Impairment of Mycobacterial But Not Viral Immunity by a Germline Human <i>STAT1</i> Mutation
Stéphanie Boisson‐Dupuis(Hôpital Necker-Enfants Malades), Catherine Dargemont(Centre National de la Recherche Scientifique), Claire Fieschi(Inserm), Nicolas Thomassin(Centre Hospitalier de l'Agglomération de Nevers), Sergio D. Rosenzweig(National Institute of Allergy and Infectious Diseases), Jeff Harris(University of California, San Francisco), Steven M. Holland(National Institute of Allergy and Infectious Diseases), Robert D. Schreiber(Washington University in St. Louis), Jean‐Laurent Casanova(Hôpital Necker-Enfants Malades)
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Abstract
Interferons (IFN) alpha/beta and gamma induce the formation of two transcriptional activators: gamma-activating factor (GAF) and interferon-stimulated gamma factor 3 (ISGF3). We report a natural heterozygous germline STAT1 mutation associated with susceptibility to mycobacterial but not viral disease. This mutation causes a loss of GAF and ISGF3 activation but is dominant for one cellular phenotype and recessive for the other. It impairs the nuclear accumulation of GAF but not of ISGF3 in heterozygous cells stimulated by IFNs. Thus, the antimycobacterial, but not the antiviral, effects of human IFNs are principally mediated by GAF.
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