Life-threatening influenza pneumonitis in a child with inherited IRF9 deficiency

Abstract

Life-threatening pulmonary influenza can be caused by inborn errors of type I and III IFN immunity. We report a 5-yr-old child with severe pulmonary influenza at 2 yr. She is homozygous for a loss-of-function allele. Her cells activate gamma-activated factor (GAF) STAT1 homodimers but not IFN-stimulated gene factor 3 (ISGF3) trimers (STAT1/STAT2/IRF9) in response to IFN-α2b. The transcriptome induced by IFN-α2b in the patient's cells is much narrower than that of control cells; however, induction of a subset of IFN-stimulated gene transcripts remains detectable. In vitro, the patient's cells do not control three respiratory viruses, influenza A virus (IAV), parainfluenza virus (PIV), and respiratory syncytial virus (RSV). These phenotypes are rescued by wild-type IRF9, whereas silencing IRF9 expression in control cells increases viral replication. However, the child has controlled various common viruses in vivo, including respiratory viruses other than IAV. Our findings show that human IRF9- and ISGF3-dependent type I and III IFN responsive pathways are essential for controlling IAV.

Impaired type I interferon activity and exacerbated inflammatory responses in severe Covid-19 patients

“…Comorbidities (such as hypertension, diabetes mellitus, overweight) are risk factors for severe Covid-19 and could negatively impact IFN production as well as exacerbate inflammatory responses [28][29][30] . Genetic host susceptibility can be also suspected since inherited monogenic disorders in children 31,32 or susceptibility variants in adults 33 , each involving the type I IFN pathway, have been associated with life-threatening influenza infections. Identification of patients with insufficient IFN production could define a high-risk population that could benefit from IFN-α or -β supplementation in conjunction with antiviral drugs when available.…”

Homozygous STAT2 gain-of-function mutation by loss of USP18 activity in a patient with type I interferonopathy

“…Patients with autosomal recessive, complete IFNAR1 , IFNAR2 (Duncan et al, 2015), JAK1 (Eletto et al, 2016), TYK2 (Kreins et al, 2015), STAT1 (Dupuis et al, 2003), STAT2 (Hambleton et al, 2013), and IRF9 (Hernandez et al, 2018) deficiencies suffer from severe infectious diseases. Patients with IFNAR1, IFNAR2, STAT2, and IRF9 deficiencies are exclusively prone to viral diseases (Duncan et al, 2015;Hambleton et al, 2013;Hernandez et al, 2019;Hernandez et al, 2018), while patients with TYK2 and STAT1 deficiencies are also prone to mycobacterial disease (Del Bel et al, 2017;Kreins et al, 2015;Wu and Holland, 2015). In contrast, Type I Interferonopathies are monogenic disorders that result from autoinflammation caused by excessive IFN-I activity (Rodero and Crow, 2016).…”

Epidemiological survey in a day care center following toddler sudden death due to human metapneumovirus infection

“…Immunodeficiency has been linked to severe viral respiratory infections. Additional associations include TLR4 mutations with severe RSV bronchiolitis [8], IFIH1 loss-of-function mutations (which prevent sensing of viral RNA) with severe RNA virus (RSV and human rhinovirus) infections [9], and IRF7 [10] and IRF 9 [11] with severe influenza pneumonitis. All these genes are involved in innate immunity and interferon pathways and have been implicated in a theory proposing that monogenic inborn errors of immunity underlie susceptibility to specific infections [12].…”