and their unique downstream pathways have been identied. Here, we summarize their roles in the innate immune response to virus infection, discrimination between self and viral nucleic acids and inhibition by virulent factors and provide some recent advances in the coordination between innate and adaptive immune activation. 2008 Published by Elsevier Ltd.

Article history: Received 2 June 2008 Accepted 9 June 2008 Available online xxxx Keywords: Pattern recognition receptors Type I interferons Nucleic acids

1. Introduction All living organisms have developed several kinds of mechanisms to protect themselves from invasion by exogenous microorganisms, including viruses. Although the production of neutralizing antibodies and activation of cytotoxic T lymphocytes (CTL) or natural killer (NK) cells are essential for a specic and effective antiviral immune response, other host cells also possess some immune mechanism to prevent viral infection. Although multiple cytokines and chemokines are produced by several kinds of host cells in viral infection, type I IFNs are the principal cytokines involved in the antiviral response. Type I IFNs include multiple IFN-a isoforms, a single IFN-b, and other members, such as IFN-e, -j, -x and so on [1]. In contrast to type II IFN (IFN-c), which is exclusively produced by T cells and NK cells, type I IFNs can be produced by all nucleated cells in response to virus infection. Type III IFNs, comprised of IFN-k1, k2 and k3, have also recently been identied [2]. These IFNs each have different receptors but share downstream signaling molecules and regulate the same genes. IFNs have pleiotropic functions. They increase the expression of intrinsic proteins including TRIM5a, Fv, Mx, eIF2a and 20 50 OAS, and induce apoptosis of virus-infected cells and cellular resistance to viral infection [3]. In addition they activate NK cells and dendritic cells (DC) and induce the activation of the adap-

tive immune system [4]. The expression of type I IFN and cytokine genes is regulated by an intracellular signaling pathway that is activated by germline-encoded PRRs. These receptors recognize molecular patterns specic to microorganisms, such as viral genome nucleic acids. Nucleic acids such as DNA and RNA are essential components of all living organisms, so discrimination between self and non-self nucleic acids is essential especially in virus infection. Recent advances in research into innate immunity have revealed that this discrimination relies, to a great extent, on PRRs including Toll-like receptors (TLRs), retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs), and nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs). Here, we review the current understanding of innate immune recognition of viruses and discrimination between self and viral nucleic acids, and provide some recent advances in coordination between innate immune signaling and adaptive immune activation. 2. Innate immune receptors for virus sensing 2.1. Endosomal TLRs in DCs Several kinds of viruses utilize host endocytic pathways at the cell entry phase or budding, so they are inevitably surveyed by endosomal innate immune sensors. Endosomal TLRs, including TLR3, TLR7, TLR8 and TLR9, share the property of being activated by nucleic acids. Their expression can be increased by type I IFNs but their distribution is restricted. TLR7 and TLR9 are highly expressed in plasmacytoid DCs (pDCs) which are expert cells known to produce a large amount of type I IFNs in response to

* Corresponding author. Address: Laboratory of Host Defense, WPI Immunology Frontier Research Center, Osaka University, 3-1 Yamada-oka, Suita, Osaka 5650871, Japan. Fax: +81 6 6879 8305. E-mail address: sakira@biken.osaka-u.ac.jp (S. Akira). 1043-4666/$ - see front matter 2008 Published by Elsevier Ltd. doi:10.1016/j.cyto.2008.07.009

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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 trafcking of TLR7 and TLR9 from ER to endosome [6], but what triggers this TLR-trafcking 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 domain-

containing 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 [911]. 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 decient 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 trafcking 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 proteinprotein interaction regions for downstream signaling.

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with West Nile virus [17] and inuenza virus [18]. In both cases inammatory responses are decreased in TLR3 decient 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 identied 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 broblasts. RIG-I and MDA5 share two N-terminal CARDs followed by an RNA helicase domain [19] while LGP2 lacks a CARD. RIG-I binds 50 -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 inuenza virus, VSV and Japanese encephalitis virus (JEV) while MDA5 recognizes picorna family such as encephalomyocarditis virus (EMCV), Theilers virus and Mengo virus [22]. Therefore, RIG-I and MDA5 decient 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 [2427]. 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-inammatory cytokines, especially IL-12. However, type-I IFNs are produced by virus-infected cells such as broblasts 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 specic manner. Although TLR7 and TLR8 recognize GU of AU rich sequences of ssRNA viruses such as inuenza 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 specicity 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 50 -triphosphorylated ssRNA [20]. In the case of inuenza 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 Please cite this article in press as: Koyama S et al., Innate j.cyto.2008.07.009

hand, it is recognized by RIG-I ubiquitously expressed in most cell types, such as broblasts 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 inuenza 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 (CpGDNA) 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 [3941], 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 Bform 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) [4850], while TLR4 produces a response to retrovirus and respiratory syncytial virus (RSV) [51,52]. While viral proteins recognized by these surface TLRs trigger pro-inammatory 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,

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Fig. 2. DNA sensing in virus infection. TLR9 recognizes CpG-DNA and DNA viruses, including HSV-1, HSV-2 and CMV. TLR9 shares MyD88 and a downstream signaling pathway with TLR7 and ER protein UNC93B1 also plays a key role in trafcking of TLR9 from ER to endosome. In TLR9-independent DNA sensing, DNAs enter into the cytoplasm which activates the infected cells via TBK1 and IRF3 but the receptor and adaptor involved are still unknown. Their activities are more potent in ds right-hand Bform DNA than in left-handed Z-form DNA.

but are silent in normal conditions. As dsRNA generated by viral replication and virus DNA rich in CpG motifs are not normally found in our body, it is easy to consider that our innate immune system recognizes them as foreign molecules. In contrast to these nucleic acids, ssRNA abundantly exists not only in pathogens but also in host cells. It is, therefore, essential for the host to detect and discriminate viral ssRNA from self ssRNA. However, the mechanism of this robust discrimination is not fully understood. For example, although the 50 triphosphate on many ssRNAs of viruses is absent from mRNA and transfer RNA but is found in ribosomal RNA, which abundantly exists in host cells, only the 50 triphosphate on viruses can induce RIG-I activation [59,60]. Recently RNase L activation in infected host cells was shown to generate small self RNAs which can induce an innate immune response via RLRs [61]. In addition, it is known that TLR7/8 and TLR9 also recognize host RNA and DNA. Therefore, it is necessary for absolute discrimination by the host innate immune system to recognize some additional factors such as the methylation state, certain sequences and intracellular localization of RNA, or restricted endosomal expression of TLRs for viral recognition where host nucleic acids have limited access [6264]. 4. Virulent factor for inhibition of host immune response Viruses have developed several kinds of immune evasion strategies to proliferate within host cells. Their main target is the type I Please cite this article in press as: Koyama S et al., Innate j.cyto.2008.07.009

IFN response. Viruses can inhibit type I IFNs by many strategies i.e. inhibition of IFN synthesis, interference of IFN receptor signaling and so on [65]. For example, vaccinia virus E3L and inuenza virus NS1 which possess a dsRNA-binding site are thought to inhibit type I IFN production through dsRNA sequestration [66,67]. As E3L also possesses a DNA-binding site, it might sequester viral DNA from host DNA sensing [68]. NS1 protein was also indicated to inhibit the function of IPS1 and RIG-I [69]. Viruses without such abilities to suppress the host type I IFN responses are generally low pathogenic and available for vaccine strains. 5. Adaptive immunity against viruses through innate immune signaling pathway Recent advances in the understanding of innate immunity show that the activation of the innate immune system is essential for subsequent adaptive immune responses including specic antibody production and CTL activation which play a key role in protection against virus infection. A recent report indicated that the adaptive immune response elicited by inactivated whole inuenza virus vaccine containing viral ssRNA was strictly governed by the TLR7/MyD88 pathway, but not by the RIG-I/IPS-1 pathway, although both pathways concurrently controlled the innate immune response [37]. However, the innate immune response elicited by a DNA vaccine containing CpG-DNA was dependent on TBK1, but not on the TLR9/MyD88 pathway [47]. These results sug-

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gested that the innate immune pathway engaged for protective immunity against virus infection was different according to the source of antigen. 6. Conclusion This review has illustrated the recent progress in understanding how a host discriminates between viruses and self components by innate immune receptors and elicits an inammatory response involving type I IFNs and other cytokines. Much remains to be claried about the complex interplay between host and virus, but elucidating such mechanisms in detail is essential for not only the development of a clinical approach such as nucleic acid-based immunotherapy and TLR based vaccine adjuvant but also the understanding of the pathogenesis of diverse viral diseases. Acknowledgments We thank members of Akira Laboratory, Prof. Toshihiro Horii and his laboratory members for discussions and contributions to the work discussed here. This work was supported by grants from the Ministry of Education, Culture, Sports, Science and Technology in Japan. References
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Please cite this article in press as: Koyama S et al., Innate j.cyto.2008.07.009

immune response to viral infection, Cytokine (2008), doi:10.1016/