IRF9 is an integral transcription factor in mediating type-I interferon antiviral-response, as part of ISGF3. Our aim is to report a family where several members showed a striking susceptibility to viral-infection and IRF9-deficient.
The index patient is a 10yo boy, born at term from healthy, consanguineous-parents. From the first-year of life, he suffered severe viral-infections (bronchiolitis-RSV, disseminated-chickenpox, EV-encephalitis, influenza-A/B, dengue-fever and zika-virus disease). Immunological study showed a mild CD4+T and B-lymphopaenia and hypogammaglobulinaemia. Another remarkable feature is the rapidity with which septic-shock episodes develop.
Genetic analysis revealed a homozygous splicing mutation in IRF9 gene [c.577+1G>T (NM_006084)], which was confirmed in homozygosity in the proband and his sister, and in heterozygosity in both parents. Skipping of exon-5 generated a frameshift and a premature stop codon (p.Glu166LeufsTer80). No expression of IRF9 was observed in: unstimulated or IFNα-stimulated patient-PBMCs and 293T-cells transfected with c.577+1G>T IRF9-construct. After IFNα stimulation or RSV-infection of primary fibroblasts, initial steps of signalling cascade were conserved in IRF9-/-, but no induction of ISGs (MX,IFIT3,ISG15) was observed. In cell lines where IRF9 expression was targeted by CRISPR/Cas9-technology, an impaired induction of ISGs after IFNα treatment was noted and decreased cellular control of viral-replication. In contrast, transfection of patient-cells with wt, but not mutant, IRF9 enhanced their ability to control the replication of various viruses.
The marked susceptibility to virus-infections associated with IRF9-deficiency emphasises that children presenting with unexpectedly severe consequences after either viral infection or vaccination (live-attenuated) should be evaluated bearing in mind the possibility of immune defects affecting IFN-system.