Immune evasion and recognition of the syphilis spirochete in blood and skin of secondary syphilis patients: Two immunologically distinct compartments

PLoS Neglected Tropical Diseases

Volumn 6, Issue 7, 2012, Pages

  Cruz, Adriana R ^a   Ramirez, Lady G ^a   Zuluaga, Ana V ^a   Pillay, Allan ^b   Abreu, Christine ^c   Valencia, Carlos A ^a   la Vake, Carson ^c   Cervantes, Jorge L ^c   Dunham Ems, Star ^c   Cartun, Richard ^d   Mavilio, Domenico ^e   Radolf, Justin D ^c,f   Salazar, Juan C ^a,c,f  

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

^b CENTERS FOR DISEASE CONTROL AND PREVENTION   (United States)

^c UNIVERSITY OF CONNECTICUT HEALTH CENTER   (United States)

^d HARTFORD HOSPITAL   (United States)

^e HUMANITAS CLINICAL AND RESEARCH CENTER   (Italy)

^f Division of Pediatric Infectious Diseases   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CD14 ANTIGEN; CD16 ANTIGEN; CD4 ANTIGEN; CD40 ANTIGEN; CD56 ANTIGEN; CD68 ANTIGEN; CD8 ANTIGEN; CD83 ANTIGEN; GLYCOPROTEIN P 15095; INTERLEUKIN 10; INTERLEUKIN 1BETA; INTERLEUKIN 6; TUMOR NECROSIS FACTOR ALPHA; OPSONIN;

ADULT; ANTIGEN RECOGNITION; ARTICLE; CELLULAR IMMUNITY; CLINICAL ARTICLE; CONTROLLED STUDY; DENDRITIC CELL; FEMALE; FLOW CYTOMETRY; HUMAN; HUMAN CELL; HUMAN TISSUE; IMMUNE EVASION; IMMUNE RESPONSE; IMMUNOHISTOCHEMISTRY; IMMUNOPHENOTYPING; MALE; MONOCYTE; OPSONIZATION; PERIPHERAL BLOOD MONONUCLEAR CELL; REAL TIME POLYMERASE CHAIN REACTION; REVERSE TRANSCRIPTION POLYMERASE CHAIN REACTION; SKIN BIOPSY; SYPHILIS; TREPONEMA PALLIDUM; BLOOD; GENE EXPRESSION PROFILING; IMMUNOLOGY; MACROPHAGE; MICROBIOLOGY; MIDDLE AGED; PATHOGENICITY; PHAGOCYTOSIS; SKIN;

ADULT; BLOOD; FEMALE; FLOW CYTOMETRY; GENE EXPRESSION PROFILING; HUMANS; IMMUNE EVASION; IMMUNITY, CELLULAR; IMMUNOHISTOCHEMISTRY; MACROPHAGES; MALE; MIDDLE AGED; OPSONIN PROTEINS; PHAGOCYTOSIS; SKIN; SYPHILIS; TREPONEMA PALLIDUM;

EID: 84864620354     PISSN: 19352727     EISSN: 19352735     Source Type: Journal    
DOI: 10.1371/journal.pntd.0001717     Document Type: Article

References (101)

1. LaFond RE, Lukehart SA, (2006) Biological basis for syphilis. Clin Microbiol Rev 19: 29-49.
2. Radolf JD, Hazlett KRO, Lukehart SA, (2006) Pathogenesis of Syphilis. In: Radolf JD, Lukehart SA, editors. Pathogenic Treponemes: Cellular and Molecular Biology Norfolk, UK Caister Academic Press pp. 197-236.
3. Schmid G, Rowley JT, Samuelson J, Tun Y, Guraiib M, et al. (2009) World Health Organization (WHO) 2005 Global Estimates of the Incidence and Prevalence of Sexually Transmitted Infections (STIs). WHO/CDC Symposium: Congenital Syphilis and the 2005 WHO Estimates of STI Incidence and Prevalence: Using the Second to Help Eliminate the First.
4. Lukehart SA, (2004) Syphilis. In: Brauwald E, Faucci AS, Hauser SL, Longo DL, Jameson JL, editors. Harrison's Principles of Internal Medicine New York McGraw Hill pp. 977-985.
5. Baughn RE, Musher DM, (2005) Secondary syphilitic lesions. Clin Microbiol Rev 18: 205-216.
6. Stokes JH, Beerman H, Ingraham NR, (1944) Modern Clinical Syphilology Philadelphia W.B. Saunders.
7. Peeling RW, Hook EW III, (2006) The pathogenesis of syphilis: the Great Mimicker, revisited. J Pathol 208: 224-232 10.1002/path.1903 [doi].
8. Cruz AR, Pillay A, Zuluaga AV, Ramirez LG, Duque JE, et al. (2010) Secondary syphilis in cali, Colombia: new concepts in disease pathogenesis. PLoS Negl Trop Dis 4: e690 10.1371/journal.pntd.0000690 [doi].
9. Kampmeier RH, (1964) The late manifestations of syphilis: skeletal, visceral, and cardiovascular. Med Clin North Am 48: 667-697.
10. Norgard MV, Arndt LL, Akins DR, Curetty LL, Harrich DA, et al. (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.
11. 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.
12. 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.
13. 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.
14. 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.
15. 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.
16. 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.
17. Salazar JC, Duhnam-Ems S, LaVake CJ, Cruz AR, Moore MW, et al. (2009) Activation of human monocytes by live Borrelia burgdorferi generates TLR2-dependent and-independent responses which include induction of IFN-beta. PLoS Pathog 5: e1000444 10.1371/journal.ppat.1000444 [doi].
18. Walker EM, Borenstein LA, Blanco DR, Miller JN, Lovett MA, (1991) Analysis of outer membrane ultrastructures of pathogenic Treponema and Borrelia species by freeze-fracture electron microscopy. J Bacteriol 173: 5585-5588.
19. Cameron CE, (2006) The T. pallidum outer membrane and outer membrane proteins. In: Radolf JD, Lukehart SA, editors. Pathogenic Treponema: Molecular and Cellular Biology Norwich, UK Caister Academic Press pp. 237-266.
20. Bourell KW, Schulz W, Norgard MV, Radolf JD, (1994) Treponema pallidum rare outer membrane proteins: analysis of mobility by freeze-fracture electron microscopy. J Bacteriol 176: 1598-1608.
21. Jones JD, Bourell KW, Norgard MV, Radolf JD, (1995) Membrane topology of Borrelia burgdorferi and Treponema pallidum lipoproteins. Infect Immun 63: 2424-2434.
22. Radolf JD, Norgard MV, Schulz WW, (1989) Outer membrane ultrastructure explains the limited antigenicity of virulent Treponema pallidum. Proc Natl Acad Sci U S A 86: 2051-2055.
23. Cervantes JL, Dunham-Ems SM, La Vake CJ, Petzke MM, Sahay B, et al. (2011) Phagosomal signaling by Borrelia burgdorferi in human monocytes involves Toll-like receptor (TLR) 2 and TLR8 cooperativity and TLR8-mediated induction of IFN-{beta}. Proc Natl Acad Sci U S A 108: 3683-3688 1013776108 [pii];10.1073/pnas.1013776108 [doi].
24. Desrosiers DC, Anand A, Luthra A, Dunham-Ems SM, Ledoyt M, et al. (2011) TP0326, a Treponema pallidum beta-barrel assembly machinery A (BamA) orthologue and rare outer membrane protein. Mol Microbiol 80: 1496-1515 10.1111/j.1365-2958.2011.07662.x [doi].
25. Cox DL, Luthra A, Dunham-Ems S, Desrosiers DC, Salazar JC, et al. (2010) Surface immunolabeling and consensus computational framework to identify candidate rare outer membrane proteins of Treponema pallidum. Infect Immun 78: 5178-5194 IAI.00834-10 [pii];10.1128/IAI.00834-10 [doi].
26. Anand A, Luthra A, Dunham-Ems S, Caimano MJ, Karanian C, et al. (2012) TprC/D (Tp0117/131), a trimeric, pore-forming rare outer membrane protein of Treponema pallidum, has a bipartite domain structure. J Bacteriol JB.00101-12 [pii];10.1128/JB.00101-12 [doi].
27. Lukehart SA, Shaffer JM, Baker-Zander SA, (1992) A subpopulation of Treponema pallidum is resistant to phagocytosis: possible mechanisms of persistence. J Infect Dis 166: 1449-1453.
28. 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.
29. Lukehart SA, Baker-Zander SA, Cheri Lloyd RM, Sell S, (1980) Characterization of lymphocyte responsiveness in early experimental syphilis. II. Nature of cellular infiltration and Treponema pallidum distribution in testicular lesions. J Immunol 124: 461-467.
30. Sell S, Baker-Zander SA, Lloyd RM, (1980) T-cell hyperplasia of lymphoid tissues of rabbits infected with Treponema pallidum: evidence for a vigorous immune response. Sex Transm Dis 7: 74-84.
31. Sell S, Baker-Zander S, Powell HC, (1982) Experimental syphilitic orchitis in rabbits: ultrastructural appearance of Treponema pallidum during phagocytosis and dissolution by macrophages in vivo. Lab Invest 46: 355-364.
32. Van Voorhis WC, Barrett LK, Nasio JM, Plummer FA, Lukehart SA, (1996) Lesions of primary and secondary syphilis contain activated cytolytic T cells. Infect Immun 64: 1048-1050.
33. Van Voorhis WC, Barrett LK, Koelle DM, Nasio JM, Plummer FA, et al. (1996) Primary and secondary syphilis lesions contain mRNA for Th1 cytokines. J Infect Dis 173: 491-495.
34. Leader BT, Godornes C, Vanvoorhis WC, Lukehart SA, (2007) CD4+ lymphocytes and gamma interferon predominate in local immune responses in early experimental syphilis. Infect Immun 75: 3021-3026 IAI.01973-06 [pii];10.1128/IAI.01973-06 [doi].
35. Engelkens HJ, ten Kate FJ, Judanarso J, Vuzevski VD, van Lier JBH, et al. (1993) The localisation of treponemes and characterisation of the inflammatory infiltrate in skin biopsies from patients with primary or secondary syphilis, or early infectious yaws. Genitourin Med 69: 102-107.
36. McBroom RL, Styles AR, Chiu MJ, Clegg C, Cockerell CJ, et al. (1999) Secondary syphilis in persons infected with and not infected with HIV-1: a comparative immunohistologic study. Am J Dermatopathol 21: 432-441.
37. Tosca A, Lehou J, Hatjivasiliou M, Varelzidis A, Stratigos JD, (1988) Infiltrate of syphilitic lesions before and after treatment. Genitourin Med 64: 289-293.
38. Stary G, Klein I, Bruggen MC, Kohlhofer S, Brunner PM, et al. (2010) Host defense mechanisms in secondary syphilitic lesions: a role for IFN-gamma-/IL-17-producing CD8+ T cells? Am J Pathol 177: 2421-2432 S0002-9440(10)60294-5 [pii];10.2353/ajpath.2010.100277 [doi].
39. Rock KL, (1996) A new foreign policy: MHC class I molecules monitor the outside world. Immunol Today 17: 131-137 0167569996806050 [pii].
40. 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.
41. Mavilio D, Lombardo G, Benjamin J, Kim D, Follman D, et al. (2005) Characterization of CD56-/CD16+ natural killer (NK) cells: a highly dysfunctional NK subset expanded in HIV-infected viremic individuals. Proc Natl Acad Sci U S A 102: 2886-2891 0409872102 [pii];10.1073/pnas.0409872102 [doi].
42. Oliviero B, Varchetta S, Paudice E, Michelone G, Zaramella M, et al. (2009) Natural killer cell functional dichotomy in chronic hepatitis B and chronic hepatitis C virus infections. Gastroenterol 137: 1151-60, 1160 S0016-5085(09)00821-X [pii];10.1053/j.gastro.2009.05.047 [doi].
43. Salazar JC, Cruz AR, Pope CD, Valderrama L, Trujillo R, et al. (2007) Treponema pallidum elicits innate and adaptive cellular immune responses in skin and blood during secondary syphilis: a flow-cytometric analysis. J Infect Dis 195: 879-887.
44. 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.
45. Chen CY, Chi KH, George RW, Cox DL, Srivastava A, et al. (2006) Diagnosis of gastric syphilis by direct immunofluorescence staining and real-time PCR testing. J Clin Microbiol 44: 3452-3456 44/9/3452 [pii];10.1128/JCM.00721-06 [doi].
46. Colonna M, Trinchieri G, Liu YJ, (2004) Plasmacytoid dendritic cells in immunity. Nat Immunol 5: 1219-1226.
47. Narbutt J, Lesiak A, Sysa-Jedrzejowska A, Smolewski P, Robak T, et al. (2006) The number and distribution of blood dendritic cells in the epidermis and dermis of healthy human subjects. Folia Histochem Cytobiol 44: 61-63.
48. Li W, Janowicz DM, Fortney KR, Katz BP, Spinola SM, (2009) Mechanism of human natural killer cell activation by Haemophilus ducreyi. J Infect Dis 200: 590-598 10.1086/600123 [doi].
49. Zhang R, Zheng X, Li B, Wei H, Tian Z, (2006) Human NK cells positively regulate γδ T cells in response to Mycobacterium tuberculosis. J Immunol 176: 2610-2616.
50. Krutzik SR, Tan B, Li H, Ochoa MT, Liu PT, et al. (2005) TLR activation triggers the rapid differentiation of monocytes into macrophages and dendritic cells. Nat Med 11: 653-660 nm1246 [pii];10.1038/nm1246 [doi].
51. Pope V, Larsen SA, Rice RJ, Goforth SN, Parham CE, et al. (1994) Flow cytometric analysis of peripheral blood lymphocyte immunophenotypes in persons infected with Treponema pallidum. Clin Diagn Lab Immunol 1: 121-124.
52. Jensen JR, Thestrup-Pedersen K, From E, (1983) Fluctuations in natural killer cell activity in early syphilis. Br J Vener Dis 59: 30-32.
53. Poli A, Michel T, Theresine M, Andres E, Hentges F, Zimmer J, (2009) CD56bright natural killer (NK) cells: an important NK cell subset. Immunology 126: 458-465 IMM3027 [pii];10.1111/j.1365-2567.2008.03027.x [doi].
54. Cooper MA, Fehniger TA, Caligiuri MA, (2001) The biology of human natural killer-cell subsets. Trends Immunol 22: 633-640 S1471-4906(01)02060-9 [pii].
55. Klose N, Coulibaly B, Tebit DM, Nauwelaers F, Spengler HP, et al. (2007) Immunohematological reference values for healthy adults in Burkina Faso. Clin Vaccine Immunol 14: 782-784 CVI.00044-07 [pii];10.1128/CVI.00044-07 [doi].
56. Carlson JA, Dabiri G, Cribier B, Sell S, (2011) The immunopathobiology of syphilis: the manifestations and course of syphilis are determined by the level of delayed-type hypersensitivity. Am J Dermatopathol 33: 433-460 10.1097/DAD.0b013e3181e8b587 [doi];00000372-201107000-00001 [pii].
57. Radolf JD, Lukehart SA, (2006) Immunology of Syphilis. In: Radolf JD, Lukehart SA, editors. Pathogenic Treponemes: Cellular and Molecular Biology Norfolk, UK Caister Academic Press pp. 285-322.
58. Muller H, Eisendle K, Brauninger W, Kutzner H, Cerroni L, et al. (2011) Comparative analysis of immunohistochemistry, polymerase chain reaction and focus-floating microscopy for the detection of Treponema pallidum in mucocutaneous lesions of primary, secondary and tertiary syphilis. Br J Dermatol 165: 50-60 10.1111/j.1365-2133.2011.10314.x [doi].
59. Holness CL, Simmons DL, (1993) Molecular cloning of CD68, a human macrophage marker related to lysosomal glycoproteins. Blood 81: 1607-1613.
60. Suttles J, Stout RD, (2009) Macrophage CD40 signaling: a pivotal regulator of disease protection and pathogenesis. Semin Immunol 21: 257-264 S1044-5323(09)00057-8 [pii];10.1016/j.smim.2009.05.011 [doi].
61. Fernandez-Ruiz E, Somoza C, Sanchez-Madrid F, Lanier LL, (1995) CD28/CTLA-4 ligands: the gene encoding CD86 (B70/B7.2) maps to the same region as CD80 (B7/B7.1) gene in human chromosome 3q13-q23. Eur J Immunol 25: 1453-1456 10.1002/eji.1830250548 [doi].
62. 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.
63. Salcedo TW, Azzoni L, Wolf SF, Perussia B, (1993) Modulation of perforin and granzyme messenger RNA expression in human natural killer cells. J Immunol 151: 2511-2520.
64. Krahenbuhl O, Rey C, Jenne D, Lanzavecchia A, Groscurth P, et al. (1988) Characterization of granzymes A and B isolated from granules of cloned human cytotoxic T lymphocytes. J Immunol 141: 3471-3477.
65. Monroe KM, McWhirter SM, Vance RE, (2010) Induction of type I interferons by bacteria. Cell Microbiol 12: 881-890 CMI1478 [pii];10.1111/j.1462-5822.2010.01478.x [doi].
66. 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.
67. 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.
68. Stetson DB, Medzhitov R, (2006) Type I interferons in host defense. Immunity 25: 373-381 S1074-7613(06)00392-X [pii];10.1016/j.immuni.2006.08.007 [doi].
69. Petzke MM, Brooks A, Krupna MA, Mordue D, Schwartz I, (2009) Recognition of Borrelia burgdorferi, the Lyme Disease Spirochete, by TLR7 and TLR9 Induces a Type I IFN Response by Human Immune Cells. J Immunol jimmunol.0901390 [pii];10.4049/jimmunol.0901390 [doi].
70. Miettinen M, Veckman V, Latvala S, Sareneva T, Matikainen S, et al. (2008) Live Lactobacillus rhamnosus and Streptococcus pyogenes differentially regulate Toll-like receptor (TLR) gene expression in human primary macrophages. J Leukoc Biol 84: 1092-1100 jlb.1206737 [pii];10.1189/jlb.1206737 [doi].
71. Lukehart SA, Miller JN, (1978) Demonstration of the in vitro phagocytosis of Treponema pallidum by rabbit peritoneal macrophages. J Immunol 121: 2014-2024.
72. Baker-Zander SA, Shaffer JM, Lukehart SA, (1993) Characterization of the serum requirement for macrophage-mediated killing of Treponema pallidum ssp. pallidum: relationship to the development of opsonizing antibodies. FEMS Immunol Med Microbiol 6: 273-279.
73. Shi C, Pamer EG, (2011) Monocyte recruitment during infection and inflammation. Nat Rev Immunol 11: 762-774 nri3070 [pii];10.1038/nri3070 [doi].
74. Villablanca EJ, Russo V, Mora JR, (2008) Dendritic cell migration and lymphocyte homing imprinting. Histol Histopathol 23: 897-910.
75. Geijtenbeek TB, Krooshoop DJ, Bleijs DA, van Vliet SJ, van Duijnhoven GC, et al. (2000) DC-SIGN-ICAM-2 interaction mediates dendritic cell trafficking. Nat Immunol 1: 353-357.
76. Baker-Zander S, Sell S, (1980) A histopathologic and immunologic study of the course of syphilis in the experimentally infected rabbit. Demonstration of long-lasting cellular immunity. Am J Pathol 101: 387-413.
77. Sell S, Gamboa D, Baker-Zander SA, Lukehart SA, Miller JN, (1980) Host response to Treponema pallidum in intradermally-infected rabbits: evidence for persistence of infection at local and distant sites. J Invest Dermatol 75: 470-475.
78. Bjerke JR, Krogh HK, Matre R, (1981) In situ identification of mononuclear cells in cutaneous infiltrates in discoid lupus erythematosus, sarcoidosis and secondary syphilis. Acta Dermatologica Venereologica 61: 371-380.
79. Salazar JC, Cruz A, Valderrama L, Pope C, Trujillo R, et al. (2005) Immunity in early syphilis: pathway to HIV infection. 16th meeting of the ISSTDR.
80. Wenhai L, Jianzhong Z, Cao Y, (2004) Detection of Treponema pallidum in skin lesions of secondary syphilis and characterization of the inflammatory infiltrate. Dermatology 208: 94-97.
81. Lukehart SA, (2008) Scientific monogamy: thirty years dancing with the same bug: 2007 Thomas Parran Award Lecture. Sex Transm Dis 35: 2-7 10.1097/OLQ.0b013e318162c4f2 [doi];00007435-200801000-00002 [pii].
82. Blander JM, (2007) Coupling Toll-like receptor signaling with phagocytosis: potentiation of antigen presentation. Trends Immunol 28: 19-25.
83. Jutras I, Desjardins M, (2005) Phagocytosis: at the crossroads of innate and adaptive immunity. Annu Rev Cell Dev Biol 21: 511-527.
84. Bouis DA, Popova TG, Takashima A, Norgard MV, (2001) Dendritic cells phagocytose and are activated by Treponema pallidum. Infect Immun 69: 518-528.
85. Rittig MG, Haupl T, Burmester GR, (1994) Coiling phagocytosis: a way for MHC class I presentation of bacterial antigens? Int Arch Allergy Immunol 103: 4-10.
86. Segura E, Valladeau-Guilemond J, Donnadieu MH, Sastre-Garau X, Soumelis V, et al. (2012) Characterization of resident and migratory dendritic cells in human lymph nodes. J Exp Med 209: 653-660 jem.20111457 [pii];10.1084/jem.20111457 [doi].
87. Stenger S, Mazzaccaro RJ, Uyemura K, Cho S, Barnes PF, et al. (1997) Differential effects of cytolytic T cell subsets on intracellular infection. Science 276: 1684-1687.
88. Jiang J, Zenewicz LA, San Mateo LR, Lau LL, Shen H, (2003) Activation of antigen-specific CD8 T cells results in minimal killing of bystander bacteria. J Immunol 171: 6032-6038.
89. Sykes JA, Miller JN, (1971) Intracellular location of Treponema pallidum (Nichols strain) in the rabbit testis. Infect Immun 4: 307-314.
90. Sykes JA, Miller JN, Kalan AJ, (1974) Treponema pallidum within cells of a primary chancre from a human female. Br J Vener Dis 50: 40-44.
91. Sykes JA, Kalan J, (1975) Intracellular Treponema pallidum in cells of a syphilitic lesion of the uterine cervix. Am J Obstet Gynecol 122: 361-367.
92. 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.
93. Henry T, Brotcke A, Weiss DS, Thompson LJ, Monack DM, (2007) Type I interferon signaling is required for activation of the inflammasome during Francisella infection. J Exp Med 204: 987-994 jem.20062665 [pii];10.1084/jem.20062665 [doi].
94. Roux CM, Rolan HG, Santos RL, Beremand PD, Thomas TL, et al. (2007) Brucella requires a functional Type IV secretion system to elicit innate immune responses in mice. Cell Microbiol 9: 1851-1869 CMI922 [pii];10.1111/j.1462-5822.2007.00922.x [doi].
95. Stanley SA, Johndrow JE, Manzanillo P, Cox JS, (2007) The Type I IFN response to infection with Mycobacterium tuberculosis requires ESX-1-mediated secretion and contributes to pathogenesis. J Immunol 178: 3143-3152 178/5/3143 [pii].
96. 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.
97. 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.
98. Latz E, Visintin A, Espevik T, Golenbock DT, (2004) Mechanisms of TLR9 activation. J Endotoxin Res 10: 406-412.
99. Forsbach A, Nemorin JG, Montino C, Muller C, Samulowitz U, et al. (2008) Identification of RNA sequence motifs stimulating sequence-specific TLR8-dependent immune responses. J Immunol 180: 3729-3738 180/6/3729 [pii].
100. Ganguly D, Chamilos G, Lande R, Gregorio J, Meller S, et al. (2009) Self-RNA-antimicrobial peptide complexes activate human dendritic cells through TLR7 and TLR8. J Exp Med 206: 1983-1994 jem.20090480 [pii];10.1084/jem.20090480 [doi].
101. Liu CC, Perussia B, Young JD, (2000) The emerging role of IL-15 in NK-cell development. Immunol Today 21: 113-116.