Interferons induce the formation of two transcriptional activators: gamma-activating factor (GAF) and interferon-stimulated gamma factor 3 (ISGF3). A natural heterozygous germline STAT1 mutation associated with susceptibility to mycobacterial but not viral disease was found in two unrelated patients with unexplained mycobacterial disease. This mutation caused a loss of GAF and ISGF3 activation but was dominant for one cellular phenotype and recessive for the other. It impaired the nuclear accumulation of GAF but not of ISGF3 in cells stimulated by interferons, implying that the antimycobacterial but not the antiviral effects of human interferons are mediated by GAF. More recently, two patients have been identified with homozygous STAT-1 mutations who developed both post–BCG vaccination disseminated disease and lethal viral infections. The mutations in these patients caused a complete lack of STAT-1 and resulted in a lack of formation of both GAF and ISGF3.