Pathogen recognition by innate receptors

Kumagai, Yutaro; Takeuchi, Osamu; Akira, Shizuo

doi:10.1007/s10156-008-0596-1

Cited by 198 publications

(195 citation statements)

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“…There are 3 major classes of such receptors: Toll-like receptors (TLRs), RIG-I-like helicases (RLHs) and NOD-like receptors (1). During infection, nucleic acids derived from microbes are recognized by TLRs and RLHs, which then trigger a series of signaling events leading to the production of type I IFNs and proinflammatory cytokines.…”

Section: Icrobial Infection-induced Host Immune Responses Arementioning

confidence: 99%

ERIS, an endoplasmic reticulum IFN stimulator, activates innate immune signaling through dimerization

Sun

Chen

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

722

625

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We report here the identification and characterization of a protein, ERIS, an endoplasmic reticulum (ER) IFN stimulator, which is a strong type I IFN stimulator and plays a pivotal role in response to both non-self-cytosolic RNA and dsDNA. ERIS (also known as STING or MITA) resided exclusively on ER membrane. The ER retention/ retrieval sequence RIR was found to be critical to retain the protein on ER membrane and to maintain its integrity. ERIS was dimerized on innate immune challenges. Coumermycin-induced ERIS dimerization led to strong and fast IFN induction, suggesting that dimerization of ERIS was critical for self-activation and subsequent downstream signaling.innate immunity ͉ type I IFN ͉ functional cDNA library screening ͉ cytosolic RNA and dsDNA ͉ ER retention signal M icrobial infection-induced host immune responses are initiated by the germline-encoded pattern recognition receptors, which recognize components specific to microorganisms. There are 3 major classes of such receptors: Toll-like receptors (TLRs), RIG-I-like helicases (RLHs) and NOD-like receptors (1). During infection, nucleic acids derived from microbes are recognized by TLRs and RLHs, which then trigger a series of signaling events leading to the production of type I IFNs and proinflammatory cytokines.RLHs have recently been identified to sense the invading viruses in the cytoplasm. Unlike TLRs, which are expressed in specific cells like macrophages and dendritic cells, RLHs are found in most cell types (2). They contain caspase recruitment domain (CARD) and DExD/H helicase domain. RLHs interact with microbial nucleotides through their helicase domain. The N-terminal CARDs are responsible for activating downstream signaling pathways that mediate type I IFN production. Genetic analyses demonstrate that RIG-I and MDA5 sense distinct types of viruses (3-5). RIG-I and MDA5 use a common adaptor molecule, IPS-1 (also known as Cardif, MAVS, or VISA) (6-9). IPS-1 is found to reside on the mitochondrial membrane by its C-terminal transmembrane (TM) domain. It also contains a CARD-like domain at its N-terminus, which mediates the interaction with MDA5 or RIG-I. IPS-1 transmits the signal to TANK-binding kinase-1 (TBK1)/I B kinase i (IKKi; also known as IKK ) and the IKK complex to activate interferon regulatory factor (IRF)-3/IRF-7 and NF-B, respectively, collectively eliciting innate antiviral immune responses, including type I IFN production.On the other hand, dsDNA in the cytosol, for example, genomic DNA from intracellular bacteria (e.g., Listeria, Legionella), also causes a strong host immune response independent of TLRs, leading to the induction of type I IFN. A recent report has indicated that the molecule DAI (also known as ZBP1) might serve as a cytosolic dsDNA sensor (10). However, ZBP1 Ϫ/Ϫ cells showed normal type I IFN production in response to dsDNA stimulation (11). Meanwhile, reports showed that IPS-1/Cardif/MAVS/VISA was not required for dsDNA-caused innate immune activation (12).The signaling induced by cytoplasmic dsDNA leading ...

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Section: Icrobial Infection-induced Host Immune Responses Arementioning

confidence: 99%

ERIS, an endoplasmic reticulum IFN stimulator, activates innate immune signaling through dimerization

Sun

Chen

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

722

625

View full text Add to dashboard Cite

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“…These PAMPs are recognized by host cellular pattern recognition receptors (PRRs) with various chemical specificities, including the Nod-like receptors (NLRs), Rig-like receptors (RLRs), C-type lectin receptors (CLRs), and Toll-like receptors (TLRs) (28). In addition, a number of cytosolic receptors have recently been implicated in the detection of foreign double-stranded DNA (dsDNA) within infected cells (24,25,50).…”

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confidence: 99%

Type I Interferons Mediate the Innate Cytokine Response to Recombinant Fowlpox Virus but Not the Induction of Plasmacytoid Dendritic Cell-Dependent Adaptive Immunity

Lousberg

Fraser

Tovey

et al. 2010

J Virol

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“…13 TLRs are pattern recognition receptors present on diverse cell types that recognize specific molecular patterns present in molecules that are broadly shared by pathogens but distinguishable from host molecules, collectively referred to as pathogen-associated molecular patterns (PAMPs). 14,15 There are 10 TLRs in the human genome; toxic LPS, to Ribi's 'detoxified' monophosphoryl lipid A in the 1980s, [25][26][27][28][29] and culminating in extensive clinical trials and now awaiting imminent approval by the FDA and commercialization as MPL TM (Fig. 1) is instructive, and the lessons learned can be adduced to developing other TLR agonistic adjuvants.…”

mentioning

confidence: 99%

“…53,54 As mentioned earlier, aluminum salts these are trans-membrane proteins with an extracellular domain having leucine-rich repeats (LRR) and a cytosolic domain called the Toll/IL-1 receptor (TIR) domain. 15 The ligands for these receptors are highly conserved microbial molecules such as LPS (recognized by TLR4), lipopeptides (TLR2 in combination with TLR1 or TLR6), flagellin (TLR5), single stranded RNA (TLR7 and TLR8), double stranded RNA (TLR3), CpG motif-containing DNA (recognized by TLR9), and profilin present on uropathogenic bacteria (TLR 11). 16,17 The activation of TLRs by their cognate ligands leads to production of inflammatory cytokines, and upregulation of MHC molecules and co-stimulatory signals in antigen-presenting cells as well as activating natural killer (NK) cells (innate immune response), in addition to priming and amplifying T-, and B-cell effector functions [18][19][20][21] (adaptive immune responses).…”

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confidence: 99%

Potential adjuvantic properties of innate immune stimuli

et al. 2009

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Just as the prescient comment by Gaston Ramon was relegated to the last footnote of his 1926 paper, 1 so has research on the mechanisms of action of adjuvants, until recently, languished as parenthetical annotations and addenda in the archives of immunology and vaccine development. Ramon defined immunological adjuvants as "substances used in combination with a specific antigen that produced a more robust immune response than the antigen alone." Interestingly enough, he was referring to his empirical findings that the addition of bread crumbs, tapioca, saponin and 'starch oil' to antigenic preparations greatly enhanced antibody responses to diphtheria or tetanus. 2 A year later, the adjuvanticity of aluminum salts (primarily phosphate and hydroxide) was discovered by Glenny and coworkers. 3 In the 83 years that have elapsed, the repertoire of investigational adjuvants has grown to encompass a very wide range of materials, 4 but aluminum salt-based mineral salts (generically, and incorrectly, termed "alum") have remained the only adjuvants currently approved by the FDA. Aluminum salts have enjoyed a good safety record, but they are weak adjuvants for antibody induction and induce a T helper-2 (T H 2)-skewed, rather than a T helper-1 (T H 1) response. 5,6 Furthermore, not only are aluminum salts ineffective at inducing cytotoxic T lymphocyte (CTL) or mucosal IgA antibody responses, but also have a propensity to induce IgE responses, which have been associated with allergic reactions in some subjects. 5,6 Very recent reports implicate the Nalp3 inflammasome, a component of the innate immune response, as the effector limb of alum-associated adjuvanticity. [7][8][9] In 1962, Dresser observed that injection of purified soluble proteins not only failed to stimulate an immune response, but tolerized animals unless a bacterial extract was admixed with the protein immunogen. 10 This led him to redefine adjuvanticity as "a property of a substance which can act as a physiological switch, directing at least some immunologically competent cells to respond by making antibody rather than by becoming immunologically paralyzed by the antigen," 11 confirming Johnson's earlier observations that lipopolysaccharide (LPS) from Gram-negative bacteria exerted potent adjuvant properties, 12 and perhaps paved the way for the subsequent discovery of the wide range of microorganism-derived adjuvants. 13 TLRs are pattern recognition receptors present on diverse cell types that recognize specific molecular patterns present in molecules that are broadly shared by pathogens but distinguishable from host molecules, collectively referred to as pathogen-associated molecular patterns (PAMPs). 14,15 There are 10 TLRs in the human genome;

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Pathogen recognition by innate receptors

Cited by 198 publications

References 100 publications

ERIS, an endoplasmic reticulum IFN stimulator, activates innate immune signaling through dimerization

ERIS, an endoplasmic reticulum IFN stimulator, activates innate immune signaling through dimerization

Type I Interferons Mediate the Innate Cytokine Response to Recombinant Fowlpox Virus but Not the Induction of Plasmacytoid Dendritic Cell-Dependent Adaptive Immunity

Potential adjuvantic properties of innate immune stimuli

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