INTRACELLULAR SYSTEMS FOR DETECTION OF EXOGENOUS NUCLEIC ACIDS AND TRIGGERING MECHANISMS OF IMMUNE RESPONSE TO DNA INTERNALIZATION

Abstract. There are some specific mechanisms in cell that detect the invasion into the cell of any foreign molecules, so-called pathogen-associated molecular patterns (PAMPs). The recognition of these PAMPs is realized by Toll-like receptors or is due to the cytosolic sensors action. In recent years much attention is directed to the investigation of foreign nucleic acids sensing and detection in cell. Nowadays some sensors of doublestranded DNA, such as STING, DAI, members of NOD-like protein family, RIG-like helicases, proteins of HIN-200 family are identified. Some of sensors interact with double-stranded DNA directly. The others are characterized as mediators of signal transduction from unknown DNA-sensor in the series of following molecular events. Induction of nuclear transcription factors NF-κB and IRF3/IRF7 to produce IFNβ or processing of proinflammatory cytokines IL-1β and IL-18 by means of inflammasome formation is a result of activation of cascade events induced by cytosolic DNA. In the review we combine information concerning signaling pathways characterized sensing of intracellular double-stranded DNA that results in the development of the cellular immune response.

1. Олишевский С.В., Козак В.В., Яниш Ю.В., Рыбалко С.Л., Шляховенко В.А. Иммуностимулирующая CpG-ДНК: перспективы клинического применения в онкологии // Онкология. – 2006. – Т. 8. – С. 209-217. Olishevskiy S.V., Kozak V.V., Yanish Yu.V., Rybalko S.L., Shlyakhovenko V.A. Immunostimuliruyushchaya CpG-DNK: perspektivy klinicheskogo primeneniya v onkologii [Immunostimulatory CpG DNA: prospects for clinical use in oncology]. Onkologiya – Oncology, 2006, vol. 8, pp. 209-217.

2. Ракофф-Наум С., Меджитов Р. Роль Toll-подобных рецепторов в репарации тканей и канцерогенезе // Биохимия. – 2008. – Т. 73. – С. 690-698. Rakoff-Naum S., Medzhitov R. Rol` Toll-podobnykh retseptorov v reparatsii tkaney i kantserogeneze [Role of Toll-like receptors in tissue repair and carcinogenesis]. Biokhimiya – Biochemistry, 2008, vol. 73, pp. 690-698.

3. Челобанов Б.П., Лактионов П.П., Власов В.В. Белки, участвующие в связывании и поглощении клетками нуклеиновых кислот // Биохимия. – 2006. – Т. 71, № 6. – С. 725-741. Chelobanov B.P., Laktionov P.P., Vlasov V.V. Belki, uchastvuyushchie v svyazyvanii i pogloshchenii kletkami nukleinovykh kislot [Proteins involved in binding and uptake of nucleic acids by the cell]. Biokhimiya – Biochemistry, 2006, vol. 71, no. 6, pp. 725-741.

4. Ablasser A., Bauernfeind F., Hartmann G., Latz E., Fitzgerald K.A., Hornung V. RIG-I-dependent sensing of poly(dA:dT) through the induction of an RNA polymerase III-transcribed RNA intermediate. Nat. Immunol., 2009, vol. 10, no. 10, pp. 1065-1072.

5. Agostini L., Martinon F., Burns K., McDermott M.F., Hawkins P.N., Tschopp J. NALP3 forms an IL-1 beta-processing inflammasome with increased activity in Muckle-Wells autoinflammatory disorder. Immunity, 2004, vol. 20, no. 3, pp. 319-325.

6. Akira S., Uematsu S., Takeuchi O. Pathogen recognition and innate immunity. Cell, 2006, vol. 124, no. 4, pp. 783-801.

7. Alexopoulou L., Holt A.C., Medzhitov R., Flavell R.A. Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature, 2001, vol. 413, no. 6857, pp. 732-738.

8. Barbalat R., Ewald S.E., Mouchess M.L., Barton G.M. Nucleic acid recognition by the innate immune system. Annu. Rev. Immunol., 2011, vol. 29, pp. 185-214.

9. Barber G.N. Cytoplasmic DNA innate immune pathways. Immunol. Rev., 2011, vol. 243, no. 1, pp. 99-108.

10. Barber G.N. Innate immune DNA sensing pathways: STING, AIMII and the regulation of interferon production and inflammatory responses. Curr. Opin. Immunol., 2011, vol. 23, no. 1, pp. 10-20.

11. Blasius A.L., Beutler B. Intracellular toll-like receptors. Immunity, 2010, vol. 32, no. 3, pp. 305-315.

12. Bode C., Zhao G., Steinhagen F., Kinjo T., Klinman D.M. CpG DNA as a vaccine adjuvant. Expert Rev. Vaccines, 2011, vol. 10, no. 4, pp. 499-511.

13. Chen M., Zhang W., Xu W., Zhang F., Xiong S. Blockade of TLR9 signaling in B cells impaired anti-dsDNA antibody production in mice induced by activated syngenic lymphocyte-derived DNA immunization. Mol. Immunol., 2011, vol. 48, no. 12-13, pp. 1532-1539.

14. Chien Y., Kim S., Bumeister R., Loo Y.M., Kwon S.W., Johnson C.L., Balakireva M.G., Romeo Y., Kopelovich L., Gale M.Jr., Yeaman C., Camonis J.H., Zhao Y., White M.A. RalB GTPase-mediated activation of the IkappaB family kinase TBK1 couples innate immune signaling to tumor cell survival. Cell, 2006, vol. 127, no. 1, pp. 157-170.

15. Chiu Y.H., Macmillan J.B., Chen Z.J. RNA polymerase III detects cytosolic DNA and induces type I interferons through the RIG-I pathway. Cell, 2009, vol. 138, no. 3, pp. 576-591.

16. Crow Y.J., Hayward B.E., Parmar R., Robins P., Leitch A., Ali M., Black D.N., van Bokhoven H., Brunner H.G., Hamel B.C., Corry P.C., Cowan F.M., Frints S.G., Klepper J., Livingston J.H., Lynch S.A., Massey R.F., Meritet J.F., Michaud J.L., Ponsot G., Voit T., Lebon P., Bonthron D.T., Jackson A.P., Barnes D.E., Lindahl T. Mutations in the gene encoding the 3‘-5‘ DNA exonuclease TREX1 cause Aicardi-Goutieres syndrome at the AGS1 locus. Nat. Genet., 2006, vol. 38, no. 8, pp. 917-920.

17. Crow Y.J., Leitch A., Hayward B.E., Garner A., Parmar R., Griffith E., Ali M., Semple C., Aicardi J., Babul-Hirji R., Baumann C., Baxter P., Bertini E., Chandler K.E., Chitayat D., Cau D., Dery C., Fazzi E., Goizet C., King M.D., Klepper J., Lacombe D., Lanzi G., Lyall H., Martinez-Frias M.L., Mathieu M., McKeown C., Monier A., Oade Y., Quarrell O.W., Rittey C.D., Rogers R.C., Sanchis A., Stephenson J.B., Tacke U., Till M., Tolmie J.L., Tomlin P., Voit T., Weschke B., Woods C.G., Lebon P., Bonthron D.T., Ponting C. P., Jackson A.P. Mutations in genes encoding ribonuclease H2 subunits cause Aicardi-Goutieres syndrome and mimic congenital viral brain infection. Nat. Genet., 2006, vol. 38, no. 8, pp. 910-916.

18. Decker P., Singh-Jasuja H., Haager S., K tter I., Rammensee H.G. Nucleosome, the main autoantigen in systemic lupus erythematosus, induces direct dendritic cell activation via a MyD88-independent pathway: consequences on inflammation. J. Immunol., 2005, vol. 174, pp. 3326-3334.

19. Diebold S.S., 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, vol. 303, pp. 1529-1531.

20. Dolgova E.V., Proskurina A.S., Nikolin V.P., Popova N.A., Alyamkina E.A., Orishchenko K.E., Rogachev V.A., Efremov Y.R., Dubatolova T.D., Prokopenko A.V., Chernykh E.R., Ostanin A.A., Taranov O.S., Omigov V.V., Zagrebelniy S.N., Bogachev S.S., Shurdov M.A. “Delayed death” phenomenon: A synergistic action of cyclophosphamide and exogenous DNA. Gene, 2012, vol. 495, pp. 134-145.

21. Edelmann K.H., Richardson-Burns S., Alexopoulou L., Tyler K.L., Flavell R.A., Oldstone M.B. Does Tolllike receptor 3 play a biological role in virus infections? Virology, 2004, vol. 322, pp. 231-238.

22. Eitel J., Suttorp N., Opitz B. Innate immune recognition and inflammasome activation in listeria monocytogenes infection. Front. Microbiol., 2010, vol. 1, no. 149, pp. 1-7.

23. Fernandes-Alnemri T., Wu J., Yu J.W., Datta P., Miller B., Jankowski W., Rosenberg S., Zhang J., Alnemri E.S. The pyroptosome: a supramolecular assembly of ASC dimers mediating inflammatory cell death via caspase-1 activation. Cell Death Differ., 2007, vol. 14, no. 9, pp. 1590-1604.

24. Fernandes-Alnemri T., Yu J.W., Datta P., Wu J., Alnemri E.S. AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA. Nature, 2009, vol. 458, no. 7237, pp. 509-513.

25. Franchi L., Warner N., Viani K., Nunez G. Function of Nod-like receptors in microbial recognition and host defense. Immunol. Rev., 2009, vol. 227, no. 1, pp. 106-128.

26. Heil F., Hemmi H., Hochrein H., Ampenberger F., Kirschning C., Akira S., Lipford G., Wagner H., Bauer S. Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science, 2004, vol. 303, pp. 1526-1529.

27. Honda K., Takaoka A., Taniguchi T. Type I interferon [corrected] gene induction by the interferon regulatory factor family of transcription factors. Immunity, 2006, vol. 25, no. 3, pp. 349-360.

28. Hornung V., Ablasser A., Charrel-Dennis M., Bauernfeind F., Horvath G., Caffrey D.R., Latz E., Fitzgerald K.A. AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC. Nature, 2009, vol. 458, no. 7237, pp. 514-518.

29. Inohara N., Ogura Y., Fontalba A., Gutierrez O., Pons F., Crespo J., Fukase K., Inamura S., Kusumoto S., Hashimoto M., Foster S.J., Moran A.P., Fernandez-Luna J.L., Nunez G. Host recognition of bacterial muramyl dipeptide mediated through NOD2. Implications for Crohn‘s disease. J. Biol. Chem., 2003, vol. 278, no. 8, pp. 5509-5512.

30. Ishii K.J., Kawagoe T., Koyama S., Matsui K., Kumar H., Kawai T., Uematsu S., Takeuchi O., Takeshita F., Coban C., Akira S. TANK-binding kinase-1 delineates innate and adaptive immune responses to DNA vaccines. Nature, 2008, vol. 451, no. 7179, pp. 725-729.

31. Ishikawa H., Barber G.N. STING is an endoplasmic reticulum adaptor that facilitates innate immune signaling. Nature, 2008, vol. 455, no. 7213, pp. 674-678.

32. Ishikawa H., Barber G.N. The STING pathway and regulation of innate immune signaling in response to DNA pathogens. Cell Mol. Life Sci., 2011, vol. 68, no. 7, pp. 1157-1165.

33. Ishikawa H., Ma Z., Barber G.N. STING regulates intracellular DNA-mediated, type I interferondependent innate immunity. Nature, 2009, vol. 461, no. 7265, pp. 788-792.

34. Iwasaki A., Medzhitov R. Regulation of adaptive immunity by the innate immune system. Science, 2010, vol. 327, no. 5963, pp. 291-295.

35. Kaiser W.J., Upton J.W., Mocarski E.S. Receptor-interacting protein homotypic interaction motif-dependent control of NF-kappa B activation via the DNA-dependent activator of IFN regulatory factors. J. Immunol., 2008, vol. 181, no. 9, pp. 6427-6434.

36. Kato H., Takeuchi O., Sato S., Yoneyama M., Yamamoto M., Matsui K., Uematsu S., Jung A., Kawai T., Ishii K.J., Yamaguchi O., Otsu K., Tsujimura T., Koh C.S., Reis e Sousa C., Matsuura Y., Fujita T., Akira S. Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature, 2006, vol. 441, no. 7089, pp. 101-105.

37. Kawai T., Akira S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat. Immunol., 2010, vol. 11, no. 5, pp. 373-384.

38. Kawai T., Akira S. Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity, 2011, vol. 34, no. 5, pp. 637-650.

39. Kis-Toth K., Szanto A., Thai T.H., Tsokos G.C. Cytosolic DNA-activated human dendritic cells are potent activators of the adaptive immune response. J. Immunol., 2011, vol. 187, no. 3, pp. 1222-1234.

40. Krieg A.M. Therapeutic potential of Toll-like receptor 9 activation. Nat. Rev. Drug Discov., 2006, vol. 5, no. 6, pp. 471-484.

41. Krieg A.M. Development of TLR9 agonists for cancer therapy. J. Clin. Invest., 2007, vol. 117, pp. 1184-1194.

42. Krieg A.M., Yi A.K., Matson S., Waldschmidt T.J., Bishop G.A., Teasdale R., Koretzky G.A., Klinman D.M. CpG motifs in bacterial DNA trigger direct B-cell activation. Nature, 1995, vol. 374, pp. 546-549.

43. Kumagai Y., Akira S. Identification and functions of pattern-recognition receptors. J. Allergy Clin. Immunol., 2010, vol. 125, no. 5, pp. 985-992.

44. Latz E., Schoenemeyer A., Visintin A., Fitzgerald K.A., Monks B.G., Knetter C.F., Lien E., Nilsen N.J., Espevik T., Golenbock D.T. TLR9 signals after translocating from the ER to CpG DNA in the lysosome. Nat. Immunol., 2004, vol. 5, pp. 190-198.

45. Lee M.S., Kim Y.J. Signaling pathways downstream of pattern-recognition receptors and their cross talk. Annu. Rev. Biochem., 2007, vol. 76, pp. 447-480.

46. Lee-Kirsch M.A., Gong M., Chowdhury D., Senenko L., Engel K., Lee Y.A., de Silva U., Bailey S.L., Witte T., Vyse T.J., Kere J., Pfeiffer C., Harvey S., Wong A., Koskenmies S., Hummel O., Rohde K., Schmidt R.E., Dominiczak A.F., Gahr M., Hollis T., Perrino F.W., Lieberman J., Hubner N. Mutations in the gene encoding the 3’-5’ DNA exonuclease TREX1 are associated with systemic lupus erythematosus. Nat. Genet., 2007, vol. 39, no. 9, pp. 1065-1067.

47. Likhacheva A.S., Nikolin V.P., Popova N.A., Dubatolova T.D., Strunkin D.N., Rogachev V.A., Sebeleva T.E., Erofeev I.S., Bogachev S.S., Yakubov L.A., Shurdov M.A. Integration of human DNA fragments into the cell genomes of certain tissues from adult mice treated with cytostatic cyclophosphamide in combination with human DNA. Gene Ther. Mol. Biol., 2007, vol. 11, pp. 185-202.

48. Likhacheva A.S., Nikolin V.P., Popova N.A., Rogachev V.A., Prokhorovich M.A., Sebeleva T.E., Bogachev S.S., Shurdov M.A. Exogenous DNA can be captured by stem cells and be involved in their rescue from death after lethal-dose γ-radiation. Gene Ther. Mol. Biol., 2007, vol. 11, pp. 305-314.

49. Lladser A., Mougiakakos D., Tufvesson H., Ligtenberg M.A., Quest A.F., Kiessling R., Ljungberg K. DAI (DLM-1/ZBP1) as a genetic adjuvant for DNA vaccines that promotes effective antitumor CTL immunity. Mol. Ther., 2011, vol. 19, no. 3, pp. 594-601.

50. MacCabe K.M., Hemphill A., Akkari Y., Jakobs P.M., Pauw D., Olson S.B., Mosos R.E., Grompe M. ERCC1 is required for FANCD2 focus formation. Mol. Genet. Metab., 2008, vol. 95, no. 1-2, pp. 66-73.

51. Martin D.A., Elkon K.B. Intracellular mammalian DNA stimulates myeloid dendritic cells to produce type I interferons predominantly through a toll-like receptor 9-independent pathway. Arthritis Rheum., 2006, vol. 54, pp. 951-962.

52. Martinon F., Burns K., Tschopp J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol. Cell, 2002, vol. 10, no. 2, pp. 417-426.

53. Martinon F., Petrilli V., Mayor A., Tardivel A., Tschopp J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature, 2006, vol. 440, no. 7081, pp. 237-241.

54. Martinon F., Tschopp J. NLRs join TLRs as innate sensors of pathogens. Trends Immunol., 2005, vol. 26, no. 8, pp. 447-454.

55. Matzinger P. Tolerance, danger, and the extended family. Annu. Rev. Immunol., 1994, vol. 12, pp. 991-1045.

56. Mazur D.J., Perrino F.W. Structure and expression of the TREX1 and TREX2 3‘ --> 5‘ exonuclease genes. J. Biol. Chem., 2001, vol. 276, no. 18, pp. 14718-14727.

57. Medzhitov R. Recognition of microorganisms and activation of the immune response. Nature, 2007, vol. 449, pp. 819-826.

58. Meylan E., Tschopp J., Karin M. Intracellular pattern recognition receptors in the host response. Nature, 2006, vol. 442, no. 7098, pp. 39-44.

59. Miyahira A.K., Shahangian A., Hwang S., Sun R., Cheng G. TANK-binding kinase-1 plays an important role during in vitro and in vivo type I IFN responses to DNA virus infections. J. Immunol., 2009, vol. 182, no. 4, pp. 2248-2257.

60. Nazmi A., Mukhopadhyay R., Dutta K., Basu A. STING mediates neuronal innate immune response following japanese encephalitis virus infection. Sci. Rep., 2012, vol. 2, pp. 347.

61. Niedernhofer L.J., Odijk H., Budzowska M., van Drunen E., Maas A., Theil A.F., de Wit J., Jaspers N.G., Boverloo H.B., Hoeijmakers J.H., Kanaar R. The structure-specific endonuclease Ercc1-Xpf is required to resolve DNA interstrand cross-link-induced double-strand breaks. Mol. Cell Biol., 2004, vol. 24, no. 13, pp. 5776-5787.

62. Patel S.J., Jindal R., King K.R., Tilles A.W., Yarmush M.L. The inflammatory response to double stranded DNA in endothelial cells is mediated by NFκB and TNFα. PLoS One, 2011, vol. 6, no. 5, e19910.

63. Petrilli V., Dostert C., Muruve D.A., Tschopp J. The inflammasome: a danger sensing complex triggering innate immunity. Curr. Opin. Immunol., 2007, vol. 19, no. 6, pp. 615-622.

64. Randall R.E., Goodbourn S. Interferons and viruses: an interplay between induction, signalling, antiviral responses and virus countermeasures. J. Gen. Virol., 2008, vol. 89, pp. 1-47.

65. Roberts T.L., Idris A., Dunn J.A., Kelly G.M., Burnton C.M., Hodgson S., Hardy L.L., Garceau V., Sweet M.J., Ross I.L., Hume D.A., Stacey K.J. HIN-200 proteins regulate caspase activation in response to foreign cytoplasmic DNA. Science, 2009, vol. 323, no. 5917, pp. 1057-1060.

66. Saito T., Fujita N., Yoshimori T., Akira S. Regulation of dsDNA-induced innate immune responses by membrane trafficking. Autophagy, 2010, vol. 6, no. 3, pp. 430-432.

67. Saitoh T., Fujita N., Hayashi T., Takahara K., Satoh T., Lee H., Matsunaga K., Kageyama S., Omori H., Noda T., Yamamoto N., Kawai T., Ishii K., Takeuchi O., Yoshimori T., Akira S. Atg9a controls dsDNA-driven dynamic translocation of STING and the innate immune response. Proc. Natl. Acad. Sci. USA, 2009, vol. 106, no. 49, pp. 20842-20846.

68. Satoh T., Kato H., Kumagai Y., Yoneyama M., Sato S., Matsushita K., Tsujimura T., Fujita T., Akira S., Takeuchi O. LGP2 is a positive regulator of RIG-I- and MDA5-mediated antiviral responses. Proc. Natl. Acad. Sci. USA, 2010, vol. 107, no. 4, pp. 1512-1517.

69. Shao W., Yeretssian G., Doiron K., Hussain S.N., Saleh M. The caspase-1 digestome identifies the glycolysis pathway as a target during infection and septic shock. J. Biol. Chem., 2007, vol. 282, no. 50, pp. 36321-36329.

70. Sharma S., Fitzgerald K.A. Innate immune sensing of DNA. PLoS Pathog., 2011, vol. 7, no. 4, p. e1001310.

71. Shi Y., Evans J.E., Rock K.L. Molecular identification of a danger signal that alerts the immune system to dying cells. Nature, 2003, vol. 425, no. 6957, pp. 516-521.

72. Shirota H., Ishii K.J., Takakuwa H., Klinman D.M. Contribution of interferon-beta to the immune activation induced by double-stranded DNA. Immunology, 2006, vol. 118, pp. 302-310.

73. Stetson D.B., Ko J.S., Heidmann T., Medzhitov R. Trex1 prevents cell-intrinsic initiation of autoimmunity. Cell, 2008, vol. 134, no. 4, pp. 587-598.

74. Stetson D.B., Medzhitov R. Type I interferons in host defense. Immunity, 2006, vol. 25, no. 3, pp. 373-381.

75. Suzuki K., Mori A., Ishii K.J., Saito J., Singer D.S., Klinman D.M., Krause P.R., Kohn L.D. Activation of target-tissue immune-recognition molecules by double-stranded polynucleotides. Proc. Natl. Acad. Sci. USA, 1999, vol. 96, pp. 2285-2290.

76. Takaoka A., Taniguchi T. Cytosolic DNA recognition for triggering innate immune responses. Adv. Drug Deliv. Rev., 2008, vol. 60, no. 7, pp. 847-857.

77. Takaoka A., Wang Z., Choi M.K., Yanai H., Negishi H., Ban T., Lu Y., Miyagishi M., Kodama T., Honda K., Ohba Y., Taniguchi T. DAI (DLM-1/ZBP1) is a cytosolic DNA sensor and an activator of innate immune response. Nature, 2007, vol. 448, no. 7152, pp. 501-505.

78. Takeshita F., Ishii K.J. Intracellular DNA sensors in immunity. Curr. Opin. Immunol., 2008, vol. 20, no. 4, pp. 383-388.

79. Tang C.K., Pietersz G.A. Intracellular detection and immune signaling pathways of DNA vaccines. Expert Rev. Vaccines, 2009, vol. 8, no. 9, pp. 1161-1670.

80. Tang H.L., Cyster J.G. Chemokine Up-regulation and activated T cell attraction by maturing dendritic cells. Science, 1999, vol. 284, no. 5415, pp. 819-822.

81. Tian J., Avalos A.M., Mao S.Y., Chen B., Senthil K., Wu H., Parroche P., Drabic S., Golenbock D., Sirois C., Hua J., An L.L., Audoly L., La Rosa G., Bierhaus A., Naworth P., Marshak-Rothstein A., Crow M.K., Fitzgerald K.A., Latz E., Kiener P.A., Coyle A.J. Toll-like receptor 9-dependent activation by DNA-containing immune complexes is mediated by HMGB1 and RAGE. Nat. Immunol., 2007, vol. 8, no. 5, pp. 487-496.

82. Unterholzner L., Keating S.E., Baran M., Horan K.A., Jensen S. B., Sharma S., Sirois C. M., Jin T., Latz E., Xiao T.S., Fitzgerald K.A., Paludan S.R., Bowie A.G. IFI16 is an innate immune sensor for intracellular DNA. Nat. Immunol., 2010, vol. 11, no. 11, pp. 997-1004.

83. Viala J., Chaput C., Boneca I.G., Cardona A., Girardin S.E., Moran A.P., Athman R., Memet S., Huerre M.R., Coyle A.J., DiStefano P.S., Sansonetti P.J., Labigne A., Bertin J., Philpott D.J., Ferrero R.L. Nod1 responds to peptidoglycan delivered by the Helicobacter pylori cag pathogenicity island. Nat. Immunol., 2004, vol. 5, no. 11, pp. 1166-1174.

84. Vilaysane A., Muruve D.A. The innate immune response to DNA. Semin. Immunol., 2009, vol. 21, no. 4, pp. 208-214.

85. Wang Z., Choi M.K., Ban T., Yanai H., Negishi H., Lu Y., Tamura T., Takaoka A., Nishikura K., Taniguchi T. Regulation of innate immune responses by DAI (DLM-1/ZBP1) and other DNA-sensing molecules. Proc. Natl. Acad. Sci. USA, 2008, vol. 105, no. 14, pp. 5477-5482.

86. Xiao T. Innate immune recognition of nucleic acids. Immunol. Res., 2009, vol. 43, no. 1-3, pp. 98-108.

87. Xie L., Fang L., Wang D., Luo R., Cai K., Chen H., Xiao S. Molecular cloning and functional characterization of porcine DNA-dependent activator of IFN-regulatory factors (DAI). Dev. Comp. Immunol., 2010, vol. 34, no. 3, pp. 293-299.

88. Yamamoto M., Sato S., Hemmi H., Hoshino K., Kaisho T., Sanjo H., Takeuchi O., Sugiyama M., Okabe M., Takeda K., Akira S. Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway. Science, 2003, vol. 301, no. 5633, pp. 640-643.

89. Yanai H., Ban T., Wang Z., Choi M.K., Kawamura T., Negishi H., Nakasato M., Lu Y., Hangai S., Koshiba R., Savitsky D., Ronfani L., Akira S., Bianchi M. E., Honda K., Tamura T., Kodama T., Taniguchi T. HMGB proteins function as universal sentinels for nucleic-acid-mediated innate immune responses. Nature, 2009, vol. 462, no. 7269, pp. 99-103.

90. Yang P., An H., Liu X., Wen M., Zheng Y., Rui Y., Cao X. The cytosolic nuclei acid sensor LRRFIP1 mediates the production of type I interferon via a beta-catenin-dependent pathway. Nat. Immunol., 2010, vol. 11, no. 6, pp. 487-494.

91. Yang Y.G., Lindahl T., Barnes D.E. Trex1 exonuclease degrades ssDNA to prevent chronic checkpoint activation and autoimmune disease. Cell, 2007, vol. 131, no. 5, pp. 873-886.

92. Yasuda K., Ogawa Y., Yamane I., Nishikawa M., Takakura Y. Macrophage activation by a DNA/cationic liposome complex requires endosomal acidification and TLR9-dependent and -independent pathways. J. Leukoc. Biol., 2005, vol. 77, pp. 71-79.

93. Yasuda K., Richez C., Uccellini M.B., Richards R.J., Bonegio R.G., Akira S., Monestier M., Corley R.B., Viglianti G.A., Marshak-Rothstein A., Rifkin I.R. Requirement for DNA CpG content in TLR9-dependent dendritic call activation induced by DNA-containing immune complexes. J. Immunol., 2009, vol. 183, no. 5, pp. 3109-3117.

94. Yi A.K., Tuetken R., Redford T., Waldschmidt M., Kirsch J., Krieg A.M. CpG motifs in bacterial DNA activate leukocytes through the pH-dependent generation of reactive oxygen species. J. Immunol., 1998, vol. 160, no. 10, pp. 4755-4761.

95. Yoneyama M., Fujita T. RNA recognition and signal transduction by RIG-I-like receptors. Immunol. Rev., 2009, vol. 227, no. 1, pp. 54-65.

96. Yoneyama M., Kikuchi M., Matsumoto K., Imaizumi T., Miyagishi M., Taira K., Foy E., Loo Y.M., Gale M.Jr., Akira S., Yonehara S., Kato A., Fujita T. Shared and unique functions of the DExD/H-box helicases RIG-I, MDA5, and LGP2 in antiviral innate immunity. J. Immunol., 2005, vol. 175, no. 5, pp. 2851-2858.

97. Yoneyama M., Kikuchi M., Natsukawa T., Shinobu N., Imaizumi T., Miyagishi M., Taira K., Akira S., Fujita T. The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. Nat. Immunol., 2004, vol. 5, no. 7, pp. 730-737.

98. Zhong B., Zhang L., Lei C., Li Y., Mao A.P., Yang Y., Wang Y.Y., Zhang X.L., Shu H.B. The ubiquitin ligase RNF5 regulates antiviral responses by mediating degradation of the adaptor protein MITA. Immunity, 2009, vol. 30, no. 3, pp. 397-407.