Top

Published in:

01-03-2009

Innate immune recognition of nucleic acids

Author: Tsan Xiao

Published in: Immunologic Research | Issue 1-3/2009

Abstract

The innate immune system employs a number of pattern recognition receptor families in response to DNAs and RNAs, either from invading microbes or within the hosts. These include the Toll-like receptors (TLRs), the retinoic acid inducible gene I (RIG-I) like receptors (RLRs), and the nucleotide-binding domain leucine-rich repeat/NOD-like receptor (NLRs), among other potential sensors in the cytoplasm. These receptors are composed of modular domain architecture, with ligand binding/sensing domains and signaling domains regulated either through dimerization/oligomerization, or conformational changes directed by enzymatic activities. Signaling pathways from different families of receptors converge on their respective common adapter proteins and lead to activation of transcription factors or caspases. Many of these receptors induce orchestrated responses to similar ligands from different cell types, resulting in redundant and complementary immunity to infections. This highly efficient defense system is a double-edged sword: inappropriate reaction to host ligands leads to compromised innate tolerance and autoimmune diseases. Structural studies of innate immune receptors and their signaling pathways are essential in our understanding of pattern recognition mechanisms and design of more efficient vaccine adjuvants.

Jenner E. An inquiry into the causes and effects of the variolae vaccinae, a disease discovered in some Western counties of England. London: Sampson Low; 1798.

Janeway CA, Jr. Approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harb Symp Quant Biol. 1989;54 Pt 1: 1–13.PubMed

Poltorak A, He X, Smirnova I, Liu M-Y, 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.PubMedCrossRef

Medzhitov R, Preston-Hurlburt P, Janeway CA, Jr. A human homologue of the Drosophila toll protein signals activation of adaptive immunity. Nature. 1997;388:394–7.PubMedCrossRef

Yoneyama M, Kikuchi M, Natsukawa T, Shinobu N, Imaizumi T, Miyagishi M, et al. The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. Nat Immunol. 2004;5:730–7.PubMedCrossRef

Rakoff-Nahoum S, Paglino J, Eslami-Varzaneh F, Edberg S, Medzhitov R. Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell. 2004;118:229–41.PubMedCrossRef

Tian J, Avalos AM, Mao SY, Chen B, Senthil K, Wu H, et al. Toll-like receptor 9-dependent activation by DNA-containing immune complexes is mediated by HMGB1 and RAGE. Nat Immunol. 2007;8:487–96.PubMedCrossRef

Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell. 2006;124:783–801.PubMedCrossRef

Marshak-Rothstein A, Rifkin IR. Immunologically active autoantigens: the role of toll-like receptors in the development of chronic inflammatory disease. Annu Rev Immunol. 2007;25:419–41.PubMedCrossRef

10.

Pichlmair A, Reis e Sousa C. Innate recognition of viruses. Immunity. 2007;27:370–83.PubMedCrossRef

11.

Lee HK, Lund JM, Ramanathan B, Mizushima N, Iwasaki A. Autophagy-dependent viral recognition by plasmacytoid dendritic cells. Science. 2007;315:1398–401.PubMedCrossRef

12.

Kawai T, Akira S. Innate immune recognition of viral infection. Nat Immunol. 2006;7:131–7.PubMedCrossRef

13.

Meier A, Alter G, Frahm N, Sidhu H, Li B, Bagchi A, et al. MyD88-dependent immune activation mediated by human immunodeficiency virus type 1-encoded Toll-like receptor ligands. J Virol. 2007;81:8180–91.PubMedCrossRef

14.

Le Goffic R, Balloy V, Lagranderie M, Alexopoulou L, Escriou N, Flavell R, et al. Detrimental contribution of the Toll-like receptor (TLR)3 to influenza A virus-induced acute pneumonia. PLoS Pathog. 2006;2:e53.PubMedCrossRef

15.

Daffis S, Samuel MA, Suthar MS, Gale M, Jr, Diamond MS. Toll-like receptor-3 has a protective role against West Nile virus infection. J Virol. 20 August 2008 [Epub ahead of print].

16.

Wang T, Town T, Alexopoulou L, Anderson JF, Fikrig E, Flavell RA. Toll-like receptor 3 mediates West Nile virus entry into the brain causing lethal encephalitis. Nat Med. 2004;10:1366–73.PubMedCrossRef

17.

Alexopoulou L, Holt AC, Medzhitov R, Flavell RA. Recognition of double-stranded RNA and activation of NF-kB by Toll-like receptor 3. Nature. 2001;413:732–8.PubMedCrossRef

18.

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.PubMedCrossRef

19.

Heil F, Ahmad-Nejad P, Hemmi H, Hochrein H, Ampenberger F, Gellert T, et al. The Toll-like receptor 7 (TLR7)-specific stimulus loxoribine uncovers a strong relationship within the TLR7, 8 and 9 subfamily. Eur J Immunol. 2003;33:2987–97.PubMedCrossRef

20.

Haas T, Metzger J, Schmitz F, Heit A, Muller T, Latz E, et al. The DNA sugar backbone 2’ deoxyribose determines toll-like receptor 9 activation. Immunity. 2008;28:315–23.PubMedCrossRef

21.

Higgins D, Marshall JD, Traquina P, Van Nest G, Livingston BD. Immunostimulatory DNA as a vaccine adjuvant. Expert Rev Vaccines. 2007;6:747–59.PubMedCrossRef

22.

Hou B, Reizis B, Defranco AL. Toll-like receptors activate innate and adaptive immunity by using dendritic cell-intrinsic and -extrinsic mechanisms. Immunity. 2008;29:272–82.PubMedCrossRef

23.

Latz E, Schoenemeyer A, Visintin A, Fitzgerald KA, Monks BG, Knetter CF, et al. TLR9 signals after translocating from the ER to CpG DNA in the lysosome. Nat Immunol. 2004;5:190–8.PubMedCrossRef

24.

Kim YM, Brinkmann MM, Paquet ME, Ploegh HL. UNC93B1 delivers nucleotide-sensing toll-like receptors to endolysosomes. Nature. 2008;452:234–8.PubMedCrossRef

25.

Eaton-Bassiri A, Dillon SB, Cunningham M, Rycyzyn MA, Mills J, Sarisky RT, et al. Toll-like receptor 9 can be expressed at the cell surface of distinct populations of tonsils and human peripheral blood mononuclear cells. Infect Immun. 2004;72:7202–11.PubMedCrossRef

26.

Kleinman ME, Yamada K, Takeda A, Chandrasekaran V, Nozaki M, Baffi JZ, et al. Sequence- and target-independent angiogenesis suppression by siRNA via TLR3. Nature. 2008;452:591–7.PubMedCrossRef

27.

Lande R, Gregorio J, Facchinetti V, Chatterjee B, Wang YH, Homey B, et al. Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide. Nature. 2007;449:564–9.PubMedCrossRef

28.

O’Neill LA. How Toll-like receptors signal: what we know and what we don’t know. Curr Opin Immunol. 2006;18:3–9.PubMedCrossRef

29.

Bell JK, Botos I, Hall PR, Askins J, Shiloach J, Segal DM, et al. The molecular structure of the Toll-like receptor 3 ligand-binding domain. Proc Natl Acad Sci U S A. 2005;102:10976–80.PubMedCrossRef

30.

Choe J, Kelker MS, Wilson IA. Crystal structure of human toll-like receptor 3 (TLR3) ectodomain. Science. 2005;309:581–5.PubMedCrossRef

31.

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.PubMedCrossRef

32.

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.PubMedCrossRef

33.

Liu L, Botos I, Wang Y, Leonard JN, Shiloach J, Segal DM, et al. Structural basis of toll-like receptor 3 signaling with double-stranded RNA. Science. 2008;320:379–81.PubMedCrossRef

34.

Jin MS, Lee JO. Structures of the Toll-like receptor family and its ligand complexes. Immunity. 2008;29:182–91.PubMedCrossRef

35.

O’Neill LA, Bowie AG. The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling. Nat Rev Immunol. 2007;7:353–64.PubMedCrossRef

36.

Cirl C, Wieser A, Yadav M, Duerr S, Schubert S, Fischer H, et al. Subversion of Toll-like receptor signaling by a unique family of bacterial Toll/interleukin-1 receptor domain-containing proteins. Nat Med. 2008;14:399–406.PubMedCrossRef

37.

von Bernuth H, Picard C, Jin Z, Pankla R, Xiao H, Ku CL, et al. Pyogenic bacterial infections in humans with MyD88 deficiency. Science. 2008;321:691–6.CrossRef

38.

Xu Y, Tao X, Shen B, Horng T, Medzhitov R, Manley JL, et al. Structural basis for signal transduction by the Toll/interleukin-1 receptor domains. Nature. 2000;408:111–5.PubMedCrossRef

39.

Tao X, Xu Y, Zheng Y, Beg AA, Tong L. An extensively associated dimer in the structure of the C713S mutant of the TIR domain of human TLR2. Biochem Biophys Res Commun. 2002;299:216–21.PubMedCrossRef

40.

Khan JA, Brint EK, O’Neill LA, Tong L. Crystal structure of the Toll/interleukin-1 receptor domain of human IL-1RAPL. J Biol Chem. 2004;279:31664–70.PubMedCrossRef

41.

Nyman T, Stenmark P, Flodin S, Johansson I, Hammarstrom M, Nordlund P. The crystal structure of the human toll-like receptor-10 cytoplasmic domain reveals a putative signaling dimer. J Biol Chem. 2008;283:11861–5.PubMedCrossRef

42.

Sultzer BM. Genetic control of leucocyte responses to endotoxin. Nature. 1968;219:1253–4.PubMedCrossRef

43.

Bartfai T, Behrens MM, Gaidarova S, Pemberton J, Shivanyuk A, Rebek J Jr. A low molecular weight mimic of the Toll/IL-1 receptor/resistance domain inhibits IL-1 receptor-mediated responses. Proc Natl Acad Sci U S A. 2003;100:7971–6.PubMedCrossRef

44.

Loiarro M, Capolunghi F, Fanto N, Gallo G, Campo S, Arseni B, et al. Pivotal advance: inhibition of MyD88 dimerization and recruitment of IRAK1 and IRAK4 by a novel peptidomimetic compound. J Leukoc Biol. 2007;82:801–10.PubMedCrossRef

45.

Khor CC, Chapman SJ, Vannberg FO, Dunne A, Murphy C, Ling EY, et al. A Mal functional variant is associated with protection against invasive pneumococcal disease, bacteremia, malaria and tuberculosis. Nat Genet. 2007;39:523–8.PubMedCrossRef

46.

Ishii KJ, Koyama S, Nakagawa A, Coban C, Akira S. Host innate immune receptors and beyond: making sense of microbial infections. Cell Host Microbe. 2008;3:352–63.PubMedCrossRef

47.

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.PubMedCrossRef

48.

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.PubMed

49.

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.PubMedCrossRef

50.

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.PubMedCrossRef

51.

Kato H, Takeuchi O, Mikamo-Satoh E, Hirai R, Kawai T, Matsushita K, et al. Length-dependent recognition of double-stranded ribonucleic acids by retinoic acid-inducible gene-I and melanoma differentiation-associated gene 5. J Exp Med. 2008;205:1601–10.PubMedCrossRef

52.

Saito T, Hirai R, Loo YM, Owen D, Johnson CL, Sinha SC, et al. Regulation of innate antiviral defenses through a shared repressor domain in RIG-I and LGP2. Proc Natl Acad Sci U S A. 2007;104:582–7.PubMedCrossRef

53.

Saito T, Gale M Jr. Differential recognition of double-stranded RNA by RIG-I-like receptors in antiviral immunity. J Exp Med. 2008;205:1523–7.PubMedCrossRef

54.

Cui S, Eisenacher K, Kirchhofer A, Brzozka K, Lammens A, Lammens K, et al. The C-terminal regulatory domain is the RNA 5’-triphosphate sensor of RIG-I. Mol Cell. 2008;29:169–79.PubMedCrossRef

55.

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.PubMedCrossRef

56.

Potter JA, Randall RE, Taylor GL. Crystal structure of human IPS-1/MAVS/VISA/Cardif caspase activation recruitment domain. BMC Struct Biol. 2008;8:11.PubMedCrossRef

57.

Seth RB, Sun L, Ea CK, Chen ZJ. Identification characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-kappaB and IRF 3. Cell. 2005;122:669–82.PubMedCrossRef

58.

Meylan E, Curran J, Hofmann K, Moradpour D, Binder M, Bartenschlager R, et al. Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus. Nature. 2005;437:1167–72.PubMedCrossRef

59.

Xu LG, Wang YY, Han KJ, Li LY, Zhai Z, Shu HB. VISA is an adapter protein required for virus-triggered IFN-beta signaling. Mol Cell. 2005;19:727–40.PubMedCrossRef

60.

Qin H, Srinivasula SM, Wu G, Fernandes-Alnemri T, Alnemri ES, Shi Y. Structural basis of procaspase-9 recruitment by the apoptotic protease-activating factor 1. Nature. 1999;399:549–57.PubMedCrossRef

61.

Chou JJ, Matsuo H, Duan H, Wagner G. Solution structure of the RAIDD CARD and model for CARD/CARD interaction in caspase-2 and caspase-9 recruitment. Cell. 1998;94:171–80.PubMedCrossRef

62.

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.PubMedCrossRef

63.

Stetson DB, Medzhitov R. Recognition of cytosolic DNA activates an IRF3-dependent innate immune response. Immunity. 2006;24:93–103.PubMedCrossRef

64.

Spies B, Hochrein H, Vabulas M, Huster K, Busch DH, Schmitz F, et al. Vaccination with plasmid DNA activates dendritic cells via Toll-like receptor 9 (TLR9) but functions in TLR9-deficient mice. J Immunol. 2003;171:5908–12.PubMed

65.

Babiuk S, Mookherjee N, Pontarollo R, Griebel P, den Hurk S, Hecker R, et al. TLR9 −/− and TLR9 +/+ mice display similar immune responses to a DNA vaccine. Immunology. 2004;113:114–20.PubMedCrossRef

66.

Hoffman HM, Mueller JL, Broide DH, Wanderer AA, Kolodner RD. Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome. Nat Genet. 2001;29:301–5.PubMedCrossRef

67.

Hoffman HM, Rosengren S, Boyle DL, Cho JY, Nayar J, Mueller JL, et al. Prevention of cold-associated acute inflammation in familial cold autoinflammatory syndrome by interleukin-1 receptor antagonist. Lancet. 2004;364:1779–85.PubMedCrossRef

68.

Petrilli V, Dostert C, Muruve DA, Tschopp J. The inflammasome: a danger sensing complex triggering innate immunity. Curr Opin Immunol. 2007;19:615–22.PubMedCrossRef

69.

Ye Z, Ting JP. NLR, the nucleotide-binding domain leucine-rich repeat containing gene family. Curr Opin Immunol. 2008;20:3–9.PubMed

70.

Masumoto J, Taniguchi S, Ayukawa K, Sarvotham H, Kishino T, Niikawa N, et al. ASC, a novel 22-kDa protein, aggregates during apoptosis of human promyelocytic leukemia HL-60 cells. J Biol Chem. 1999;274:33835–8.PubMedCrossRef

71.

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.PubMedCrossRef

72.

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.PubMedCrossRef

73.

Muruve DA, Petrilli V, Zaiss AK, White LR, Clark SA, Ross PJ, et al. The inflammasome recognizes cytosolic microbial and host DNA and triggers an innate immune response. Nature. 2008;452:103–7.PubMedCrossRef

74.

Halle A, Hornung V, Petzold GC, Stewart CR, Monks BG, Reinheckel T, et al. The NALP3 inflammasome is involved in the innate immune response to amyloid-beta. Nat Immunol. 2008;9:857–65.PubMedCrossRef

75.

Martinon F, Petrilli V, Mayor A, Tardivel A, Tschopp J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature. 2006;440:237–41.PubMedCrossRef

76.

Dostert C, Petrilli V, Van Bruggen R, Steele C, Mossman BT, Tschopp J. Innate immune activation through Nalp3 inflammasome sensing of asbestos and silica. Science. 2008;320:674–7.PubMedCrossRef

77.

Hornung V, Bauernfeind F, Halle A, Samstad EO, Kono H, Rock KL, et al. Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nat Immunol. 2008;9:847–56.PubMedCrossRef

78.

Cruz CM, Rinna A, Forman HJ, Ventura AL, Persechini PM, Ojcius DM. ATP activates a reactive oxygen species-dependent oxidative stress response and secretion of proinflammatory cytokines in macrophages. J Biol Chem. 2007;282:2871–9.PubMedCrossRef

79.

Sansonetti PJ. The innate signaling of dangers and the dangers of innate signaling. Nat Immunol. 2006;7:1237–42.PubMedCrossRef

80.

Schwartz T, Behlke J, Lowenhaupt K, Heinemann U, Rich A. Structure of the DLM-1-Z-DNA complex reveals a conserved family of Z-DNA-binding proteins. Nat Struct Biol. 2001;8:761–5.PubMedCrossRef

81.

Deigendesch N, Koch-Nolte F, Rothenburg S. ZBP1 subcellular localization and association with stress granules is controlled by its Z-DNA binding domains. Nucleic Acids Res. 2006;34:5007–20.PubMedCrossRef

82.

Kim YG, Muralinath M, Brandt T, Pearcy M, Hauns K, Lowenhaupt K, et al. A role for Z-DNA binding in vaccinia virus pathogenesis. Proc Natl Acad Sci U S A. 2003;100:6974–9.PubMedCrossRef

83.

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.PubMedCrossRef

84.

Ishii KJ, Kawagoe T, Koyama S, Matsui K, Kumar H, Kawai T, et al. TANK-binding kinase-1 delineates innate and adaptive immune responses to DNA vaccines. Nature. 2008;451:725–9.PubMedCrossRef

85.

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.PubMed

86.

Kanzler H, Barrat FJ, Hessel EM, Coffman RL. Therapeutic targeting of innate immunity with Toll-like receptor agonists and antagonists. Nat Med. 2007;13:552–9.PubMedCrossRef

Title: Innate immune recognition of nucleic acids
Author: Tsan Xiao
Publication date: 01-03-2009
Publisher: Humana Press Inc
Published in: Immunologic Research / Issue 1-3/2009
Print ISSN: 0257-277X
Electronic ISSN: 1559-0755
DOI: https://doi.org/10.1007/s12026-008-8053-x

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Innate immune recognition of nucleic acids

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 1-3/2009

Introduction

Amplification mechanisms for the enhancement of antigen-mediated mast cell activation

Activation and regulation of Toll-Like Receptors (TLRs) by helminth parasites

The influence of sphingosine-1-phosphate receptor signaling on lymphocyte trafficking: How a bioactive lipid mediator grew up from an “immature” vascular maturation factor to a “mature” mediator of lymphocyte behavior and function

Advances in treatment for chronic granulomatous disease

The technological transformation of patient-driven human immunology research