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Laboratory of Mycobacteria, Division of Bacterial Products,
Laboratory of Enteric and Sexually Transmitted Diseases, Division of Bacterial Products, and
Retroviral Immunology Section, Laboratory of Retrovirology, Division of Viral Products, Center for Biologics Evaluation and Research, Rockville, MD 20852
Bacterial DNA containing unmethylated CpG motifs activates
mammalian lymphocytes and macrophages to produce cytokines and
polyclonal Ig. These include IFN-
, IL-12, TNF-
, and IL-6, which
are important in the control of intracellular bacterial infection.
Here, we show that bacterial DNA, as well as synthetic oligonucleotides
containing CpG motifs, induce protection against large lethal doses of
Francisella tularensis live vaccine strain (LVS) and
Listeria monocytogenes. Methylation of DNA at CpG
dinucleotides or inversion of the motif abolished this protection.
Surprisingly, DNA-mediated protection was highly dependent on
lymphocytes, particularly B cells, as well as the production of
IFN-. Optimal protection was elicited 2–3 days after inoculation
with DNA and persisted for up to 2 wk. Further, animals surviving
lethal challenge developed pathogen-specific secondary immunity. These
findings indicate that host innate immune responses to bacterial DNA
may contribute to the induction of protective immunity to bacteria and
the subsequent development of memory.
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S. Raghavan, J. Nystrom, M. Fredriksson, J. Holmgren, and A. M. Harandi Orally Administered CpG Oligodeoxynucleotide Induces Production of CXC and CC Chemokines in the Gastric Mucosa and Suppresses Bacterial Colonization in a Mouse Model of Helicobacter pylori Infection Infect. Immun., December 1, 2003; 71(12): 7014 - 7022. [Abstract] [Full Text] [PDF]
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J. B. Jorgensen, L.-H. Johansen, K. Steiro, and A. Johansen CpG DNA Induces Protective Antiviral Immune Responses in Atlantic Salmon (Salmo salar L.) J. Virol., November 1, 2003; 77(21): 11471 - 11479. [Abstract] [Full Text] [PDF]
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H. Shao, S. Lei, S. L. Sun, J. Xiang, H. J. Kaplan, and D. Sun CpG-Containing Oligodeoxynucleotide 1826 Converts the Weak Uveitogenic Rat Interphotoreceptor Retinoid-Binding Protein Peptide 1181-1191 into a Strong Uveitogen J. Immunol., November 1, 2003; 171(9): 4780 - 4785. [Abstract] [Full Text] [PDF]
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P. Daftarian, S. Ali, R. Sharan, S. F. Lacey, C. La Rosa, J. Longmate, C. Buck, R. F. Siliciano, and D. J. Diamond Immunization with Th-CTL Fusion Peptide and Cytosine-Phosphate-Guanine DNA in Transgenic HLA-A2 Mice Induces Recognition of HIV-Infected T Cells and Clears Vaccinia Virus Challenge J. Immunol., October 15, 2003; 171(8): 4028 - 4039. [Abstract] [Full Text] [PDF]
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A. A. Ashkar, S. Bauer, W. J. Mitchell, J. Vieira, and K. L. Rosenthal Local Delivery of CpG Oligodeoxynucleotides Induces Rapid Changes in the Genital Mucosa and Inhibits Replication, but Not Entry, of Herpes Simplex Virus Type 2 J. Virol., August 15, 2003; 77(16): 8948 - 8956. [Abstract] [Full Text] [PDF]
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N. B. Ray and A. M. Krieg Oral Pretreatment of Mice with CpG DNA Reduces Susceptibility to Oral or Intraperitoneal Challenge with Virulent Listeria monocytogenes Infect. Immun., August 1, 2003; 71(8): 4398 - 4404. [Abstract] [Full Text] [PDF]
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I. Gursel, M. Gursel, H. Yamada, K. J. Ishii, F. Takeshita, and D. M. Klinman Repetitive Elements in Mammalian Telomeres Suppress Bacterial DNA-Induced Immune Activation J. Immunol., August 1, 2003; 171(3): 1393 - 1400. [Abstract] [Full Text] [PDF]
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D. Verthelyi, M. Gursel, R. T. Kenney, J. D. Lifson, S. Liu, J. Mican, and D. M. Klinman CpG Oligodeoxynucleotides Protect Normal and SIV-Infected Macaques from Leishmania Infection J. Immunol., May 1, 2003; 170(9): 4717 - 4723. [Abstract] [Full Text] [PDF]
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Y. Wang and A. M. Krieg Synergy between CpG- or non-CpG DNA and specific antigen for B cell activation Int. Immunol., February 1, 2003; 15(2): 223 - 231. [Abstract] [Full Text] [PDF]
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W. Jiang, H. J. Baker, and B. F. Smith Mucosal Immunization with Helicobacter, CpG DNA, and Cholera Toxin Is Protective Infect. Immun., January 1, 2003; 71(1): 40 - 46. [Abstract] [Full Text] [PDF]
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A. M. Harandi, K. Eriksson, and J. Holmgren A Protective Role of Locally Administered Immunostimulatory CpG Oligodeoxynucleotide in a Mouse Model of Genital Herpes Infection J. Virol., December 20, 2002; 77(2): 953 - 962. [Abstract] [Full Text] [PDF]
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H. Yamada, I. Gursel, F. Takeshita, J. Conover, K. J. Ishii, M. Gursel, S. Takeshita, and D. M. Klinman Effect of Suppressive DNA on CpG-Induced Immune Activation J. Immunol., November 15, 2002; 169(10): 5590 - 5594. [Abstract] [Full Text] [PDF]
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 L. SFONDRINI, D. BESUSSO, C. RUMIO, M. RODOLFO, S. MENARD, and A. BALSARI Prevention of spontaneous mammary adenocarcinoma in HER-2/neu transgenic mice by foreign DNA FASEB J, November 1, 2002; 16(13): 1749 - 1754. [Abstract] [Full Text] [PDF]
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K. Heckelsmiller, K. Rall, S. Beck, A. Schlamp, J. Seiderer, B. Jahrsdorfer, A. Krug, S. Rothenfusser, S. Endres, and G. Hartmann Peritumoral CpG DNA Elicits a Coordinated Response of CD8 T Cells and Innate Effectors to Cure Established Tumors in a Murine Colon Carcinoma Model J. Immunol., October 1, 2002; 169(7): 3892 - 3899. [Abstract] [Full Text] [PDF]
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M. Gierynska, U. Kumaraguru, S.-K. Eo, S. Lee, A. Krieg, and B. T. Rouse Induction of CD8 T-Cell-Specific Systemic and Mucosal Immunity against Herpes Simplex Virus with CpG-Peptide Complexes J. Virol., June 5, 2002; 76(13): 6568 - 6576. [Abstract] [Full Text] [PDF]
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Y. He, R. Vemulapalli, and G. G. Schurig Recombinant Ochrobactrum anthropi Expressing Brucella abortus Cu,Zn Superoxide Dismutase Protects Mice against B. abortus Infection Only after Switching of Immune Responses to Th1 Type Infect. Immun., May 1, 2002; 70(5): 2535 - 2543. [Abstract] [Full Text] [PDF]
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M. Gursel, D. Verthelyi, I. Gursel, K. J. Ishii, and D. M. Klinman Differential and competitive activation of human immune cells by distinct classes of CpG oligodeoxynucleotide J. Leukoc. Biol., May 1, 2002; 71(5): 813 - 820. [Abstract] [Full Text] [PDF]
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R. Dudani, Y. Chapdelaine, H. van Faassen, D. K. Smith, H. Shen, L. Krishnan, and S. Sad Preexisting Inflammation Due to Mycobacterium bovis BCG Infection Differentially Modulates T-Cell Priming against a Replicating or Nonreplicating Immunogen Infect. Immun., April 1, 2002; 70(4): 1957 - 1964. [Abstract] [Full Text] [PDF]
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N. P. Juffermans, J. C. Leemans, S. Florquin, A. Verbon, A. H. Kolk, P. Speelman, S. J. H. van Deventer, and T. van der Poll CpG Oligodeoxynucleotides Enhance Host Defense during Murine Tuberculosis Infect. Immun., January 1, 2002; 70(1): 147 - 152. [Abstract] [Full Text] [PDF]
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Z. K. Ballas, A. M. Krieg, T. Warren, W. Rasmussen, H. L. Davis, M. Waldschmidt, and G. J. Weiner Divergent Therapeutic and Immunologic Effects of Oligodeoxynucleotides with Distinct CpG Motifs J. Immunol., November 1, 2001; 167(9): 4878 - 4886. [Abstract] [Full Text] [PDF]
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 G. Auf, A. F. Carpentier, L. Chen, C. Le Clanche, and J.-Y. Delattre Implication of Macrophages in Tumor Rejection Induced by CpG-oligodeoxynucleotides Without Antigen Clin. Cancer Res., November 1, 2001; 7(11): 3540 - 3543. [Abstract] [Full Text] [PDF]
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T. Hayashi, S. P. Rao, K. Takabayashi, J. H. Van Uden, R. S. Kornbluth, S. M. Baird, M. W. Taylor, D. A. Carson, A. Catanzaro, and E. Raz Enhancement of Innate Immunity against Mycobacterium avium Infection by Immunostimulatory DNA Is Mediated by Indoleamine 2,3-Dioxygenase Infect. Immun., October 1, 2001; 69(10): 6156 - 6164. [Abstract] [Full Text] [PDF]
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I. Gursel, M. Gursel, K. J. Ishii, and D. M. Klinman Sterically Stabilized Cationic Liposomes Improve the Uptake and Immunostimulatory Activity of CpG Oligonucleotides J. Immunol., September 15, 2001; 167(6): 3324 - 3328. [Abstract] [Full Text] [PDF]
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B. E. Britigan, T. S. Lewis, M. Waldschmidt, M. L. McCormick, and A. M. Krieg Lactoferrin Binds CpG-Containing Oligonucleotides and Inhibits Their Immunostimulatory Effects on Human B Cells J. Immunol., September 1, 2001; 167(5): 2921 - 2928. [Abstract] [Full Text] [PDF]
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A. Al-Mariri, A. Tibor, P. Mertens, X. De Bolle, P. Michel, J. Godefroid, K. Walravens, and J.-J. Letesson Protection of BALB/c Mice against Brucella abortus 544 Challenge by Vaccination with Bacterioferritin or P39 Recombinant Proteins with CpG Oligodeoxynucleotides as Adjuvant Infect. Immun., August 1, 2001; 69(8): 4816 - 4822. [Abstract] [Full Text] [PDF]
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M. Hafner, R. Zawatzky, C. Hirtreiter, W. A. Buurman, B. Echtenacher, T. Hehlgans, and D. N. Mannel Antimetastatic Effect of CpG DNA Mediated by Type I IFN Cancer Res., July 1, 2001; 61(14): 5523 - 5528. [Abstract] [Full Text] [PDF]
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H. Weighardt, C. Feterowski, M. Veit, M. Rump, H. Wagner, and B. Holzmann Increased Resistance Against Acute Polymicrobial Sepsis in Mice Challenged with Immunostimulatory CpG Oligodeoxynucleotides Is Related to an Enhanced Innate Effector Cell Response J. Immunol., October 15, 2000; 165(8): 4537 - 4543. [Abstract] [Full Text] [PDF]
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G. B. Lipford, T. Sparwasser, S. Zimmermann, K. Heeg, and H. Wagner CpG-DNA-Mediated Transient Lymphadenopathy Is Associated with a State of Th1 Predisposition to Antigen-Driven Responses J. Immunol., August 1, 2000; 165(3): 1228 - 1235. [Abstract] [Full Text] [PDF]
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V. C. Dreisbach, S. Cowley, and K. L. Elkins Purified Lipopolysaccharide from Francisella tularensis Live Vaccine Strain (LVS) Induces Protective Immunity against LVS Infection That Requires B Cells and Gamma Interferon Infect. Immun., April 1, 2000; 68(4): 1988 - 1996. [Abstract] [Full Text] [PDF]
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J. Fensterle, L. Grode, J. Hess, and S. H. E. Kaufmann Effective DNA Vaccination Against Listeriosis by Prime/Boost Inoculation with the Gene Gun J. Immunol., October 15, 1999; 163(8): 4510 - 4518. [Abstract] [Full Text] [PDF]
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