Chronic mucocutaneous candidiasis disease (CMCD) may be caused by autosomal dominant (AD) IL-17F deficiency or autosomal recessive (AR) IL-17RA deficiency. Here, using whole-exome sequencing, we identified heterozygous germline mutations in STAT1 in 47 patients from 20 kindreds with AD CMCD. Previously described heterozygous STAT1 mutant alleles are loss-of-function and cause AD predisposition to mycobacterial disease caused by impaired STAT1-dependent cellular responses to IFN-γ. Other loss-of-function STAT1 alleles cause AR predisposition to intracellular bacterial and viral diseases, caused by impaired STAT1-dependent responses to IFN-α/β, IFN-γ, IFN-λ, and IL-27. In contrast, the 12 AD CMCD-inducing STAT1 mutant alleles described here are gain-of-function and increase STAT1-dependent cellular responses to these cytokines, and to cytokines that predominantly activate STAT3, such as IL-6 and IL-21. All of these mutations affect the coiled-coil domain and impair the nuclear dephosphorylation of activated STAT1, accounting for their gain-of-function and dominance. Stronger cellular responses to the STAT1-dependent IL-17 inhibitors IFN-α/β, IFN-γ, and IL-27, and stronger STAT1 activation in response to the STAT3-dependent IL-17 inducers IL-6 and IL-21, hinder the development of T cells producing IL-17A, IL-17F, and IL-22. Gain-of-function STAT1 alleles therefore cause AD CMCD by impairing IL-17 immunity.

Tuberculosis Vaccine Conundrum: Some children experience severe clinical disease when they are vaccinated against tuberculosis, an attenuated live vaccine that is normally innocuous in humans. Several germline mutations have been identified that account for this susceptibility, and now Bogunovic et al. (p. 1684 , published online 2 August) add another to the list— ISG15 . Uncovering this mutation, which is inherited in an autosomal recessive manner, was a surprise because studies with mice deficient in ISG15 showed enhanced susceptibility to some viral, but not bacterial, infections. Nevertheless, patients lacking ISG15 were not able to produce adequate amounts of interferon-γ, a cytokine critical for clearance of the bacteria.

Key Points: AD STAT1 GOF is the most common genetic cause of inherited CMC and is not restricted to a specific age or ethnic group. STAT1 GOF underlies a variety of infectious and autoimmune features, as well as carcinomas and aneurysms associated with a poor outcome.

A genetic cause for severe influenza: Although chicken soup and plenty of rest get most kids through an influenza virus infection, some require hospitalization. Ciancanelli et al. report on one child who suffered severely from influenza because of null mutations in the gene for transcription factor IRF7. Cells isolated from this patient could not make enough secreted antiviral proteins, called interferons, to halt viral replication. The requirement for IRF7 seems quite specific, because this patient recovers normally from other common childhood viral infections. Science , this issue p. 448