Activation of human monocytes by live Borrelia burgdorferi generates TLR2-dependent and -independent responses which include induction of IFN-β

PLoS Pathogens

Volumn 5, Issue 5, 2009, Pages

  Salazar, Juan C ^a,b   Duhnam Ems, Star ^b   La Vake, Carson ^b   Cruz, Adriana R ^c   Moore, Meagan W ^b   Caimano, Melissa J ^b   Velez Climent, Leonor ^a,b   Shupe, Jonathan ^b   Krueger, Winfried ^b   Radolf, Justin D ^b  

^a Farmington   (United States)

^b UNIVERSITY OF CONNECTICUT HEALTH CENTER   (United States)

^c CENTRO INTERNACIONAL DE ENTRENAMIENTO E INVESTIGACIONES MÉDICAS CIDEIM   (Colombia)

Author keywords

[No Author keywords available]

Indexed keywords

BACTERIUM LYSATE; BETA INTERFERON; INTERLEUKIN 10; INTERLEUKIN 18; INTERLEUKIN 1BETA; INTERLEUKIN 1BETA CONVERTING ENZYME; INTERLEUKIN 6; TOLL LIKE RECEPTOR 2; TUMOR NECROSIS FACTOR ALPHA; CYTOKINE; TLR5 PROTEIN, HUMAN; TOLL LIKE RECEPTOR 5;

ARTICLE; BORRELIA BURGDORFERI; CELL ACTIVATION; CELL INTERACTION; CONTROLLED STUDY; CYTOKINE PRODUCTION; ENZYME ACTIVATION; GENETIC TRANSCRIPTION; GENOME; HUMAN; HUMAN CELL; INTERFERON INDUCTION; MACROPHAGE; MICROARRAY ANALYSIS; MONOCYTE; NONHUMAN; NUCLEOTIDE SEQUENCE; PERIPHERAL BLOOD MONONUCLEAR CELL; PHAGOCYTOSIS; PHAGOSOME; SPIROCHETE; UNINDEXED SEQUENCE; ADULT; ANIMAL; BACTERIOLYSIS; BIOSYNTHESIS; BORRELIA INFECTION; C57BL MOUSE; CELL CULTURE; DNA MICROARRAY; FEMALE; GENE EXPRESSION PROFILING; GENE EXPRESSION REGULATION; GENETICS; IMMUNOLOGY; MALE; METABOLISM; MIDDLE AGED; MOUSE; SIGNAL TRANSDUCTION;

BACTERIA (MICROORGANISMS); BORRELIA BURGDORFERI; MURINAE; SPIROCHAETALES;

ADULT; ANIMALS; BACTERIOLYSIS; BORRELIA BURGDORFERI; BORRELIA INFECTIONS; CELLS, CULTURED; CYTOKINES; FEMALE; GENE EXPRESSION PROFILING; GENE EXPRESSION REGULATION; HUMANS; INTERFERON-BETA; INTERLEUKIN-18; MACROPHAGES; MALE; MICE; MICE, INBRED C57BL; MIDDLE AGED; MONOCYTES; OLIGONUCLEOTIDE ARRAY SEQUENCE ANALYSIS; SIGNAL TRANSDUCTION; TOLL-LIKE RECEPTOR 2; TOLL-LIKE RECEPTOR 5; TRANSCRIPTION, GENETIC;

EID: 67249115186     PISSN: 15537366     EISSN: 15537374     Source Type: Journal    
DOI: 10.1371/journal.ppat.1000444     Document Type: Article

References (125)

1. Steere AC, Coburn J, Glickstein L (2004) The emergence of Lyme disease. J Clin Invest 113: 1093-1101. (Pubitemid 38544091)
2. Salazar JC, Pope CD, Sellati TJ, Feder HM Jr, Kiely TG, et al. (2003) Coevolution of markers of innate and adaptive immunity in skin and peripheral blood of patients with erythema migrans. J Immunol 171: 2660-2670. (Pubitemid 37025580)
3. Wormser GP, Dattwyler RJ, Shapiro ED, Halperin JJ, Steere AC, et al. (2006) The clinical assessment, treatment, and prevention of lyme disease, human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis 43: 1089-1134. (Pubitemid 44637131)
4. Feder HM Jr, Johnson BJ, O'Connell S, Shapiro ED, Steere AC, et al. (2007) A critical appraisal of "chronic Lyme disease". N Engl J Med 357: 1422-1430.
5. Smith RP, Schoen RT, Rahn DW, Sikand VK, Nowakowski J, et al. (2002) Clinical characteristics and treatment outcome of early Lyme disease in patients with microbiologically confirmed erythema migrans. Ann Intern Med 136: 421-428. (Pubitemid 34233173)
6. Asch ES, Bujak DI, Weiss M, Peterson MG, Weinstein A (1994) Lyme disease: an infectious and postinfectious syndrome. J Rheum 21: 454-461. (Pubitemid 24102829)
7. Klempner MS, Hu LT, Evans J, Schmid CH, Johnson GM, et al. (2001) Two controlled trials of antibiotic treatment in patients with persistent symptoms and a history of Lyme disease. N Engl J Med 345: 85-92. (Pubitemid 32634566)
8. Norgard MV, Riley BS, Richardson JA, Radolf JD (1995) Dermal inflammation elicited by synthetic analogs of Treponema pallidum and Borrelia burgdorferi lipoproteins. Infect Immun 63: 1507-1515.
9. Norgard MV, Arndt LL, Akins DR, Curetty LL, Harrich DA, Radolf JD (1996) Activation of human monocytic cells by Treponema pallidum and Borrelia burgdorferi lipoproteins and synthetic lipopeptides proceeds via a pathway distinct from that of lipopolysaccharide but involves the transcriptional activator NF-κB. Infect Immun 64: 3845-3852. (Pubitemid 26298713)
10. Aliprantis AO, Yang RB, Mark MR, Suggett S, Devaux B, et al. (1999) Cell activation and apoptosis by bacterial lipoproteins through toll-like receptor-2. Science 285: 736-739. (Pubitemid 129505077)
11. Lien E, Sellati TJ, Yoshimura A, Flo TH, Rawadi G, et al. (1999) Toll-like receptor 2 functions as a pattern recognition receptor for diverse bacterial products. J Biol Chem 274: 33419-33425. (Pubitemid 129511647)
12. Sellati TJ, Bouis DA, Caimano MJ, Feulner JA, Ayers C, et al. (1999) Activation of human monocytic cells by Borrelia burgdorferi and Treponema pallidum is facilitated by CD14 and correlates with surface exposure of spirochetal lipoproteins. J Immunol 163: 2049-2056. (Pubitemid 29382209)
13. Brightbill HD, Libraty DH, Krutzik SR, Yang RB, Belisle JT, et al. (1999) Host defense mechanisms triggered by microbial lipoproteins through toll-like receptors. Science 285: 732-736. (Pubitemid 129505076)
14. Wooten RM, Ma Y, Yoder RA, Brown JP, Weis JH, et al. (2002) Toll-like receptor 2 is required for innate, but not acquired, host defense to Borrelia burgdorferi. J Immunol 168: 348-355. (Pubitemid 34014136)
15. Salazar JC, Pope CD, Moore MW, Pope J, Kiely TG, et al. (2005) Lipoprotein-dependent and -independent immune responses to spirochetal infection. Clin Diagn Lab Immunol 12: 949-958.
16. Brandt ME, Riley BS, Radolf JD, Norgard MV (1990) Immunogenic integral membrane proteins of Borrelia burgdorferi are lipoproteins. Infect Immun 58: 983-991. (Pubitemid 20117029)
17. Radolf JD, Goldberg MS, Bourell KW, Baker SI, Jones JD, et al. (1995) Characterization of outer membranes isolated from Borrelia burgdorferi, the Lyme disease spirochete. Infect Immun 63: 2154-2163.
18. Fraser CM, Casjens S, Huang WM, Sutton GG, Clayton R, et al. (1997) Genomic sequence of a Lyme disease spirochaete, Borrelia burgdorferi. Nature 390: 580-586.
19. Takayama K, Rothenberg RJ, Barbour AG (1987) Absence of lipopolysaccharide in the Lyme disease spirochete, Borrelia burgdorferi. Infect Immun 55: 2311-2313.
20. Akira S, Uematsu S, Takeuchi O (2006) Pathogen recognition and innate immunity. Cell 124: 783-801. (Pubitemid 43261452)
21. Wooten RM, Ying MA, Yoder RA, Brown JP, Weis JH, et al. (2002) Toll-like receptor 2 plays a pivotal role in host defense and inflammatory response to Borrelia burgdorferi. Vector Borne Zoonotic Dis 2: 275-278.
22. Hirschfeld M, Kirschning CJ, Schwandner R, Wesche H, Weis JH, et al. (1999) Inflammatory signaling by Borrelia burgdorferi lipoproteins is mediated by toll-like receptor 2. J Immunol 163: 2382-2386. (Pubitemid 29399155)
23. Alexopoulou L, Thomas V, Schnare M, Lobet Y, Anguita J, et al. (2002) Hyporesponsiveness to vaccination with Borrelia burgdorferi OspA in humans and in TLR1- and TLR2-deficient mice. Nat Med 8: 878-884. (Pubitemid 34887253)
24. Wooten RM, Morrison TB, Weis JH, Wright SD, Thieringer R, et al. (1998) The role of CD14 in signaling mediated by outer membrane lipoproteins of Borrelia burgdorferi. J Immunol 160: 5485-5492. (Pubitemid 28267840)
25. Benhnia MR, Wroblewski D, Akhtar MN, Patel RA, Lavezzi W, et al. (2005) Signaling through CD14 attenuates the inflammatory response to Borrelia burgdorferi, the agent of Lyme disease. J Immunol 174: 1539-1548.
26. Sellati TJ, Waldrop SL, Salazar JC, Bergstresser PR, Picker LJ, et al. (2001) The cutaneous response in humans to Treponema pallidum lipoprotein analogues involves cellular elements of both innate and adaptive immunity. J Immunol 166: 4131-4140. (Pubitemid 32224945)
27. Giambartolomei GH, Dennis VA, Lasater BL, Philipp MT (1999) Induction of pro- and anti-inflammatory cytokines by Borrelia burgdorferi lipoproteins in monocytes is mediated by CD14. Infect Immun 67: 140-147. (Pubitemid 29021641)
28. Wang G, Ma Y, Buyuk A, McClain S, Weis JJ, et al. (2004) Impaired host defense to infection and Toll-like receptor 2-independent killing of Borrelia burgdorferi clinical isolates in TLR2-deficient C3H/HeJ mice. FEMS Microbiol Lett 231: 219-225. (Pubitemid 38251603)
29. Liu N, Montgomery RR, Barthold SW, Bockenstedt LK (2004) Myeloid Differentiation Antigen 88 Deficiency Impairs Pathogen Clearance but Does Not Alter Inflammation in Borrelia burgdorferi-Infected Mice. Infect Immun 72: 3195-3203. (Pubitemid 38697740)
30. Behera AK, Hildebrand E, Uematsu S, Akira S, Coburn J, et al. (2006) Identification of a TLR-independent pathway for Borrelia burgdorferi-induced expression of matrix metalloproteinases and inflammatory mediators through binding to integrin alpha 3 beta 1. J Immunol 177: 657-664. (Pubitemid 43939180)
31. Shin OS, Isberg R, Akira S, Uematsu S, Behera AK, et al. (2008) Distinct roles for MyD88, TLR2, TLR5, and TLR9 in phagocytosis of Borrelia burgdorferi and inflammatory signaling. Infect Immun 76: 2341-2351.
32. Moore MW, Cruz AR, LaVake CJ, Marzo AL, Eggers CH, et al. (2007) Phagocytosis of Borrelia burgdorferi and Treponema pallidum Potentiates Innate Immune Activation and Induces Gamma Interferon Production. Infect Immun 75: 2046-2062. (Pubitemid 46559474)
33. Cruz AR, Moore MW, La Vake CJ, Eggers CH, Salazar JC, et al. (2008) Phagocytosis of Borrelia burgdorferi, the Lyme disease spirochete, potentiates innate immune activation and induces apoptosis in human monocytes. Infect Immun 76: 56-70.
34. Benach JL, Habicht GS, Gocinski BL, Coleman JL (1984) Phagocytic cell responses to in vivo and in vitro exposure to the Lyme disease spirochete. Yale J Biol Med 57: 599-605. (Pubitemid 15151052)
35. Rittig MG, Krause A, Haupl T, Schaible UE, Modolell M, et al. (1992) Coiling phagocytosis is the preferential phagocytic mechanism for Borrelia burgdorferi. Infect Immun 60: 4205-4212.
36. Montgomery RR, Nathanson MH, Malawista SE (1994) Fc- and non-Fc mediated phagocytosis of Borrelia burgdorferi. J Infect Dis 170: 890-893. (Pubitemid 24296568)
37. Montgomery RR, Malawista SE (1996) Entry of Borrelia burgdorferi into macrophages is end-on and leads to degradation in lysosomes. Infect Immun 64: 2867-2872. (Pubitemid 26226865)
38. Montgomery RR, Booth CJ, Wang X, Blaho VA, Malawista SE, et al. (2007) Recruitment of macrophages and polymorphonuclear leukocytes in Lyme carditis. Infect Immun 75: 613-620. (Pubitemid 46203423)
39. Montgomery RR, Lusitani D, de Boisfleury CA, Malawista SE (2002) Human phagocytic cells in the early innate immune response to Borrelia burgdorferi. J Infect Dis 185: 1773-1779. (Pubitemid 34615472)
40. Toshchakov V, Jones BW, Perera PY, Thomas K, Cody MJ, Zhang S, et al. (2002) TLR4, but not TLR2, mediates IFN-beta-induced STAT1alpha/beta-dependent gene expression in macrophages. Nat Immunol 3: 392-398. (Pubitemid 34308628)
41. Kawai T, Akira S (2007) TLR signaling. Semin Immunol 19: 24-32. (Pubitemid 46498752)
42. Miller JC, Ma Y, Crandall H, Wang X, Weis JJ (2008) Gene expression profiling provides insights into the pathways involved in inflammatory arthritis development: murine model of Lyme disease. Exp Mol Pathol 85: 20-27.
43. Miller JC, Ma Y, Bian J, Sheehan KC, Zachary JF, et al. (2008) A Critical Role for Type I IFN in Arthritis Development following Borrelia burgdorferi Infection of Mice. J Immunol 181: 8492-8503.
44. Blander JM (2007) Signalling and phagocytosis in the orchestration of host defence. Cell Microbiol 9: 290-299. (Pubitemid 46092159)
45. Sellati TJ, Bouis DA, Kitchens RL, Darveau RP, Pugin J, et al. (1998) Treponema pallidum and Borrelia burgdorferi lipoproteins and synthetic lipopeptides activate monocytic cells via a CD14-dependent pathway distinct from that used by lipopolysaccharide. J Immunol 160: 5455-5464. (Pubitemid 28267837)
46. Cabral ES, Gelderblom H, Hornung RL, Munson PJ, Martin R, et al. (2006) Borrelia burgdorferi lipoprotein-mediated TLR2 stimulation causes the downregulation of TLR5 in human monocytes. J Infect Dis 193: 849-859.
47. Sadik CD, Hunfeld KP, Bachmann M, Kraiczy P, Eberhardt W, et al. (2008) Systematic analysis highlights the key role of TLR2/NF-kappaB/MAP kinase signaling for IL-8 induction by macrophage-like THP-1 cells under influence of Borrelia burgdorferi lysates. Int J Biochem Cell Biol.
48. Zhao Z, McCloud B, Fleming R, Klempner MS (2007) Borrelia burgdorferi-induced monocyte chemoattractant protein-1 production in vivo and in vitro. Biochem Biophys Res Commun 358: 528-533. (Pubitemid 46766598)
49. Brown CR, Blaho VA, Loiacono CM (2003) Susceptibility to experimental Lyme arthritis correlates with KC and monocyte chemoattractant protein-1 production in joints and requires neutrophil recruitment via CXCR2. J Immunol 171: 893-901. (Pubitemid 36871402)
50. Yasukawa H, Ohishi M, Mori H, Murakami M, Chinen T, et al. (2003) IL-6 induces an anti-inflammatory response in the absence of SOCS3 in macrophages. Nat Immunol 4: 551-556. (Pubitemid 36701338)
51. Sato N, Ahuja SK, Quinones M, Kostecki V, Redick RL, et al. (2000) CC chemokine receptor (CCR)2 is required for Langerhans cell migration and localization T helper cell type 1 (Th1)-inducing dendritic cells: absence of CCR2 shifts the Leishmania major-resistant phenotype to a susceptible state dominated by the cytokines, B cell outgrowth, and sustained neutrophilic infiltration. J Exp Med 192: 205-218. (Pubitemid 30470303)
52. Curry H, Alvarez GR, Zwilling BS, Lafuse WP (2004) Toll-like receptor 2 stimulation decreases IFN-gamma receptor expression in mouse RAW264.7 macrophages. J Interferon Cytokine Res 24: 699-710. (Pubitemid 39658233)
53. Lich JD, Ting JP (2007) Monarch-1/PYPAF7 and other CATERPILLER (CLR, NOD, NLR) proteins with negative regulatory functions. Microbes Infect 9: 672-676. (Pubitemid 46628778)
54. Santis AG, Lopez-Cabrera M, Hamann J, Strauss M, Sanchez-Madrid F (1994) Structure of the gene coding for the human early lymphocyte activation antigen CD69: a C-type lectin receptor evolutionarily related with the gene families of natural killer cell-specific receptors. Eur J Immunol 24: 1692-1697. (Pubitemid 24203780)
55. Hamilton JA (2008) Colony-stimulating factors in inflammation and autoimmunity. Nat Rev Immunol 8: 533-544. doi:10.1038/nri2356.
56. Wei YJ, Sun HQ, Yamamoto M, Wlodarski P, Kunii K, et al. (2002) Type II Phosphatidylinositol 4-Kinase beta Is a Cytosolic and Peripheral Membrane Protein That Is Recruited to the Plasma Membrane and Activated by Rac-GTP. J Biol Chem 277: 46586-46593. (Pubitemid 35417657)
57. Kobayashi T, Vischer UM, Rosnoblet C, Lebrand C, Lindsay M, et al. (2000) The tetraspanin CD63/lamp3 cycles between endocytic and secretory compartments in human endothelial cells. Mol Biol Cell 11: 1829-1843. (Pubitemid 30307916)
58. Marzio R, Mauel J, Betz-Corradin S (1999) CD69 and regulation of the immune function. Immunopharmacol Immunotoxicol 21: 565-582. (Pubitemid 29409367)
59. Kumaresan PR, Lai WC, Chuang SS, Bennett M, Mathew PA (2002) CS1, a novel member of the CD2 family, is homophilic and regulates NK cell function. Molec Immunol 39: 1-8. (Pubitemid 35245377)
60. Zhu M, John S, Berg M, Leonard WJ (1999) Functional association of Nmi with Stat5 and Stat1 in IL-2- and IFNgamma-mediated signaling. Cell 96: 121-130. doi:10.1016/S0092-8674(00)80965-80974 (Pubitemid 129746804)
61. Delprat B, Schaer D, Roy S, Wang J, Puel JL, et al. (2007) FXYD6 Is a Novel Regulator of Na,K-ATPase Expressed in the Inner Ear. J Biol Chem 282: 7450-7456. (Pubitemid 47093669)
62. Ogura Y, Sutterwala FS, Flavell RA (2006) The inflammasome: first line of the immune response to cell stress. Cell 126: 659-662. (Pubitemid 44233635)
63. Drenth JP, Van der Meer JW (2006) The inflammasome-a linebacker of innate defense. N Engl J Med 355: 730-732.
64. Piccini A, Carta S, Tassi S, Lasiglie D, Fossati G, et al. (2008) ATP is released by monocytes stimulated with pathogen-sensing receptor ligands and induces IL-1beta and IL-18 secretion in an autocrine way. Proc Natl Acad Sci U S A 105: 8067-8072. (Pubitemid 351904709)
65. Kleine H, Poreba E, Lesniewicz K, Hassa PO, Hottiger MO, et al. (2008) Substrate-Assisted Catalysis by PARP10 Limits Its Activity to Mono-ADP-Ribosylation. Molecular Cell 32: 57-69.
66. Hirashima M, Kashio Y, Nishi N, Yamauchi A, Imaizumi TA, et al. (2004) Galectin-9 in physiological and pathological conditions. Glycoconj J 19: 593-600. (Pubitemid 38460942)
67. Kashio Y, Nakamura K, Abedin MJ, Seki M, Nishi N, et al. (2003) Galectin-9 Induces Apoptosis Through the Calcium-Calpain-Caspase-1 Pathway. The Journal of Immunology 170: 3631-3636. (Pubitemid 36359232)
68. Malakhova OA, Zhang DE (2008) ISG15 Inhibits Nedd4 Ubiquitin E3 Activity and Enhances the Innate Antiviral Response. J Biol Chem 283: 8783-8787.
69. Wong JJY, Pung YF, Sze NS-K, Chin KC (2006) HERC5 is an IFN-induced HECT-type E3 protein ligase that mediates type I IFN-induced ISGylation of protein targets. Proceedings of the National Academy of Sciences 103: 10735-10740. (Pubitemid 44078045)
70. Malakhov MP, Malakhova OA, Kim KI, Ritchie KJ, Zhang DE (2002) UBP43 (USP18) Specifically Removes ISG15 from Conjugated Proteins. J Biol Chem 277: 9976-9981.
71. Reich NC (2007) STAT dynamics. Cytokine Growth Factor Rev 18: 511-518. (Pubitemid 47302818)
72. Diebold SS, Kaisho T, Hemmi H, Akira S, Reis ESousa (2004) Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science 303: 1529-1531. (Pubitemid 38314425)
73. Kawai T, Sato S, Ishii KJ, Coban C, Hemmi H, et al. (2004) Interferon-alpha induction through Toll-like receptors involves a direct interaction of IRF7 with MyD88 and TRAF6. Nat Immunol 5: 1061-1068. (Pubitemid 41057726)
74. Nakao Y, Funami K, Kikkawa S, Taniguchi M, Nishiguchi M, et al. (2005) Surface-expressed TLR6 participates in the recognition of diacylated lipopeptide and peptidoglycan in human cells. J Immunol 174: 1566-1573.
75. Binder RJ, Karimeddini D, Srivastava PK (2001) Adjuvanticity of alpha 2-macroglobulin, an independent ligand for the heat shock protein receptor CD91. J Immunol 166: 4968-4972. (Pubitemid 32280707)
76. Gebbia JA, Coleman JL, Benach JL (2001) Borrelia spirochetes upregulate release and activation of matrix metalloproteinase gelatinase B (MMP-9) and collagenase 1 (MMP-1) in human cells. Infect Immun 69: 456-462. (Pubitemid 32040949)
77. Gebbia JA, Coleman JL, Benach JL (2004) Selective Induction of Matrix Metalloproteinases by Borrelia burgdorferi via Toll-Like Receptor 2 in Monocytes. J Infect Dis 189: 113-119. (Pubitemid 38122337)
78. Behera AK, Hildebrand E, Scagliotti J, Steere AC, Hu LT (2005) Induction of host matrix metalloproteinases by Borrelia burgdorferi differs in human and murine lyme arthritis. Infect Immun 73: 126-134. (Pubitemid 40041102)
79. Crandall H, Dunn DM, Ma Y, Wooten RM, Zachary JF, et al. (2006) Gene expression profiling reveals unique pathways associated with differential severity of lyme arthritis. J Immunol 177: 7930-7942. (Pubitemid 44846309)
80. Brown JP, Zachary JF, Teuscher C, Weis JJ, Wooten RM (1999) Dual role of interleukin-10 in murine Lyme disease: regulation of arthritis severity and host defense. Infect Immun 67: 5142-5150. (Pubitemid 29455284)
81. Lisinski TJ, Furie MB (2002) Interleukin-10 inhibits proinflammatory activation of endothelium in response to Borrelia burgdorferi or lipopolysaccharide but not interleukin-1beta or tumor necrosis factor alpha. J Leukoc Biol 72: 503-511.
82. Honda K, Yanai H, Negishi H, Asagiri M, Sato M, et al. (2005) IRF-7 is the master regulator of type-I interferon-dependent immune responses. Nature 434: 772-777. (Pubitemid 44739521)
83. Akira S (2000) The role of IL-18 in innate immunity. Curr Opin Immunol 12: 59-63. (Pubitemid 30093451)
84. Sato S, Sugiyama M, Yamamoto M, Watanabe Y, Kawai T, et al. (2003) Toll/IL-1 receptor domain-containing adaptor inducing IFN-beta (TRIF) associates with TNF receptor-associated factor 6 and TANK-binding kinase 1, and activates two distinct transcription factors, NF-kappa B and IFN-regulatory factor-3, in the Toll-like receptor signaling. J Immunol 171: 4304-4310. (Pubitemid 37238709)
85. Nardelli B, Zaritskaya L, Semenuk M, Cho YH, LaFleur Dw, et al. (2002) Regulatory effect of IFN-kappa, a novel type I IFN, on cytokine production by cells of the innate immune system. J Immunol 169: 4822-4830. (Pubitemid 35217145)
86. Jones KL, Muellegger RR, Means TK, Lee M, Glickstein LJ, et al. (2008) Higher mRNA levels of chemokines and cytokines associated with macrophage activation in erythema migrans skin lesions in patients from the United States than in patients from Austria with Lyme borreliosis. Clin Infect Dis 46: 85-92. (Pubitemid 351263564)
87. Shin JJ, Glickstein LJ, Steere AC (2007) High levels of inflammatory chemokines and cytokines in joint fluid and synovial tissue throughout the course of antibiotic-refractory lyme arthritis. Arthritis Rheum 56: 1325-1335. doi:10.1002/art.22441. (Pubitemid 46608658)
88. Reimer T, Schweizer M, Jungi TW (2007) Type I IFN induction in response to Listeria monocytogenes in human macrophages: evidence for a differential activation of IFN regulatory factor 3 (IRF3). J Immunol 179: 1166-1177.
89. Weiss DS, Henry T, Monack DM (2007) Francisella tularensis: activation of the inflammasome. Ann N Y Acad Sci 1105: 219-237. (Pubitemid 47507086)
90. Charrel-Dennis M, Latz E, Halmen KA, Trieu-Cuot P, Fitzgerald KA, et al. (2008) TLR-Independent Type I Interferon Induction in Response to an Extracellular Bacterial Pathogen via Intracellular Recognition of Its DNA. Cell Host Microbe 4: 543-554. (Pubitemid 352762959)
91. Linder S, Heimerl C, Fingerle V, Aepfelbacher M, Wilske B (2001) Coiling phagocytosis of Borrelia burgdorferi by primary human macrophages is controlled by CDC42Hs and Rac1 and involves recruitment of Wiskott-Aldrich syndrome protein and Arp2/3 complex. Infect Immun 69: 1739-1746. (Pubitemid 32187633)
92. Nilsen N, Nonstad U, Khan N, Knetter CF, Akira S, et al. (2004) Lipopolysaccharide and double-stranded RNA up-regulate toll-like receptor 2 independently of myeloid differentiation factor 88. J Biol Chem 279: 39727-39735. (Pubitemid 39258241)
93. Underhill DM, Ozinsky A, Hajjar AM, Stevens A, Wilson CB, et al. (1999) The Toll-like receptor 2 is recruited to macrophage phagosomes and discriminates between pathogens. Nature 401: 811-815. (Pubitemid 129515844)
94. O'Mahony DS, Pham U, Iyer R, Hawn TR, Liles WC (2008) Differential constitutive and cytokine-modulated expression of human Toll-like receptors in primary neutrophils, monocytes, and macrophages. Int J Med Sci 5: 1-8.
95. Bernardino AL, Myers TA, Alvarez X, Hasegawa A, Philipp MT (2008) Toll-like receptors: insights into their possible role in the pathogenesis of lyme neuroborreliosis. Infect Immun 76: 4385-4395.
96. Hayashi F, Smith KD, Ozinsky A, Hawn TR, Yi EC, et al. (2001) The innate immune response to bacterial flagellin is mediated by Toll- like receptor 5. Nature 410: 1099-1103. (Pubitemid 32391041)
97. Wallich R, Moter SE, Simon MM, Ebnet K, Heiberger A, et al. (1990) The Borrelia burgdorferi flagellum-associated 41-kilodalton antigen (flagellin): molecular cloning, expression, and amplification of the gene. Infect Immun 58: 1711-1719. (Pubitemid 20176361)
98. Motaleb MA, Sal MS, Charon NW (2004) The decrease in FlaA observed in a flaB mutant of Borrelia burgdorferi occurs posttranscriptionally. J Bacteriol 186: 3703-3711. (Pubitemid 38746045)
99. Montgomery RR, Nathanson MH, Malawista SE (1993) The fate of Borrelia burgdorferi, the agent for Lyme disease, in mouse macrophages. Destruction, survival, recovery. J Immunol 150: 909-915. (Pubitemid 23133670)
100. Chuang TH, Ulevitch RJ (2000) Cloning and characterization of a sub-family of human toll-like receptors: hTLR7, hTLR8 and hTLR9. Eur Cytokine Netw 11: 372-378. (Pubitemid 32268894)
101. Takeda K, Akira S (2005) Toll-like receptors in innate immunity. Int Immunol 17: 1-14.
102. Sasaki T, Suzuki A, Sasaki J, Penninger JM (2002) Phosphoinositide 3-Kinases in Inunimity: Lessons from Knockout Mice. J Biochem 131: 495-501. (Pubitemid 34456603)
103. Fukao T, Koyasu S (2003) PI3K and negative regulation of TLR signaling. Trends Immunol 24: 358-363. (Pubitemid 36830961)
104. Ozinsky A, Underhill DM, Fontenot JD, Hajjar AM, Smith KD, et al. (2000) The repertoire for pattern recognition of pathogens by the innate immune system is defined by cooperation between toll-like receptors. Proc Natl Acad Sci U S A 97: 13766-13771.
105. Dennis VA, Dixit S, O'Brien SM, Alvarez X, Pahar B, et al. (2009) Live Borrelia burgdorferi Spirochetes Elicit Inflammatory Mediators from Human Monocytes via the Toll-Like Receptor Signaling Pathway. Infect Immun 77: 1238-1245.
106. Kawai T, Akira S (2006) TLR signaling. Cell Death Differ 13: 816-825.
107. Gantner BN, Simmons RM, Canavera SJ, Akira S, Underhill DM (2003) Collaborative induction of inflammatory responses by dectin-1 and Toll-like receptor 2. J Exp Med 197: 1107-1117. (Pubitemid 36570066)
108. Drenth JP, Van der Meer JW (2006) The inflammasome-a linebacker of innate defense. N Engl J Med 355: 730-732.
109. Delprat B, Schaer D, Roy S, Wang J, Puel JL, et al. (2007) FXYD6 is a novel regulator of Na,K-ATPase expressed in the inner ear. J Biol Chem 282: 7450-7456. (Pubitemid 47093669)
110. Hornung V, Bauernfeind F, Halle A, Samstad EO, Kono H, et al. (2008) Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nat Immunol 9: 847-856. doi:10.1038/ni.1631.
111. Mariathasan S, Weiss DS, Newton K, McBride J, O'Rourke K, et al. (2006) Cryopyrin activates the inflammasome in response to toxins and ATP. Nature 440: 228-232. (Pubitemid 43372102)
112. Ren T, Zamboni DS, Roy CR, Dietrich WF, Vance RE (2006) Flagellin-deficient Legionella mutants evade caspase-1- and Naip5-mediated macrophage immunity. PLoS Pathog 2: e18. doi:10.1371/journal.ppat.0020018.
113. Miao EA, Puche-Aranda CM, Dors M, Clark AE, Bader MW, et al. (2006) Cytoplasmic flagellin activates caspase-1 and secretion of interleukin 1B via Ipaf. Nat Immunol 7: 569-575. (Pubitemid 43797337)
114. Lara-Tejero M, Sutterwala FS, Ogura Y, Grant EP, Bertin J, et al. (2006) Role of the caspase-1 inflammasome in Salmonella typhimurium pathogenesis. J Exp Med 203: 1407-1412. (Pubitemid 43877602)
115. Gavrilin MA, Bouakl IJ, Knatz NL, Duncan MD, Hall MW, et al. (2006) Internalization and phagosome escape required for Francisella to induce human monocyte IL-1β processing and release. Proc Natl Acad Sci U S A 103: 141-146. (Pubitemid 43076118)
116. Stockinger S, Decker T (2008) Novel functions of type I interferons revealed by infection studies with Listeria monocytogenes. Immunobiol 213: 889-897.
117. Yasuda K, Yu P, Kirschning CJ, Schlatter B, Schmitz F, et al. (2005) Endosomal translocation of vertebrate DNA activates dendritic cells via TLR9-dependent and -independent pathways. J Immunol 174: 6129-6136. (Pubitemid 40663802)
118. Nagarajan UM, Ojcius DM, Stahl L, Rank RG, Darville T (2005) Chlamydia trachomatis induces expression of IFN-gamma-inducible protein 10 and IFN-beta independent of TLR2 and TLR4, but largely dependent on MyD88. J Immunol 175: 450-460. (Pubitemid 40884349)
119. Opitz B, Vinzing M, Van LV, Schmeck B, Heine G, et al. (2006) Legionella pneumophila induces IFNbeta in lung epithelial cells via IPS-1 and IRF3, which also control bacterial replication. J Biol Chem 281: 36173-36179. (Pubitemid 46041351)
120. Gratz N, Siller M, Schaljo B, Pirzada ZA, Gattermeier I, et al. (2008) Group A streptococcus activates type I interferon production and MyD88-dependent signaling without involvement of TLR2, TLR4, and TLR9. J Biol Chem 283: 19879-19887.
121. O'Riordan M, Yi CH, Gonzales R, Lee KD, Portnoy DA (2002) Innate recognition of bacteria by a macrophage cytosolic surveillance pathway. Proc Natl Acad Sci U S A 99: 13861-13866. (Pubitemid 35215471)
122. Eggers CH, Caimano MJ, Clawson ML, Miller WG, Samuels DS, et al. (2002) Identification of loci critical for replication and compatibility of a Borrelia burgdorferi cp32 plasmid and use of a cp32-based shuttle vector for the expression of fluorescent reporters in the Lyme disease spirochaete. Mol Microbiol 43: 281-295. (Pubitemid 34146722)
123. Klipper-Aurbach Y, Wasserman M, Braunspiegel-Weintrob N, Borstein D, Peleg S, et al. (1995) Mathematical formulae for the prediction of the residual beta cell function during the first two years of disease in children and adolescents with insulin-dependent diabetes mellitus. Med Hypotheses 45: 486-490.
124. Dunning M, Barbosa-Morais N, Lynch A, Tavare S, Ritchie M (2008) Statistical issues in the analysis of Illumina data. BMC Bioinformatics 9: 85.
125. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2-ΔΔCT Method. Methods 25: 402-408.