In the present study, we elucidated the effect of synthetic CpG-containing
oligodeoxynucleotides (ODN) on pulmonary and disseminated
infection caused by Cryptococcus neoformans. CDF-1 mice were inoculated intratracheally with a highly virulent strain of this pathogen, which resulted in massive bacterial growth in the lung, dissemination to the brain and death. Administration of
CpG-ODN promoted the clearance of C. neoformans in the lungs, decreased their dissemination to brain and prolonged the survival of infected mice. These effects correlated well with the enhanced production of
interleukin (IL)-12 and
interferon (IFN)-gamma and attenuated secretion of
IL-4 in bronchoalveolar lavage fluids (BALF) and promoted development of Th1 cells, as indicated by the increased production of IFN-gamma by paratracheal lymph node cells upon restimulation with cryptococcal
antigens. The IFN-gamma synthesis in BALF was inhibited by depletion of CD8(+) and CD4(+) T cells on days 7 and 14 after
infection, respectively, but not by depletion of NK and gammadelta T cells. Consistent with these data, intracellular expression of IFN-gamma was detected predominantly in CD8(+) and CD4(+) T cells in the lung on days 7 and 14, respectively. The protective effect of
CpG-ODN, as shown by the prolonged survival, was completely and partially inhibited by depletion of CD4(+) or CD8(+) T cells, respectively, but not by depletion of other cells. Finally,
TNF-alpha was markedly induced by
CpG-ODN, and the protective effect of this agent was strongly inhibited by neutralizing anti-
TNF-alpha MoAb. Our results indicate that
CpG-ODN alters the Th1-Th2 cytokine balance and promotes host resistance against
infection with C. neoformans.