Mice that lack the interferon-γ receptor have profoundly altered responses to infection with bacillus Calmette-Guérin and subsequent challenge with lipopolysaccharide

Abstract

Mice with a targeted disruption of the interferon γ receptor gene (IFN-γR0/0 mice) and control wild-type mice were inoculated with the Bacillus Calmette-Guérin (BCG) strain of Mycobacterium bovis. BCG infection was not lethal for wild-type mice whereas all IFN-γR0/0 mice died ∼7-9 wk after inoculation. Histological examination at 2 and 6 wk after BCG inoculation showed that livers of IFN-γR0/0 mice had higher numbers of acid-fast bacteria than wild-type mice, especially at 6 wk. In parallel, the livers of IFN-γR0/0 mice showed a reduction in the formation of characteristic granulomas at 2 wk after inoculation. Injection of lipopolysaccharide (LPS) 2 wk after BCG inoculation was significantly less lethal for IFN-γR0/0 mice than for wild-type mice. Reduced lethality of LPS correlated with a drastically reduced production of tumor necrosis factor a (TNF-α) in the IFN-γR0/0 mice. Interleukin 1α (IL-1α) and IL-6 levels in the serum were also significantly reduced in the IFN-γR0/0 mice after BCG infection and LPS challenge. The greatly reduced capacity of BCG-infected IFN-γR0/0 mice to produce TNF-α may be an important factor in their inability to resist BCG infection. These results show that the presence of a functional IFN-γ receptor is essential for the recovery of mice from BCG infection, and that IFN-γ is a key element in the complex process whereby BCG infection leads to the sensitization to endotoxin.