DNA from Protozoan ParasitesBabesia bovis, Trypanosoma cruzi, andT. bruceiIs Mitogenic for B Lymphocytes and Stimulates Macrophage Expression of Interleukin-12, Tumor Necrosis Factor Alpha, and Nitric Oxide

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Abstract
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 parasiteBabesia bovisfor 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 parasitesB. bovis, Trypanosoma cruzi, andT. bruceiactivates macrophages to secrete inflammatory mediators associated with protective immunity. DNA fromEscherichia coliand all three parasites stimulated B-lymphocyte proliferation and increased macrophage production of interleukin-12 (IL-12), tumor necrosis factor alpha (TNF-α), and nitric oxide (NO). Regulation of IL-12 and NO production occurred at the level of transcription. The amounts of IL-12, TNF-α, and NO induced byE. coliand protozoal DNA were strongly correlated (r2> 0.9) with the frequency of CG dinucleotides in the genome, and immunostimulation by DNA occurred in the orderE. coli≥T. cruzi>T. brucei>B. bovis. Induction of inflammatory mediators byE. coli, T. brucei, andB. bovisDNA was dependent on the presence of unmethylated CpG dinucleotides. However, at high concentrations,E. coliandT. cruziDNA-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.