Modulation of host immune responses by protozoal DNA

The pathology caused by acute Babesia bovis infection is similar to that se en in severe human malaria caused by Plasmodium falciparum infection, which is related to dysregulated production of inflammatory cytokines and nitric oxide (NO). We have observed induction of NO, inducible nitric oxide synth ase (iNOS) and inflammatory cytokines in macrophages by B. bovis. Furthermo re, proliferation of lymphocytes from individuals never exposed to certain protozoal pathogens can be induced by crude protozoal parasite extracts. We have repeatedly observed stimulation of naive PBMC from cattle to antigeni c extracts of Babesia bovis. Based on recent studies demonstrating the mito genicity of bacterial and other non-vertebrate DNAs for murine B cells and macrophages, the mitogenic properties of B. bovis DNA were examined. B. bov is and E. coli DNAs induced proliferation of PBMC and purified B cells from non-exposed cattle. Stimulatory activity was reduced by DNase treatment an d methylation with CpG methylase, indicating the presence of stimulatory no n-methylated CpG motifs in the B. bovis genome. B. bovis and E. coli DNAs e nhanced IgG secretion by cultured B cells, stimulating IgG1 and more strong ly, IgG2. Several hexameric CpG immunostimulatory sequences (ISS) active fo r murine B cells were identified in an 11 kb fragment of B. bovis DNA. An o ligodeoxyribonucleotide containing one of these (AACGTT), located in the rh optry associated protein-1 (rap-1) open reading frame, stimulated B cell pr oliferation. These studies identify a potential mechanism by which protozoa l parasites may modulate host immune responses, leading to consequences suc h as hypergammaglobulinemia and splenomegaly. These results also support th e use of ISS as vaccine adjuvants to enhance Type 1 immune responses in cat tle. (C) 1999 Elsevier Science B.V. All rights reserved.