Induction of granulomas in interferon- gene-disrupted mice by avirulent but not by virulent strains of Mycobacterium tuberculosis

Abstract

Summary To gain a better understanding of the pathological role of interferon-γ (IFN-γ) in specific granuloma formation, IFN-γ gene-deficient mice (BALB/c and C57BL/6) were produced. The IFN-γ gene in embryonic stem (ES) cells was disrupted by inserting the β-galactosidase gene (lacZ) and the neomycin resistance gene (neo) at the translation initiation site in exon 1 by homologous recombination. Six-week-old IFN-γ-deficient and wild-type mice were inoculated with 103-107 bacilli of various strains of Mycobacterium tuberculosis (Kurono, H37Rv, H37Ra and BCG Pasteur) through their tail veins. The mice were examined 7 weeks later for granuloma formation. The avirulent BCG Pasteur and H37Ra strains (103-104 bacilli/ml) induced granulomas in the spleen, liver and lungs of IFN-γ-deficient mice. The granulomas consisted of epithelioid macrophages and Langhans multinucleate giant cells, but lacked caseous necrosis. The virulent Kurono and H37Rv strains induced disseminated abscesses but not granulomas in various organs of IFN-γ-deficient mice and Mac-3-positive macrophages were not detected in the abscess lesions. These results suggest that IFN-γ may be primarily responsible for macrophage activation and that other factor(s) may be involved in the granuloma formation mechanism.