Innate immune response to viral infection 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,*
    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

Article history:                                         In viral infections the host innate immune system is meant to act as a first line defense to prevent viral
Received 2 June 2008                                     invasion or replication before more specific protection by the adaptive immune system is generated. In
Accepted 9 June 2008                                     the innate immune response, pattern recognition receptors (PRRs) are engaged to detect specific viral
Available online xxxx
                                                         components such as viral RNA or DNA or viral intermediate products and to induce type I interferons
                                                         (IFNs) and other pro-inflammatory cytokines in the infected cells and other immune cells. Recently these
Keywords:                                                innate immune receptors and their unique downstream pathways have been identified. Here, we summa-
Pattern recognition receptors
                                                         rize their roles in the innate immune response to virus infection, discrimination between self and viral
Type I interferons
Nucleic acids
                                                         nucleic acids and inhibition by virulent factors and provide some recent advances in the coordination
                                                         between innate and adaptive immune activation.
                                                                                                                                Ó 2008 Published by Elsevier Ltd.

1. Introduction                                                                             tive immune system [4]. The expression of type I IFN and cytokine
                                                                                            genes is regulated by an intracellular signaling pathway that is
    All living organisms have developed several kinds of mechanisms                         activated by germline-encoded PRRs. These receptors recognize
to protect themselves from invasion by exogenous microorganisms,                            molecular patterns specific to microorganisms, such as viral gen-
including viruses. Although the production of neutralizing antibod-                         ome nucleic acids. Nucleic acids such as DNA and RNA are essential
ies and activation of cytotoxic T lymphocytes (CTL) or natural killer                       components of all living organisms, so discrimination between self
(NK) cells are essential for a specific and effective antiviral immune                       and non-self nucleic acids is essential especially in virus infection.
response, other host cells also possess some immune mechanism to                            Recent advances in research into innate immunity have revealed
prevent viral infection.                                                                    that this discrimination relies, to a great extent, on PRRs including
    Although multiple cytokines and chemokines are produced by                              Toll-like receptors (TLRs), retinoic acid-inducible gene I (RIG-I)-like
several kinds of host cells in viral infection, type I IFNs are the prin-                   receptors (RLRs), and nucleotide-binding oligomerization domain
cipal cytokines involved in the antiviral response. Type I IFNs                             (NOD)-like receptors (NLRs). Here, we review the current under-
include multiple IFN-a isoforms, a single IFN-b, and other mem-                             standing of innate immune recognition of viruses and discrimina-
bers, such as IFN-e, -j, -x and so on [1]. In contrast to type II IFN                       tion between self and viral nucleic acids, and provide some
(IFN-c), which is exclusively produced by T cells and NK cells, type                        recent advances in coordination between innate immune signaling
I IFNs can be produced by all nucleated cells in response to virus                          and adaptive immune activation.
infection. Type III IFNs, comprised of IFN-k1, k2 and k3, have also
recently been identified [2]. These IFNs each have different recep-                          2. Innate immune receptors for virus sensing
tors but share downstream signaling molecules and regulate the
same genes. IFNs have pleiotropic functions. They increase the                              2.1. Endosomal TLRs in DCs
expression of intrinsic proteins including TRIM5a, Fv, Mx, eIF2a
and 20 –50 OAS, and induce apoptosis of virus-infected cells and cel-                          Several kinds of viruses utilize host endocytic pathways at the
lular resistance to viral infection [3]. In addition they activate NK                       cell entry phase or budding, so they are inevitably surveyed by
cells and dendritic cells (DC) and induce the activation of the adap-                       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
  * Corresponding author. Address: Laboratory of Host Defense, WPI Immunology
                                                                                            but their distribution is restricted. TLR7 and TLR9 are highly
Frontier Research Center, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-
0871, Japan. Fax: +81 6 6879 8305.                                                          expressed in plasmacytoid DCs (pDCs) which are expert cells
    E-mail address: (S. Akira).                                  known to produce a large amount of type I IFNs in response to

1043-4666/$ - see front matter Ó 2008 Published by Elsevier Ltd.

    Please cite this article in press as: Koyama S et al., Innate                     immune response to viral infection, Cytokine (2008), doi:10.1016/
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virus infection. TLR3 is expressed more widely, but is mainly ex-                        containing adapter, myeloid differentiation factor 88 (MyD88).
pressed on conventional DCs (cDCs) [5]. The function of TLR8 is                          Upon exposure to its ligand, MyD88 forms a complex with inter-
not clearly known yet.                                                                   leukin-1-receptor (IL-1R)-associated kinase-4 (IRAK-4), IRAK-1, tu-
    Recently endoplasmic reticulum (ER) protein UNC93B1 turned                           mor necrosis factor-receptor associated factor 3 (TRAF3), TRAF6,
out to be essential for trafficking of TLR7 and TLR9 from ER to                           Ikka and IRF-7 [9–11]. Following the formation of this signaling
endosome [6], but what triggers this TLR-trafficking from ER to                           complex, IRF7 and nuclear factor-kappa B (NF-jB) are activated,
endosome before viral recognition by TLRs remains to be eluci-                           which results in the production of type I IFNs and cytokines (Fig. 1).
dated. A recent report suggests that TLR-sorting to the ligand                               TLR3 recognizes double-stranded (ds)RNA and triggers a signal-
may utilize autophagy, which is a cellular process for recycling                         ing pathway via a TIR domain-containing adapter inducing IFN-b
cytosolic compartments and, in the case of pDC, eliminating exog-                        (TRIF) (also known as TICAM-1) [12,13]. TRIF associates with
enous pathogen. Although cytoplasmic vesicular somatitis viruses                         TRAF3 and TRAF6 via TRAF-binding motifs which exist in its N-ter-
(VSV) in pDC are thought to be trapped by autophagosome                                  minal portion and also with receptor interacting protein (RIP) 1
expressing ATG5 and detected by TLR7 in lysosomes for a type I                           and RIP3 via RIP homotypic interaction motif (RHIM) [14,15].
IFN response [7], in non-immune cells ATG5 suppresses the type                           TRAF6 and RIP1 activate NF-jB while TRAF3 activates TRAF family
I IFN response by interaction with caspase recruitment domains                           member-associated NK-jB activator (TANK)-binding kinase 1
(CARDs) presented by RIG-I and IFN-b promoter stimulator-1                               (TBK1) and inducible IjB kinase (IKK-i). Activation of these path-
(IPS-1) [8] (Fig. 1).                                                                    ways triggers antiviral responses (Fig. 1). TLR3 also activates the
                                                                                         phosphatidylinositol-3 kinase (PI3K) pathway [16]. Tyrosine phos-
2.2. Endosomal recognition of viral RNA by TLRs                                          phorylation of TLR3 induces PI3K recruitment to the receptor and
                                                                                         subsequent activation of Akt leads to activation of IRF-3. TLR3
   TLR7 recognizes several kinds of RNA viruses, including                               plays an important role in the pathogenesis of RNA virus infections
orthomyxoviruses in pDCs. TLR7 signals through a TIR domain-                             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.

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with West Nile virus [17] and influenza virus [18]. In both cases                 hand, it is recognized by RIG-I ubiquitously expressed in most cell
inflammatory responses are decreased in TLR3 deficient mice,                       types, such as fibroblasts or cDCs in vitro [35], and probably by
which suggests that an excess production of cytokines is rather                  the alveolar macrophage in vivo [36], via its adaptor protein
harmful for the survival of mice.                                                IPS-1. In mouse lungs after intranasal infection of influenza virus
                                                                                 both TLR7/MyD88 and RIG-I/IPS-1 pathways concurrently control
2.3. Intracellular recognition of viral RNA by RLRs                              the type-I IFN response [37].

     Recently, three homologous DExD/H box RNA helicases, RIG-I,                 2.5. Endosomal and intracellular recognition of viral DNA
melanoma differentiation-associated gene 5 (MDA5) and LGP2,
were identified as cytoplasmic sensors of virus RNA, named here                       TLR9 recognizes unmethylated DNA with a CpG motif (CpG-
as RIG-like receptors (RLRs). RIG-I and MDA5 play a major role in                DNA) and DNA viruses, including herpes simplex virus (HSV)-1,
recognition of RNA viruses in cDCs, macrophages and fibroblasts.                  HSV-2 and cytomegalovirus (CMV) in pDCs. TLR9 shares the adap-
RIG-I and MDA5 share two N-terminal CARDs followed by an                         ter protein MyD88 and the downstream signaling pathway with
RNA helicase domain [19] while LGP2 lacks a CARD. RIG-I binds                    TLR7. cDCs and macrophages also respond to CpG-DNA and pro-
50 -triphosphorylated single-stranded (ss)RNA [20] and short                     duce small amounts of IFN-b through IRF-1 activation rather than
dsRNA [21] and stimulates production of type I IFNs. By contrast,                IRF-3 or IRF-7 activation [38].
MDA5 preferentially recognizes longer-dsRNA, including syn-                          Recently, it was reported that genomic DNA of viruses, such as
thetic poly-IC [22]. RIG-I recognizes a variety of RNA viruses                   adenovirus, vaccinia virus and HSV [39–41], could be also recog-
including influenza virus, VSV and Japanese encephalitis virus                    nized in a TLR9-independent manner, using an as yet unknown
(JEV) while MDA5 recognizes picorna family such as encephalo-                    recognition mechanism in the cytoplasm [42,43]. In this case,
myocarditis virus (EMCV), Theiler’s virus and Mengo virus [22].                  DNA which has entered the cytoplasm activates the infected cells
Therefore, RIG-I and MDA5 deficient mice are highly susceptible                   via TBK1 and IRF3 [44]. Actually the source of DNA is not restricted
to VSV and EMCV, respectively. In addition it was indicated that                 to viruses; but it can also come from bacteria and damaged host
the antiviral protein RNase L, which can cleave and turn a single-               cells. The activity of this DNA is more potent in ds right-hand B-
stranded portion of not only viral but also self RNA into prefer-                form DNA than in left-handed Z-form DNA, while ssDNA displays
entially double-stranded form RNA, is a ligand for RIG-I and                     no activity [40,44,45] (Fig. 2). In addition DAI (also known as
MDA5 [23].                                                                       ZBP1 or DLM1) which contains two Z-DNA binding domains, was
     The CARDs of RIG-I and MDA5 are responsible for initiating the              shown to be a potential cytoplasmic DNA sensor [46]. However,
signaling pathway. Both RIG-I and MDA5 associate with an adapter                 DAI KO mice induced a normal type I IFN response in vitro and
protein IPS-1 also known as MAVS, VISA or CARDIF, which also                     in vivo after B-DNA stimulation and also indicated DNA-vaccine-in-
contains an N-terminal CARD [24–27]. IPS-1 localizes on the outer                duced adaptive immune responses, suggesting its role is redundant
mitochondrial membrane. The IPS-1 CARD interacts with that of                    [47]. Potential cytoplasmic DNA sensors still remain to be
RIG-I or MDA5. IPS-1 then associates with TRAF3, followed by acti-               elucidated.
vation of TBK1 and Ikk-i. These kinases phosphorylate IRF3 and
IRF7 and induce type I IFN production [28,29]. IPS-1 also interacts              2.6. The recognition of viral components at the cell surface
with Fas-associated death domain-containing protein (FADD) and
leads to activation of NF-jB through cleavage of caspase-8/-10                       In addition to the endosomal TLRs, TLR2 and TLR4 have also
[30] (Fig. 1).                                                                   been suggested to be involved in recognition of viruses. TLR2 has
                                                                                 been shown to detect components of measles virus, HSV and hep-
2.4. Differential role of TLR and RLR in antiviral responses                     atitis C virus (HCV) [48–50], while TLR4 produces a response to ret-
                                                                                 rovirus and respiratory syncytial virus (RSV) [51,52]. While viral
   Occasionally both TLR and RLR are engaged for sensing the same                proteins recognized by these surface TLRs trigger pro-inflamma-
dsRNA or ssRNA. Normally dsRNA does not exist in host cells but in               tory responses, their contribution to either protective or patholog-
virus infection it is detected as not only a viral structure but also as         ical immune responses largely depends on the type of virus, route
a byproduct of viral replication. dsRNA activates macrophages and                of infection, and other host factors [53].
dendritic cells via TLR3 to secrete pro-inflammatory cytokines,
especially IL-12. However, type-I IFNs are produced by virus-in-
                                                                                 2.7. NLRs mediates innate immune activation by intracellular viral
fected cells such as fibroblasts by TLR3 independently. MDA5 rec-
                                                                                 nucleic acids
ognizes synthetic dsRNA, poly-IC, and the ssRNA virus, EMCV,
which generates dsRNA during replication, and induces the type-I
                                                                                    NLR proteins are comprised three motifs, C-terminal LRRs, cen-
IFN response [22,31]. Poly-IC is neither capable of inducing an in-
                                                                                 tral nucleotide-binding domain and N-terminal signaling domain-
nate immune response nor of working as an adjuvant in TRIF/
                                                                                 containing CARDs, and Pyrin domain or baculovirus IAP repeats
IPS-1 double knockout mice [32].
                                                                                 [54]. Cryopyrin/NALP3 was shown to recognize both ssRNA and
   In contrast to dsRNA, ssRNA abundantly exists not only in
                                                                                 dsRNA of viral origin or their synthetic versions and to induce cas-
pathogens but also in host cells. ssRNA is recognized by TLR7
                                                                                 pase-1 activation via apoptosis-associated speck-like protein con-
(or TLR8 in humans) and RIG-I in a cell-type specific manner.
                                                                                 taining a caspase-activating and recruitment domain (ASC)
Although TLR7 and TLR8 recognize GU of AU rich sequences of
                                                                                 [55,56]. In addition, some NLRs participate in nucleic acid-medi-
ssRNA viruses such as influenza virus and HIV, through TLR7
                                                                                 ated innate immune activation through caspase-1 activation
expressing cells such as pDC, or TLR8 expressing cells such as
                                                                                 [56,57], and NF-jB activation towards IFN-I production via a syn-
myeloid DC or monocytes, it is unclear whether its sequence
                                                                                 ergistic pathway activated by NOD2 [58].
specificity is dependent on the receptor or the cell [33]. In con-
trast to TLR7, RIG-I is expressed in most cell types. As described
previously, RIG-I recognizes 50 -triphosphorylated ssRNA [20]. In                3. Discrimination between self and viral nucleic acids
the case of influenza A virus infection, its negative-sense ssRNA
genome is recognized by TLR7 expressed in pDCs and a signal is                     The innate immune systems for virus sensing described above
transmitted through its adaptor protein MyD88 [34]. On the other                 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 trafficking 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 B-
form DNA than in left-handed Z-form DNA.

but are silent in normal conditions. As dsRNA generated by viral                         IFN response. Viruses can inhibit type I IFNs by many strategies i.e.
replication and virus DNA rich in CpG motifs are not normally                            inhibition of IFN synthesis, interference of IFN receptor signaling
found in our body, it is easy to consider that our innate immune                         and so on [65]. For example, vaccinia virus E3L and influenza virus
system recognizes them as foreign molecules. In contrast to these                        NS1 which possess a dsRNA-binding site are thought to inhibit
nucleic acids, ssRNA abundantly exists not only in pathogens but                         type I IFN production through dsRNA sequestration [66,67]. As
also in host cells. It is, therefore, essential for the host to detect                   E3L also possesses a DNA-binding site, it might sequester viral
and discriminate viral ssRNA from self ssRNA. However, the mech-                         DNA from host DNA sensing [68]. NS1 protein was also indicated
anism of this robust discrimination is not fully understood. For                         to inhibit the function of IPS1 and RIG-I [69]. Viruses without such
example, although the 50 triphosphate on many ssRNAs of viruses                          abilities to suppress the host type I IFN responses are generally low
is absent from mRNA and transfer RNA but is found in ribosomal                           pathogenic and available for vaccine strains.
RNA, which abundantly exists in host cells, only the 50 triphosphate
on viruses can induce RIG-I activation [59,60]. Recently RNase L                         5. Adaptive immunity against viruses through innate immune
activation in infected host cells was shown to generate small self                       signaling pathway
RNAs which can induce an innate immune response via RLRs
[61]. In addition, it is known that TLR7/8 and TLR9 also recognize                          Recent advances in the understanding of innate immunity show
host RNA and DNA. Therefore, it is necessary for absolute discrim-                       that the activation of the innate immune system is essential for
ination by the host innate immune system to recognize some addi-                         subsequent adaptive immune responses including specific anti-
tional factors such as the methylation state, certain sequences and                      body production and CTL activation which play a key role in pro-
intracellular localization of RNA, or restricted endosomal expres-                       tection against virus infection. A recent report indicated that the
sion of TLRs for viral recognition where host nucleic acids have lim-                    adaptive immune response elicited by inactivated whole influenza
ited access [62–64].                                                                     virus vaccine containing viral ssRNA was strictly governed by the
                                                                                         TLR7/MyD88 pathway, but not by the RIG-I/IPS-1 pathway,
4. Virulent factor for inhibition of host immune response                                although both pathways concurrently controlled the innate im-
                                                                                         mune response [37]. However, the innate immune response elic-
   Viruses have developed several kinds of immune evasion strat-                         ited by a DNA vaccine containing CpG-DNA was dependent on
egies to proliferate within host cells. Their main target is the type I                  TBK1, but not on the TLR9/MyD88 pathway [47]. These results sug-

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