Respiratory viral infections in otherwise healthy humans with inherited IRF7 deficiency

Abstract

Autosomal recessive IRF7 deficiency was previously reported in three patients with single critical influenza or COVID-19 pneumonia episodes. The patients’ fibroblasts and plasmacytoid dendritic cells produced no detectable type I and III IFNs, except IFN-β. Having discovered four new patients, we describe the genetic, immunological, and clinical features of seven IRF7-deficient patients from six families and five ancestries. Five were homozygous and two were compound heterozygous for IRF7 variants. Patients typically had one episode of pulmonary viral disease. Age at onset was surprisingly broad, from 6 mo to 50 yr (mean age 29 yr). The respiratory viruses implicated included SARS-CoV-2, influenza virus, respiratory syncytial virus, and adenovirus. Serological analyses indicated previous infections with many common viruses. Cellular analyses revealed strong antiviral immunity and expanded populations of influenza- and SARS-CoV-2–specific memory CD4+ and CD8+ T cells. IRF7-deficient individuals are prone to viral infections of the respiratory tract but are otherwise healthy, potentially due to residual IFN-β and compensatory adaptive immunity.

From rare disorders of immunity to common determinants of infection: Following the mechanistic thread

“…The candidate gene approach-based discovery of AR IFNAR1 and IRF7 deficiencies in four unrelated adults with critical COVID-19 aged 25-50 years who had previously been healthy provided the fundamental information that type I IFN is essential for host defense against SARS-CoV-2, but potentially otherwise redundant in host defense, even over several decades. This redundancy was confirmed not only by reports of other patients with IFNAR1 or IRF7 deficiency (Campbell et al, 2022) but also by the surprising observation of common lossof-function (LOF) alleles of IFNAR1 and IFNAR2 in the Pacific and Arctic regions, respectively (Bastard et al, 2022a;Duncan et al, 2022). Recessive inborn errors of type I IFNs, including XR TLR7 and AR IFNAR1, STAT2, and TYK2 deficiencies, were even found in about 10% of international children hospitalized for COVID-19 pneumonia (Zhang et al, 2022b).…”

“…It was not initially possible to estimate the penetrance of IRF7 and IRF9 deficiencies, as both disorders were described in single patients. A recent study showed that the penetrance of IRF7 deficiency is incomplete ( Campbell et al., 2022 ). STAT1 and STAT2 deficiencies have incomplete penetrance too, suggesting that the penetrance of IRF9 deficiency is also probably incomplete.…”

“…These deficiencies were found in four unrelated previously healthy adults aged 25–50 years hospitalized for COVID-19. Remarkably, up to seven IRF7-deficient patients have recently been diagnosed; all suffered from severe viral respiratory diseases, including influenza and COVID-19, but not from viral illnesses of other tissues ( Campbell et al., 2022 ). Two other unrelated IFNAR1-deficient patients and one TBK1-deficient patient with critical COVID-19 have also been independently reported ( Abolhassani et al., 2022 ; Khanmohammadi et al., 2022 ; Schmidt et al., 2021 ).…”

“…The causal virus, SARS-CoV-2, is an RNA virus that infects the respiratory tract, whence it can spread to other tissues via the bloodstream. Based on previous discoveries of rare inherited TLR3, IRF7, STAT1, STAT2, and IRF9 deficiencies in children with life-threatening influenza pneumonia ( Campbell et al., 2022 ; Le Voyer et al., 2021 ; Zhang, 2020a ), rare autosomal IEI affecting TLR3-dependent type I IFN immunity were discovered in patients with life-threatening COVID-19 ( Zhang et al., 2020 ). Remarkably, AR and complete defects of IFNAR1, IRF7, and TBK1 were found in previously healthy patients ( Abolhassani et al., 2022 ; Khanmohammadi et al., 2022 ; Schmidt et al., 2021 ; Zhang et al., 2020 , 2022b ).…”

Autoantibodies against type I IFNs in patients with critical influenza pneumonia

“…She has since remained well with only annual influenza vaccinations and vaccination against COVID-19 for prophylaxis. Two other patients with IRF7 deficiency suffering from severe influenza pneumonia at the ages of 7 mo and 14 yr have recently been reported ( Campbell et al, 2022 ). IRF7 is a transcription factor required for the production of the 17 type I IFNs and three type III IFNs, with IFN-β not being strictly IRF7 dependent in some cell types ( Ciancanelli et al, 2015 ; Zhang et al, 2020b ; Campbell et al, 2022 ).…”