Impaired response to interferon-alpha/beta and lethal viral disease in human STAT1 deficiency.

The receptors for interferon-α/β (IFN-α/β) and IFN-γ activate components of the Janus kinase‐signal transducer and activator of transcription (JAK‐STAT) signaling pathway, leading to the formation of at least two transcription factor complexes1. STAT1 interacts with STAT2 and p48/IRF-9 to form the transcription factor IFN-stimulated gene factor 3 (ISGF3). STAT1 dimers form γ-activated factor (GAF). ISGF3 is induced mainly by IFN-α/β, and GAF by IFN-γ, although both factors can be activated by both types of IFN. Individuals with mutations in either chain of the IFN-γ receptor (IFN-γR) are susceptible to infection with mycobacteria 2‐5 . A heterozygous STAT1 mutation that impairs GAF but not ISGF3 activation has been found in other individuals with mycobacterial disease 6 . No individuals with deleterious mutations in the IFN-α/β signaling pathway have been described. We report here two unrelated infants homozygous with respect to mutated STAT1 alleles. Neither IFN-α/β nor IFN-γ activated STAT1-containing transcription factors. Like individuals with IFN-γR deficiency, both infants suffered from mycobacterial disease, but unlike individuals with IFN-γR deficiency, both died of viral disease. Viral multiplication was not inhibited by recombinant IFN-α/β in cell lines from the two individuals. Inherited impairment of the STAT1-dependent response to human IFN-α/β thus results in susceptibility to viral disease. We studied two unrelated infants (P1 and P2) with a new clinical syndrome of severe mycobacterial and viral diseases not consistent with any known primary immunodeficiency (Fig. 1a). Infant P1 died of disseminated disease with recurrent encephalitis caused by herpes simplex virus 1 (HSV-1), whereas infant P2 died of a viral-like illness, but viral cultures and serologies could not be done (Fig. 1a). Both children had developed disseminated bacillus Calmette-Guerin (BCG) vaccine infection, which was in remission after antibiotic treatment at the time at which symptoms of viral infection appeared. We considered STAT1 to be a likely candidate gene, given its involvement in both the IFN-γ and IFN-α/β signaling pathways 1,7 . Sequencing of STAT1 in infant P1 showed a homozygous two-nucleotide deletion (of AG) in exon 20 at position