MICE THAT LACK THE INTERFERON-GAMMA RECEPTOR HAVE PROFOUNDLY ALTERED RESPONSES TO INFECTION WITH BACILLUS-CALMETTE-GUERIN AND SUBSEQUENT CHALLENGE WITH LIPOPOLYSACCHARIDE

Mice with a targeted disruption of the interferon y receptor gene (IFN -gammaR0/0 mice) and control wad-type mice were inoculated with the Ba cillus Calmette-Guerin (BCG) strain of Mycobacterium bovis. BCG infect ion was not lethal for wild-type mice whereas all IFN-gammaR0/0 mice d ied approximately 7-9 wk after inoculation. Histological examination a t 2 and 6 wk after BCG inoculation showed that livers of IFN-gammaR0/0 mice had higher numbers of acid-fast bacteria than wild-type mice, es pecially at 6 wk. In parallel, the livers of IFN-gammaR0/0 mice showed a reduction in the formation of characteristic granulomas at 2 wk aft er inoculation. Injection of lipopolysaccharide (LPS) 2 wk after BCG i noculation was significantly less lethal for IFN-gammaR0/0 mice than f or wild-type mice. Reduced lethality of LPS correlated with a drastica lly reduced production of tumor necrosis factor alpha (TNF-alpha) in t he IFN-gammaR0/0 mice. Interleukin 1alpha (IL-1alpha) and IL-6 levels in the serum were also significantly reduced in the IFN-gammaR0/0 mice after BCG infection and LPS challenge. The greatly reduced capacity o f BCG-infected IFN-gammaR0/0 mice to produce TNF-alpha may be an impor tant factor in their inability to resist BCG infection. These results show that the presence of a functional IFN-gamma receptor is essential for the recovery of mice from BCG infection, and that IFN-gamma is a key element in the complex process whereby BCG infection leads to the sensitization to endotoxin.