Mice are highly resistant to Legionella pneumophila infection. To study the natural resistance, we used A/J and C57BL/6 mice which have macrophages permissive and non-permissive for the intracellular growth of L. pneumophila, respectively. The LD50 for A/J and C57BL/6 were 2.7 x 10(7) and 7.2 x 10(7) CFU, respectively, indicating that the difference in macrophage ability to regulate the bacterial growth had some effect on susceptibility to L. pneumophila. There was no difference between both strains in elimination of the bacteria from the blood stream within 5 h after infection. When mice were challenged intravenously with a sublethal dose (4 x 10(6) CFU), the bacterial burden in the liver at day 1 was significantly higher in A/J than in C57BL/6. The bacteria, thereafter, were eliminated rapidly from the liver at a similar rate in both strains. Elimination of the bacteria from the spleen and lungs was also delayed in A/J as compared to C57BL/6. Naive spleen cells of both strains in vitro could produce a large amount of interferon-gamma (IFN-gamma) one day after they were stimulated with formalin-killed L. pneumophila. When anti-murine IFN-gamma monoclonal antibody was administered, the bacterial burden in liver, spleen and lungs significantly increased in A/J, and also in C57BL/6 to some extent. We suggest that the innate macrophages' ability to regulate the intracellular bacterial growth and the endogenous IFN-gamma produced in a very early phase play a critical role in murine natural resistance against L. pneumophila infection.