J Infect Chemother (2008) 14:86–92 DOI 10.1007/s10156-008-0596-1
© Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases 2008
REVIEW ARTICLE
Yutaro Kumagai · Osamu Takeuchi · Shizuo Akira
Pathogen recognition by innate receptors
Received: January 4, 2008
Abstract Microbial infection elicits host immune responses through germline-encoded pattern recognition receptors (PRRs). Toll-like receptors (TLRs) are evolutionarily conserved membrane-bound PRRs that recognize a broad spectrum of microbial components. Recent studies have clarified that two classes of cytosolic receptors, retinoic acid-inducible gene I (RIG-I)-like helicases (RLHs) and nucleotide binding oligomerization domain (NOD)-like receptors (NLRs), play important roles in the cytosolic recognition of invading pathogens. After microbial infection, the host utilizes these receptors differentially to mount robust immune responses. This review will describe pathogen recognition by these receptors, signaling pathways, and their in vivo roles in innate antiviral immunity.
Toll-like receptors (TLRs) are well-known PRRs. PAMPs recognized by TLRs cover a vast array of molecules – carbohydrates, lipids, proteins, and nucleic acids.2 Recent studies have revealed that another series of PRRs, nucleotide binding oligomerization domain (NOD)-like receptors (NLRs) and RIG-I-like helicases (RLHs) also play important roles in the innate immune response. After virus infection, TLRs and RLHs play differential but redundant roles in the antiviral response.3 NLRs are another series of receptors that control the TLR-independent activation of several signaling cascades. In this review, the authors will depict the molecular mechanism of the innate recognition of pathogens and the differential roles of PRRs in the antimicrobial response.
Key words Toll-like receptors · RIG-I-like helicases · NOD-like receptors · Cell signaling · Viral infection · Type-I IFN
Toll-like receptors and their signaling
Introduction After microbial infection, the host immune system evokes pleiotropic responses to eliminate the pathogen. The response initially taking place is the innate immune response. Microbial pathogens possess specific molecular patterns called pathogen-associated molecular patterns (PAMPs). The host innate immune system recognizes these PAMPs by germline-encoded pattern recognition receptors (PRRs) to elicit immune responses, such as the production of proinflammatory cytokines [e.g., type-I interferons (IFNs)] and antigen presentation. Such innate signals not only eliminate pathogens but also activate acquired immunity.1
Y. Kumagai · O. Takeuchi · S. Akira (*) Laboratory of Host Defense, WPI Immunology Frontier Research Center, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan Tel. +81-6-6879-8303; Fax +81-6-6879-8305 e-mail:
[email protected]
Until now, 13 murine TLRs and 10 human TLRs have been identified. One of the hallmarks of the TLR is its evolutionary conservation.4 By comparing peptide sequences, TLRs can be classified into several subfamilies (Fig. 1). Firstly, Toll in the fruit fly, Drosophila, was identified as a receptor involved in the antifungal immune response.5 The nematode Caenorhabditis elegans also has a TLR.6 To date, TLRs have been cloned not only from mammals but also from other vertebrates, such as jawless fish,7 and various invertebrates, such as the sea squirt,8 sea urchin,9 horseshoe crab,10 and shrimps.11 The subfamilies of TLR1, TLR2, and TLR6 recognize lipid and carbohydrate compounds from Gram-positive bacterial cell walls. TLR2 plays a key role in the recognition of peptidoglycan, lipoteichoic acid (LTA), and lipoproteins.12 TLR2 forms a heterodimer with either TLR1 or TLR6, and these heterodimers appear to be involved in the differential recognition of lipoproteins with different lipid moieties.13,14 Genetic studies have clarified that the TLR1TLR2 heterodimer recognizes triacylated lipoproteins,14 whereas the TLR2-TLR6 heterodimer recognizes diacylated lipoproteins and LTA.13 These findings are supported
87 Fig. 1. Phylogenic classification of murine (m) and human (h) Toll-like receptors (TLRs). Peptide sequences of murine TLR1–13, human TLR1–10, and Drosophila Tolls were retrieved from the NCBI database and clusterized by the ClustalW algorithm.99 A phylogenic tree generated by TreeView software100 is shown. LPS, Lipopolysaccharide; ss, single-stranded; poly (I:C), polyinosine-polycytidylic acid
mTLR6 hTLR6 mTLR10 mTLR2 hTLR1 mTLR1
hTLR2
hTLR10
Peptidoglycan Lipoproteins Lipoteichoic acid (Gram-positive bacteria)
Drosophila Toll
LPS (Gram-negative bacteria)
mTLR11
Uropathogenic bacteria. Profilin (Toxoplasma)
hTLR4
mTLR12
mTLR4
mTLR13 mTLR3
Flagellin (Gram-negative bacteria)
hTLR3
hTLR5 mTLR5 hTLR9 mTLR9
mTLR7 hTLR7 mTLR8 hTLR8
Poly (I:C)
Imidazoquinoline Viral ssRNA
CpG-DNA Hemozoin (Plasmodium)
by a recent crystallographic study which indicated that the TLR1-TLR2 heterodimer was induced by triacylated lipoproteins but not by diacylated lipoproteins.15 TLR2 is also involved in the recognition of fungal pathogens such as Candida.16 In addition to TLR2, Dectin-1, a C-type lectin with an ITAM motif in its intracellular domain, was found to interact with TLR2 to recognize yeast pathogens.17 TLR4 recognizes lipopolysaccharide (LPS), a cell-wall component of Gram-negative bacteria.18,19 The lipid portion of LPS, lipid A, is responsible for the immunostimulant activity of LPS. Recognition of LPS by TLR4 involves the accessory molecules MD-2,20 CD14,21 and LPS-binding protein (LBP).22 Examination of the crystal structure of the TLR4-MD-2 complex has indicated that the heterodimerization of MD-2 and TLR4 is induced by the presence of LPS and is essential for signal transduction.23 Some TLRs recognize proteins. TLR5 is a receptor for bacterial flagellin.24,25 TLR11 is involved in the recognition of profilin, a protein from the parasite Toxoplasma gondii.26 TLR11 is involved in the recognition of uropathogenic bacteria, although the specific component is so far unknown.27 TLR3, 7, 8, and 9 are receptors for nucleic acid and its derivatives.28–30 These TLRs are localized in cytoplasmic membrane compartments such as endosomes and lysosomes, whereas the previously mentioned TLRs are localized on the cell surface.31 TLR3 recognizes polyinosine-polycytidylic acid (poly [I:C]), a synthetic doublestranded RNA (dsRNA) that may mimic viral dsRNA generated during the replication of single-stranded RNA (ssRNA) viruses.28 Murine TLR7 and human TLR8 recognize synthetic antiviral imidazoquinoline compounds and some guanine nucleotide analogues, as well as viral ssRNA.29,32,33 On the other hand, TLR9 is a receptor for DNA with an unmethylated CpG-motif (CpG-DNA).30 Unmethylated CpG motifs are abundant in bacterial DNA,
whereas the frequency of CpG motifs in mammalian genome DNA is low and they are mostly methylated.34 CpG-DNA can induce strong type-1 helper T responses in a TLR9dependent manner.30 Viral DNA also stimulates the host immune system via TLR9.34 Also, hemozoin, a pigment from the malaria parasite Plasmodium, is recognized by TLR9.35 It is reported that TLR9 plays an important role in the pathology of cerebral malaria.36 TLR consists of multiple leucin-rich repeats (LRRs) and one Toll-interleukin (IL)-1 receptor homology (TIR) domain.2 The LRRs of TLR1, 2, 4, 5, and 6 are located to the outside of the cell. The LRRs of TLR3, 7, 8, and 9 are on the inside of the membrane compartment. The TIR domain is located in the cytosol in all TLRs. MyD88, a molecule consisting of the TIR domain and death domain (DD), associates with the TIR domain of TLRs.37 Other TIR domains containing the adaptor molecules, TRIF, TIRAP, and TRAM, are also involved in TLR signaling.38–40 MyD88 is utilized in TLR1-, 2-, 4-, 5-, 6-, 7-, and 9-mediated signaling.29,41,42 TRIF is involved in TLR3 and MyD88independent TLR4 signaling.38 TIRAP is specific for TLR2 and MyD88-dependent TLR4 signaling,39 whereas TRAM is specifically involved in MyD88-independent TRIFdependent signaling through TLR4.40 MyD88 transmits the signal to interleukin (IL)-1 receptor-associated kinase-1 (IRAK-1) and IRAK-4, which associates with MyD88 through a DD-DD interaction.43,44 IRAKs form a complex with TRAF6 interacting with Ubc13 and Uev1A, which consists of an E2 ubiquitin ligase complex,45 and this induces the activation of a complex comprising a kinase TAK1, TAK1-binding protein 1 (TAB1), TAB2, and TAB3.46,47 TAK1 then activates IκB kinase (IKK) and mitogen-activated protein kinases (MAPKs) and finally they induce the translocation of the transcription factors nuclear factor (NF)-κB and activator
88
protein-1, respectively. MyD88 also directly interacts with the transcription factor IRF-5 to induce a set of proinflammatory cytokines.48 These MyD88-dependent signals are generally essential for proinflammatory responses. In contrast, in MyD88-independent signaling, TRIF transmits the signal to RIP1 directly and to the IKK-related kinases TBK1 and IKK-i via TRAF3 to induce the activation of the transcription factors NF-κB and IRF-3, respectively.49,50 This NF-κB activation is a prerequisite for the production of some proinflammatory cytokines on stimulation of TLR4. Activated IRF-3 leads to the induction of IFN-β and IFN-inducible genes.51,52 “Professional” type-I IFN-producing cells, plasmacytoid dendritic cells (pDCs), control a particular mechanism to induce type-I IFN via TLR7 and TLR9.53 In TLR7 and TLR9 signaling in pDCs, MyD88 forms a large complex containing IRAK-1 and IRAK-4, TRAF6, IRF-7, and, possibly, osteopontin and IKKα to induce the phosphorylation of IRF-7.54–56 Activated IRF-7 then translocates to the nucleus and induces the transcription of IFN-inducible genes as well as type-I IFNs. Atg5, an essential molecule for autophagy, has also been shown to be responsible for type-I IFN production from pDCs without affecting other proinflammatory cytokine production, although the mechanism has not yet been elucidated.57
TLR-independent pathogen recognition Some bacterial components are recognized by another series of cytosolic receptors, NLRs. NLRs are characterized by the presence of a central NOD, a C-terminal LRR, and an N-terminal domain responsible for the signaling, such as the caspase recruit domain (CARD) and the PYRIN domain.58 NLRs are also evolutionarily conserved PRRs. In plants, NLRs are major innate receptors called resistant (R) proteins, and they are involved in the hypersensitive responses against pathogen infection.59 Mammalian NOD1 and NOD2, having N-terminal CARDs, recognize the bacterial peptidoglycan components γ-D-glutamyl-mesodiaminopimelic acid and muramyl dipeptide, respectively.60,61 These receptors transmit their signal via a kinase called RIP2/RICK, leading to the activation of NF-κB.62,63 Other NLR members, the NALP family, possess a PYRIN domain instead of CARD. Although the NALP family consists of 14 proteins, the function of most NALPs has not been determined.58 Among these, NALP1, NALP2, and NALP3 have been characterized to be involved in the cleavage of prointerleukin (IL)-1β and proIL-18 to mature IL-1β and IL-18 by caspase-1 in response to various stimuli.64,65 These NALPs form a complex called an inflammasome, comprising caspase-1, ASC, and caspase-5 in the case of NALP1. ASC is an adaptor protein composed of a PYRIN domain and a CARD. Caspase-1 has a CARD in addition to a protease catalytic domain. Thus, it is believed that NALPs, ASC, and caspase-1 interact with each other via homophilic interactions, leading to the catalytic activation of caspase-1.
LPS, lipoprotein, CpG-DNA, bacterial RNA, and uric acid crystals are known to stimulate NALP3.66–68 ASC has also been shown to be involved in the activation of NALP3inflammasomes. In addition, Francisella infection leads to the activation of caspase-1 in an NALP3-independent but ASC-dependent manner.67,69 Although it is hypothesized that one of the NALPs may be responsible for the recognition, a receptor for Francisella and their ligands has not yet been found. In response to Salmonella infection, IPAF, another CARD-containing NLR, is responsible for caspase-1 activation in an ATP-independent and NALP3-independent manner.70 Salmonella deficient for flagellin did not activate IPAF-inflammasomes, suggesting that flagellin is recognized by IPAF.71,72 There are indications that ASC is also involved in the IPAF-inflammasome response. Analysis of IPAF−/− and ASC−/− mice has revealed that IPAF is essential for Salmonella-induced IL-1β production, as well as macrophage cell death, whereas ASC contributes partially to the IPAF-mediated responses.70 NAIP5, an NLR protein with BIR domains, is known to be responsible for host susceptibility to the intracellular pathogen Legionella pneumophila.73,74 Although NAIP5 has been implicated in Legionella-induced caspase-1 activation, the role of NAIP5 is still controversial.75,76 RLHs are essential to viral recognition in the cytoplasm, and are comprised of RIG-I, melanoma differentiationassociated gene-5 (MDA5), and LGP2.77 The former two proteins consist of an N-terminal CARD and C-terminal helicase domain, whereas the latter lacks CARD. The helicase domains of RLHs show high similarity to those of Dicer protein, a nuclease essential for the generation of small interference RNA. Like TLRs and NLRs, RLHs are also evolutionarily conserved, and their paralogues are found in C. elegans, although their function is yet to be clarified. Human and murine RIG-I recognize paramyxoviruses, such as Newcastle disease virus (NDV), vesicular stomatitis virus (VSV), and Sendai virus (SeV); orthomyxoviruses, such as influenza virus; and Japanese encephalitis virus (JEV).78 These viral RNAs harbor triphosphate on their 5′ termini, which is essential for the recognition by RIG-I.79,80 On the other hand, MDA5 is responsible for recognizing picornaviruses, such as encephalomyocarditis virus (EMCV), Mengo virus, and Theiler’s virus, although it is still unknown what RNA structure is recognized by MDA5.78 MDA5-deficient mice, but not TLR3-deficient mice, are hyporesponsive to poly (I:C), implying certain dsRNA structures can be a ligand for MDA5.78 Recent reports on LGP2-deficient mice suggest that LGP2 is a negative regulator for the paramyxovirus and poly (I:C)elicited antiviral response, whereas it acts as a positive regulator for picornavirus-elicited responses.81 RIG-Z and MDA5 utilize the same adaptor molecule, IPS-1 (also known as MAVS, Cardif, or VISA).82,83 IPS-1 is localized on the mitochondrial membrane by its C-terminal membrane spanning domain, and it also contains CARDlike domains in its N-terminus, which mediate the interaction with RIG-I and MDA5.82,83 Recent studies have indicated that this functional interaction is controlled by
89
several factors; a RING finger-containing ubiquitin ligase – TRIM25 – ubiquitinates RIG-I, but not MDA5, and the ubiquitination is a prerequisite for RIG-I-mediated signaling,84 whereas RNF125 ubiquitinates RIG-I, MDA5, and IPS-1 to suppress RLH-mediated responses.85 A recent report has indicated that the Atg5-Atg12 conjugate, which is an essential component in autophagy, negatively regulates the RLH-IPS-1 interaction and thus inhibits RLHmediated antiviral responses.86 IPS-1 transmits the signal to TBK1/IKK-i and the IKK complex to activate IRF-3/IRF-7 and NF-κB, respectively, and elicits various innate antiviral immune responses such as type-I IFN production.82,83 dsDNA in the cytosol, such as genomic DNA from intracellular bacteria (Listeria, Legionella, etc), also elicits a host antiviral immune response in a TLR-independent manner.87,88 A recent report has indicated that the molecule DAI (also known as DLM1 or ZBP1) is a candidate for a cytosolic dsDNA detector.89 However, ZBP1−/− cells were still capable of producing type-I IFNs in response to stimulation with dsDNA (S. Akira, unpublished observation). Future studies are required to identify the mechanism of DNA-mediated immune responses, in order to facilitate the development of DNA vaccines.
In vivo roles of TLR-dependent and TLR-independent signaling in virus infection Both TLR and RLH can recognize RNA viruses and mediate innate antiviral responses to infection. It has been shown that pDCs utilize TLR to detect RNA viruses and elicit an antiviral response, such as type-I IFN production, whereas conventional DCs (cDCs) utilize RLH.90 RLHs play a pivotal role in antiviral immunity in vivo. Most RNA viruses can be recognized by RIG-I and/or MDA5. RIG-Ideficient mice are susceptible to VSV and JEV infection.78 MDA5 deficiency results in susceptibility to EMCV.78 Mice deficient in IPS-1, a common adaptor for RIG-I and MDA5, are susceptible to both VSV and EMCV.91,92 However, IPS-1−/− mice do not show susceptibility to lymphatic choriomeningitis virus (LCMV), an antisense-strand ssRNA arenavirus.93 Also, IPS-1-deficient mice are not susceptible to influenza virus infection.94 Instead of RLHs, TLR7 is reported to be important in immunity to these RNA viruses.93,94 On pulmonary infection with influenza virus, innate immune responses, such as the production of type-I IFN and chemokines, were not abolished in IPS-1deficient and TLR7-deficient or MyD88-deficient mice.94 Conversely, after systemic LCMV infection, innate immune responses were diminished in the absence of MyD88.93 Therefore, the TLR-MyD88 system is more important than the RLH-IPS-1 system in some cases of viral infection. In spite of these findings, the in vivo contributions of RLH and TLR, and those of cDCs and pDCs, in type-I IFN production against viral infection are not fully understood, because formerly used methods are not applicable to the in vivo detection of type-I IFN in single cells. We recently generated a knockin reporter mouse strain, designated the
Ifna6gfp mouse, in which green fluorescent protein (GFP) was induced under the control of the Ifna6 gene promoter.95 By checking GFP expression induced by systemic infection by NDV, it was revealed that cDCs and macrophages induced type-I IFN via the RLH-IPS-1 system and pDCs induced type-I IFN via the TLR-MyD88 system. Thus, the differential utilization of TLR and RLH by pDCs and cDCs (and macrophages), respectively, is also valid in vivo. In the case of systemic LCMV infection, we showed that the pDC, via the TLR-MyD88 system, is a major inducer of type-I IFN in vivo.93 The reason that LCMV hardly induced type-I IFN production from cDCs and macrophages still remains to be clarified. In the natural course of viral infection, it is presumed that viruses do not directly enter the host reticuloendothelial system, but that they first attack the mucosal surfaces. As a model of mucosal infection, Ifna6gfp mice were infected intranasally with NDV, and GFP expression in lung cells was examined.95 Interestingly, intranasal infection with NDV did not induce IFN-α production from pDCs. Instead, alveolar macrophages (AMs) and cDCs were the major inducers of IFN-α. In IPS-1-deficient Ifna6gfp mice, AMs did not produce IFN-α, indicating that the AM relies on the RLH-IPS-1 system to detect viruses. On the other hand, pDCs started to produce IFN-α in IPS-1-deficient mice. This indicated that the lack of an antiviral response mediated by AMs and/or cDCs via the RLH-IPS-1 system leads to the induction of responses by pDCs. Consistent with this, the viral titer increased and pDCs produced IFNα in AM-depleted mice. SeV was found to suppress IFN-α production from AMs but not from pDCs, whereas SeV with mutated C proteins (SeV Cm) induced IFN-α production from both cell types.95 Thus, it was presumed that SeV suppresses AM-mediated antiviral responses, disseminates more rapidly than NDV, and finally induces pDC-mediated antiviral responses. As expected, pulmonary infection with SeV induced GFP+ pDCs, but not GFP+ AMs in Ifna6gfp mice, whereas infection with SeV Cm induced GFP+ AMs, but not GFP+ pDCs, as occurred with NDV. Collectively, we propose a model where the host respiratory innate immune system has two different systems to detect viral infection (Fig. 2). The AM acts as a sentinel for viral infection, producing type-I IFN via the RLH system. The cDC also plays an important role in initial type-I IFN production via the RLH system. We suggest that the pDC acts as a backup system for the AM- and/or cDC-mediated antiviral system, using a different molecular system, the TLR system. These multilayered immune systems may have evolved to achieve robust type-I IFN production and antiviral responses. DNA viruses are also recognized by different receptor systems in a cell type-dependent manner. The pDC has been suggested to be a major detector of some DNA virus infections via TLR9.34 On infection with murine cytomegalovirus, the pDC recognizes viruses through TLR9 and produces type-I IFN and other cytokines, which are essential for the sequential activation of natural killer (NK) cells.96 Also, Herpes simplex virus-1 is detected by pDCs via TLR9,
90 Fig. 2. Role of innate immune systems in pulmonary infection with RNA viruses. Viruses enter the respiratory system and are initially sensed by alveolar macrophages (AMs). AMs produce type-I interferon (type I IFN) through the recognition of viruses by the retinoic acidinducible gene I (RIG-I)-like helicase (RLH)-IPS-1 system. If this AM-mediated system is damaged by an IPS-1 deficiency, AM depletion, or subversion by Sendai virus (SeV) etc, viruses start to propagate and enter into the interstitium, where plasmacytoid dendritic cells (pDCs) reside. Then pDCs start to produce type-I IFN via the TLR-MyD88 system. Type-I IFN finally induces an antiviral response in the lungs to control viral infection
Interstitium
Alveolus
endosome
virus
pDC
TLR MyD88 IPS-1 deficiency AM depletion subversion by SeV
AM RLH
type I IFN
IPS-1
antiviral response
type I IFN
in both systemic and genital infections, and this detection is a prerequisite for eliciting antiviral responses.97,98 However, recent studies have indicated that a TLR-independent DNA recognition pathway plays an important role in detecting DNA viruses both in vivo and in vitro.34 Future elucidation of the molecular mechanisms of this cytosolic DNA recognition will clarify the roles of TLR-dependent and TLRindependent pathways in anti-DNA viral responses.
Concluding remarks Our understanding of innate immune receptors, and the responses mediated by them, has greatly expanded in recent years. In particular, the identification of a series of cytosolic receptors, as well as the identification of ligands for TLRs and their downstream signaling, enables us to elucidate the fine molecular mechanisms of innate immune responses. The innate immune system is responsible for the activation of the acquired immune system in response to viral infection. However, the mechanism of this induction is yet to be clarified. Several studies have shown that the development of acquired immune responses to influenza virus and LCMV is dependent on the TLR system rather than being dependent on RLHs.93,94 However, the contribution of TLRs and RLHs may differ depending on the viruses and the route of infection, and further studies are required to identify the mechanisms of the entire antiviral immune response in vivo. The relationship between TLRs and NLRs also requires identification. We realize that current studies of the innate immune system mostly rely on analysis using cells in vitro, and that studies of immune cell behavior in vivo are vital to
type I IFN
uncover the true immune response. Future studies of immune imaging in vivo will clarify the nature of the immune response to microbial infection.
References 1. Akira S, Takeda K, Kaisho T. Toll-like receptors: critical proteins linking innate and acquired immunity. Nat Immunol 2001;2: 675–80. 2. Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell 2006;124:783–801. 3. Kawai T, Akira S. Innate immune recognition of viral infection. Nat Immunol 2006;7:131–7. 4. Roach JC, Glusman G, Rowen L, Kaur A, Purcell MK, Smith KD, et al. The evolution of vertebrate Toll-like receptors. Proc Natl Acad Sci U S A 2005;102:9577–82. 5. Lemaitre B, Nicolas E, Michaut L, Reichhart JM, Hoffmann JA. The dorsoventral regulatory gene cassette spatzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell 1996;86:973–83. 6. Pujol N, Link EM, Liu LX, Kurz CL, Alloing G, Tan MW, et al. A reverse genetic analysis of components of the Toll signaling pathway in Caenorhabditis elegans. Curr Biol 2001;11:809–21. 7. Ishii A, Matsuo A, Sawa H, Tsujita T, Shida K, Matsumoto M, et al. Lamprey TLRs with properties distinct from those of the variable lymphocyte receptors. J Immunol 2007;178:397–406. 8. Azumi K, De Santis R, De Tomaso A, Rigoutsos I, Yoshizaki F, Pinto MR, et al. Genomic analysis of immunity in a Urochordate and the emergence of the vertebrate immune system: “waiting for Godot”. Immunogenetics 2003;55:570–81. 9. Hibino T, Loza-Coll M, Messier C, Majeske AJ, Cohen AH, Terwilliger DP, et al. The immune gene repertoire encoded in the purple sea urchin genome. Dev Biol 2006;300:349–65. 10. Inamori K, Koori K, Mishima C, Muta T, Kawabata S. A horseshoe crab receptor structurally related to Drosophila Toll. J Endotoxin Res 2000;6:397–9. 11. Yang LS, Yin ZX, Liao JX, Huang XD, Guo CJ, Weng SP, et al. A Toll receptor in shrimp. Mol Immunol 2007;44:1999–2008. 12. Takeuchi O, Hoshino K, Kawai T, Sanjo H, Takada H, Ogawa T, et al. Differential roles of TLR2 and TLR4 in recognition of
91
13. 14.
15. 16.
17. 18.
19. 20. 21. 22.
23. 24.
25.
26. 27. 28. 29.
30. 31. 32. 33.
34.
gram-negative and gram-positive bacterial cell wall components. Immunity 1999;11:443–51. Takeuchi O, Kawai T, Muhlradt PF, Morr M, Radolf JD, Zychlinsky A, et al. Discrimination of bacterial lipoproteins by Toll-like receptor 6. Int Immunol 2001;13:933–40. Takeuchi O, Sato S, Horiuchi T, Hoshino K, Takeda K, Dong Z, et al. Cutting edge: role of Toll-like receptor 1 in mediating immune response to microbial lipoproteins. J Immunol 2002;169: 10–4. Jin MS, Kim SE, Heo JY, Lee ME, Kim HM, Paik SG, et al. Crystal structure of the TLR1-TLR2 heterodimer induced by binding of a tri-acylated lipopeptide. Cell 2007;130:1071–82. Netea MG, Van Der Graaf CA, Vonk AG, Verschueren I, Van Der Meer JW, Kullberg BJ. The role of toll-like receptor (TLR) 2 and TLR4 in the host defense against disseminated candidiasis. J Infect Dis 2002;185:1483–9. Brown GD, Herre J, Williams DL, Willment JA, Marshall AS, Gordon S. Dectin-1 mediates the biological effects of betaglucans. J Exp Med 2003;197:1119–24. Hoshino K, Takeuchi O, Kawai T, Sanjo H, Ogawa T, Takeda Y, et al. Cutting edge: Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product. J Immunol 1999;162:3749–52. Poltorak A, He X, Smirnova I, Liu MY, Van Huffel C, Du X, et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 1998;282:2085–8. Nagai Y, Akashi S, Nagafuku M, Ogata M, Iwakura Y, Akira S, et al. Essential role of MD-2 in LPS responsiveness and TLR4 distribution. Nat Immunol 2002;3:667–72. Jiang Z, Georgel P, Du X, Shamel L, Sovath S, Mudd S, et al. CD14 is required for MyD88-independent LPS signaling. Nat Immunol 2005;6:565–70. Jack RS, Fan X, Bernheiden M, Rune G, Ehlers M, Weber A, et al. Lipopolysaccharide-binding protein is required to combat a murine gram-negative bacterial infection. Nature 1997;389: 742–5. Kim HM, Park BS, Kim JI, Kim SE, Lee J, Oh SC, et al. Crystal structure of the TLR4-MD-2 complex with bound endotoxin antagonist Eritoran. Cell 2007;130:906–17. Hayashi F, Smith KD, Ozinsky A, Hawn TR, Yi EC, Goodlett DR, et al. The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5. Nature 2001;410:1099– 103. Uematsu S, Jang MH, Chevrier N, Guo Z, Kumagai Y, Yamamoto M, et al. Detection of pathogenic intestinal bacteria by Toll-like receptor 5 on intestinal CD11c+ lamina propria cells. Nat Immunol 2006;7:868–74. Yarovinsky F, Zhang D, Andersen JF, Bannenberg GL, Serhan CN, Hayden MS, et al. TLR11 activation of dendritic cells by a protozoan profilin-like protein. Science 2005;308:1626–9. Zhang D, Zhang G, Hayden MS, Greenblatt MB, Bussey C, Flavell RA, et al. A toll-like receptor that prevents infection by uropathogenic bacteria. Science 2004;303:1522–6. Alexopoulou L, Holt AC, Medzhitov R, Flavell RA. Recognition of double-stranded RNA and activation of NF-kappaB by Tolllike receptor 3. Nature 2001;413:732–8. Hemmi H, Kaisho T, Takeuchi O, Sato S, Sanjo H, Hoshino K, et al. Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nat Immunol 2002;3:196–200. Hemmi H, Takeuchi O, Kawai T, Kaisho T, Sato S, Sanjo H, et al. A Toll-like receptor recognizes bacterial DNA. Nature 2000;408:740–5. Barton GM, Kagan JC, Medzhitov R. Intracellular localization of Toll-like receptor 9 prevents recognition of self DNA but facilitates access to viral DNA. Nat Immunol 2006;7:49–56. Diebold SS, Kaisho T, Hemmi H, Akira S, Reis e Sousa C. Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science 2004;303:1529–31. Heil F, Hemmi H, Hochrein H, Ampenberger F, Kirschning C, Akira S, et al. Species-specific recognition of singlestranded RNA via toll-like receptor 7 and 8. Science 2004;303: 1526–9. Ishii KJ, Akira S. Innate immune recognition of, and regulation by, DNA. Trends Immunol 2006;27:525–32.
35. Coban C, Ishii KJ, Kawai T, Hemmi H, Sato S, Uematsu S, et al. Toll-like receptor 9 mediates innate immune activation by the malaria pigment hemozoin. J Exp Med 2005;201:19–25. 36. Coban C, Ishii KJ, Uematsu S, Arisue N, Sato S, Yamamoto M, et al. Pathological role of Toll-like receptor signaling in cerebral malaria. Int Immunol 2007;19:67–79. 37. Medzhitov R, Preston-Hurlburt P, Kopp E, Stadlen A, Chen C, Ghosh S, et al. MyD88 is an adaptor protein in the hToll/IL-1 receptor family signaling pathways. Mol Cell 1998;2:253–8. 38. Yamamoto M, Sato S, Hemmi H, Hoshino K, Kaisho T, Sanjo H, et al. Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway. Science 2003;301:640–3. 39. Yamamoto M, Sato S, Hemmi H, Sanjo H, Uematsu S, Kaisho T, et al. Essential role for TIRAP in activation of the signalling cascade shared by TLR2 and TLR4. Nature 2002;420:324–9. 40. Yamamoto M, Sato S, Hemmi H, Uematsu S, Hoshino K, Kaisho T, et al. TRAM is specifically involved in the Toll-like receptor 4-mediated MyD88-independent signaling pathway. Nat Immunol 2003;4:1144–50. 41. Hemmi H, Kaisho T, Takeda K, Akira S. The roles of Toll-like receptor 9, MyD88, and DNA-dependent protein kinase catalytic subunit in the effects of two distinct CpG DNAs on dendritic cell subsets. J Immunol 2003;170:3059–64. 42. Takeuchi O, Takeda K, Hoshino K, Adachi O, Ogawa T, Akira S. Cellular responses to bacterial cell wall components are mediated through MyD88-dependent signaling cascades. Int Immunol 2000;12:113–7. 43. Suzuki N, Suzuki S, Duncan GS, Millar DG, Wada T, Mirtsos C, et al. Severe impairment of interleukin-1 and Toll-like receptor signalling in mice lacking IRAK-4. Nature 2002;416:750–6. 44. Swantek JL, Tsen MF, Cobb MH, Thomas JA. IL-1 receptorassociated kinase modulates host responsiveness to endotoxin. J Immunol 2000;164:4301–6. 45. Yamamoto M, Okamoto T, Takeda K, Sato S, Sanjo H, Uematsu S, et al. Key function for the Ubc13 E2 ubiquitin-conjugating enzyme in immune receptor signaling. Nat Immunol 2006;7: 962–70. 46. Sato S, Sanjo H, Takeda K, Ninomiya-Tsuji J, Yamamoto M, Kawai T, et al. Essential function for the kinase TAK1 in innate and adaptive immune responses. Nat Immunol 2005;6:1087– 95. 47. Shim JH, Xiao C, Paschal AE, Bailey ST, Rao P, Hayden MS, et al. TAK1, but not TAB1 or TAB2, plays an essential role in multiple signaling pathways in vivo. Genes Dev 2005;19:2668– 81. 48. Takaoka A, Yanai H, Kondo S, Duncan G, Negishi H, Mizutani T, et al. Integral role of IRF-5 in the gene induction programme activated by Toll-like receptors. Nature 2005;434:243–9. 49. Meylan E, Burns K, Hofmann K, Blancheteau V, Martinon F, Kelliher M, et al. RIP1 is an essential mediator of Toll-like receptor 3-induced NF-kappa B activation. Nat Immunol 2004;5: 503–7. 50. McWhirter SM, Fitzgerald KA, Rosains J, Rowe DC, Golenbock DT, Maniatis T. IFN-regulatory factor 3-dependent gene expression is defective in Tbk1-deficient mouse embryonic fibroblasts. Proc Natl Acad Sci U S A 2004;101:233–8. 51. Sharma S, tenOever BR, Grandvaux N, Zhou GP, Lin R, Hiscott J. Triggering the interferon antiviral response through an IKKrelated pathway. Science 2003;300:1148–51. 52. Fitzgerald KA, McWhirter SM, Faia KL, Rowe DC, Latz E, Golenbock DT, et al. IKKepsilon and TBK1 are essential components of the IRF3 signaling pathway. Nat Immunol 2003;4: 491–6. 53. Cao W, Liu YJ. Innate immune functions of plasmacytoid dendritic cells. Curr Opin Immunol 2007;19:24–30. 54. Hoshino K, Sugiyama T, Matsumoto M, Tanaka T, Saito M, Hemmi H, et al. IkappaB kinase-alpha is critical for interferonalpha production induced by Toll-like receptors 7 and 9. Nature 2006;440:949–53. 55. Kawai T, Sato S, Ishii KJ, Coban C, Hemmi H, Yamamoto M, et al. Interferon-alpha induction through Toll-like receptors involves a direct interaction of IRF7 with MyD88 and TRAF6. Nat Immunol 2004;5:1061–8. 56. Uematsu S, Sato S, Yamamoto M, Hirotani T, Kato H, Takeshita F, et al. Interleukin-1 receptor-associated kinase-1 plays an essen-
92
57. 58. 59. 60.
61. 62. 63.
64.
65. 66.
67. 68. 69. 70. 71.
72.
73.
74. 75.
76.
77. 78.
tial role for Toll-like receptor (TLR)7- and TLR9-mediated interferon-{alpha} induction. J Exp Med 2005;201:915–23. Lee HK, Lund JM, Ramanathan B, Mizushima N, Iwasaki A. Autophagy-dependent viral recognition by plasmacytoid dendritic cells. Science 2007;315:1398–401. Kanneganti TD, Lamkanfi M, Nunez G. Intracellular NOD-like receptors in host defense and disease. Immunity 2007;27:549–59. DeYoung BJ, Innes RW. Plant NBS-LRR proteins in pathogen sensing and host defense. Nat Immunol 2006;7:1243–9. Chamaillard M, Hashimoto M, Horie Y, Masumoto J, Qiu S, Saab L, et al. An essential role for NOD1 in host recognition of bacterial peptidoglycan containing diaminopimelic acid. Nat Immunol 2003;4:702–7. Girardin SE, Boneca IG, Carneiro LA, Antignac A, Jehanno M, Viala J, et al. Nod1 detects a unique muropeptide from gramnegative bacterial peptidoglycan. Science 2003;300:1584–7. Chin AI, Dempsey PW, Bruhn K, Miller JF, Xu Y, Cheng G. Involvement of receptor-interacting protein 2 in innate and adaptive immune responses. Nature 2002;416:190–4. Kobayashi K, Inohara N, Hernandez LD, Galan JE, Nunez G, Janeway CA, et al. RICK/Rip2/CARDIAK mediates signalling for receptors of the innate and adaptive immune systems. Nature 2002;416:194–9. Agostini L, Martinon F, Burns K, McDermott MF, Hawkins PN, Tschopp J. NALP3 forms an IL-1beta-processing inflammasome with increased activity in Muckle-Wells autoinflammatory disorder. Immunity 2004;20:319–25. Martinon F, Burns K, Tschopp J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell 2002;10:417–26. Kanneganti TD, Ozoren N, Body-Malapel M, Amer A, Park JH, Franchi L, et al. Bacterial RNA and small antiviral compounds activate caspase-1 through cryopyrin/Nalp3. Nature 2006;440: 233–6. Mariathasan S, Weiss DS, Newton K, McBride J, O’Rourke K, Roose-Girma M, et al. Cryopyrin activates the inflammasome in response to toxins and ATP. Nature 2006;440:228–32. Martinon F, Petrilli V, Mayor A, Tardivel A, Tschopp J. Goutassociated uric acid crystals activate the NALP3 inflammasome. Nature 2006;440:237–41. Mariathasan S, Weiss DS, Dixit VM, Monack DM. Innate immunity against Francisella tularensis is dependent on the ASC/ caspase-1 axis. J Exp Med 2005;202:1043–9. Mariathasan S, Newton K, Monack DM, Vucic D, French DM, Lee WP, et al. Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf. Nature 2004;430:213–8. Franchi L, Amer A, Body-Malapel M, Kanneganti TD, Ozoren N, Jagirdar R, et al. Cytosolic flagellin requires Ipaf for activation of caspase-1 and interleukin 1beta in salmonella-infected macrophages. Nat Immunol 2006;7:576–82. Miao EA, Alpuche-Aranda CM, Dors M, Clark AE, Bader MW, Miller SI, et al. Cytoplasmic flagellin activates caspase-1 and secretion of interleukin 1beta via Ipaf. Nat Immunol 2006;7: 569–75. Wright EK, Goodart SA, Growney JD, Hadinoto V, Endrizzi MG, Long EM, et al. Naip5 affects host susceptibility to the intracellular pathogen Legionella pneumophila. Curr Biol 2003; 13:27–36. Diez E, Lee SH, Gauthier S, Yaraghi Z, Tremblay M, Vidal S, et al. Birc1e is the gene within the Lgn1 locus associated with resistance to Legionella pneumophila. Nat Genet 2003;33:55–60. Lamkanfi M, Amer A, Kanneganti TD, Munoz-Planillo R, Chen G, Vandenabeele P, et al. The Nod-like receptor family member Naip5/Birc1e restricts Legionella pneumophila growth independently of caspase-1 activation. J Immunol 2007;178:8022–7. Zamboni DS, Kobayashi KS, Kohlsdorf T, Ogura Y, Long EM, Vance RE, et al. The Birc1e cytosolic pattern-recognition receptor contributes to the detection and control of Legionella pneumophila infection. Nat Immunol 2006;7:318–25. Yoneyama M, Fujita T. Function of RIG-I-like receptors in antiviral innate immunity. J Biol Chem 2007;282:15315–8. Kato H, Takeuchi O, Sato S, Yoneyama M, Yamamoto M, Matsui K, et al. Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature 2006;441:101–5.
79. Hornung V, Ellegast J, Kim S, Brzozka K, Jung A, Kato H, et al. 5′-Triphosphate RNA is the ligand for RIG-I. Science 2006; 314:994–7. 80. Pichlmair A, Schulz O, Tan CP, Naslund TI, Liljestrom P, Weber F, et al. RIG-I-mediated antiviral responses to single-stranded RNA bearing 5′-phosphates. Science 2006;314:997–1001. 81. Venkataraman T, Valdes M, Elsby R, Kakuta S, Caceres G, Saijo S, et al. Loss of DExD/H box RNA helicase LGP2 manifests disparate antiviral responses. J Immunol 2007;178:6444–55. 82. Kawai T, Takahashi K, Sato S, Coban C, Kumar H, Kato H, et al. IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction. Nat Immunol 2005;6:981–8. 83. Seth RB, Sun L, Ea CK, Chen ZJ. Identification and characterization of MAVS a mitochondrial antiviral signaling protein that activates NF-kappaB and IRF 3. Cell 2005;122:669–82. 84. Gack MU, Shin YC, Joo CH, Urano T, Liang C, Sun L, et al. TRIM25 RING-finger E3 ubiquitin ligase is essential for RIG-Imediated antiviral activity. Nature 2007;446:916–20. 85. Arimoto K, Takahashi H, Hishiki T, Konishi H, Fujita T, Shimotohno K. Negative regulation of the RIG-I signaling by the ubiquitin ligase RNF125. Proc Natl Acad Sci U S A 2007;104: 7500–5. 86. Jounai N, Takeshita F, Kobiyama K, Sawano A, Miyawaki A, Xin KQ, et al. The Atg5 Atg12 conjugate associates with innate antiviral immune responses. Proc Natl Acad Sci U S A 2007;104: 14050–5. 87. Ishii KJ, Coban C, Kato H, Takahashi K, Torii Y, Takeshita F, et al. A Toll-like receptor-independent antiviral response induced by double-stranded B-form DNA. Nat Immunol 2006;7: 40–8. 88. Stetson DB, Medzhitov R. Recognition of cytosolic DNA activates an IRF3-dependent innate immune response. Immunity 2006;24:93–103. 89. Takaoka A, Wang Z, Choi MK, Yanai H, Negishi H, Ban T, et al. DAI (DLM-1/ZBP1) is a cytosolic DNA sensor and an activator of innate immune response. Nature 2007;448:501–5. 90. Kato H, Sato S, Yoneyama M, Yamamoto M, Uematsu S, Matsui K, et al. Cell type-specific involvement of RIG-I in antiviral response. Immunity 2005;23:19–28. 91. Kumar H, Kawai T, Kato H, Sato S, Takahashi K, Coban C, et al. Essential role of IPS-1 in innate immune responses against RNA viruses. J Exp Med 2006;203:1795–803. 92. Sun Q, Sun L, Liu HH, Chen X, Seth RB, Forman J, et al. The specific and essential role of MAVS in antiviral innate immune responses. Immunity 2006;24:633–42. 93. Jung A, Kato H, Kumagai Y, Kumar H, Kawai T, Takeuchi O, et al. Lymphocytoid choriomeningitis virus activates plasmacytoid dendritic cells and induces a cytotoxic T-cell response via MyD88. J Virol 2008;82:196–206. 94. Koyama S, Ishii KJ, Kumar H, Tanimoto T, Coban C, Uematsu S, et al. Differential role of TLR- and RLR-signaling in the immune responses to influenza A virus infection and vaccination. J Immunol 2007;179:4711–20. 95. Kumagai Y, Takeuchi O, Kato H, Kumar H, Matsui K, Morii E, et al. Alveolar macrophages are the primary interferon-alpha producer in pulmonary infection with RNA viruses. Immunity 2007;27:240–52. 96. Krug A, French AR, Barchet W, Fischer JA, Dzionek A, Pingel JT, et al. TLR9-dependent recognition of MCMV by IPC and DC generates coordinated cytokine responses that activate antiviral NK cell function. Immunity 2004;21:107–19. 97. Lund J, Sato A, Akira S, Medzhitov R, Iwasaki A. Toll-like receptor 9-mediated recognition of Herpes simplex virus-2 by plasmacytoid dendritic cells. J Exp Med 2003;198:513–20. 98. Lund JM, Linehan MM, Iijima N, Iwasaki A. Cutting Edge: Plasmacytoid dendritic cells provide innate immune protection against mucosal viral infection in situ. J Immunol 2006;177: 7510–4. 99. ClustalW WWW System. http://clustalw.ddbj.nig.ac.jp/ Accessed 21 Mar 2008. 100. Comput Appl Biosci. 1996 Aug;12(4):357–8. TreeView: an application to display phylogenetic trees on personal computers. Page RD. Division of Environmental and Evolutionary Biology University of Glasgow UK.
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