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Infection and Immunity, April 2001, p. 2162-2171, Vol. 69, No. 4
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.4.2162-2171.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

DNA from Protozoan Parasites Babesia bovis, Trypanosoma cruzi, and T. brucei Is Mitogenic for B Lymphocytes and Stimulates Macrophage Expression of Interleukin-12, Tumor Necrosis Factor Alpha, and Nitric Oxide

Lisl K. M. Shoda,1,dagger Kimberly A. Kegerreis,1 Carlos E. Suarez,2 Isabel Roditi,3 Ricardo S. Corral,4 Gustavo M. Bertot,4 Junzo Norimine,1 and Wendy C. Brown1,*

Program in Vector-Borne Diseases, Department of Veterinary Microbiology and Pathology,1 and Animal Disease Research Unit, USDA Agricultural Research Service,2 Washington State University, Pullman, Washington 99164; Institute for Cell Biology, University of Bern, Bern, Switzerland3; and Laboratory of Virology, Hospital de Ninõs "Dr. Ricardo Gutierrez," Buenos Aires, Argentina4

Received 20 October 2000/Returned for modification 29 November 2000/Accepted 5 January 2001

The activation of innate immune responses by genomic DNA from bacteria and several nonvertebrate organisms represents a novel mechanism of pathogen recognition. We recently demonstrated the CpG-dependent mitogenic activity of DNA from the protozoan parasite Babesia bovis for bovine B lymphocytes (W. C. Brown, D. M. Estes, S. E. Chantler, K. A. Kegerreis, and C. E. Suarez, Infect. Immun. 66:5423-5432, 1998). However, activation of macrophages by DNA from protozoan parasites has not been demonstrated. The present study was therefore conducted to determine whether DNA from the protozan parasites B. bovis, Trypanosoma cruzi, and T. brucei activates macrophages to secrete inflammatory mediators associated with protective immunity. DNA from Escherichia coli and all three parasites stimulated B-lymphocyte proliferation and increased macrophage production of interleukin-12 (IL-12), tumor necrosis factor alpha (TNF-alpha ), and nitric oxide (NO). Regulation of IL-12 and NO production occurred at the level of transcription. The amounts of IL-12, TNF-alpha , and NO induced by E. coli and protozoal DNA were strongly correlated (r2 > 0.9) with the frequency of CG dinucleotides in the genome, and immunostimulation by DNA occurred in the order E. coli >=  T. cruzi > T. brucei > B. bovis. Induction of inflammatory mediators by E. coli, T. brucei, and B. bovis DNA was dependent on the presence of unmethylated CpG dinucleotides. However, at high concentrations, E. coli and T. cruzi DNA-mediated macrophage activation was not inhibited following methylation. The recognition of protozoal DNA by B lymphocytes and macrophages may provide an important innate defense mechanism to control parasite replication and promote persistent infection.

* Corresponding author. Mailing address: Department of Veterinary Microbiology and Pathology, Washington State University, Pullman, WA 99164-7040. Phone: (509) 335-6067. Fax: (509) 335-8529. E-mail: wbrown{at}vetmed.wsu.edu.

dagger Present address: Entelos, Inc., Menlo Park, CA 94025.

Infection and Immunity, April 2001, p. 2162-2171, Vol. 69, No. 4
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.4.2162-2171.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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