A number sign (#) is used with this entry because of evidence that immunodeficiency-39 with increased susceptibility to viral infections (IMD39) is caused by homozygous or compound heterozygous mutation in the IRF7 gene (605047) on chromosome 11p15.

Immunodeficiency-39 (IMD39) with increased susceptibility to viral infections is an autosomal recessive immunologic disorder characterized by life-threatening respiratory infections due to certain viruses, mainly influenza A, SARS-CoV-2, and RSV. The age of onset is highly variable, ranging from early childhood to mid-adulthood. Affected individuals are often seropositive for antibodies against other viruses without a history of previous life-threatening respiratory infections, suggesting incomplete penetrance toward some viral infections. Laboratory studies show intact T- and B-cell adaptive responses to environmental viral exposures and vaccination, including MMR. Immunologic cells show impaired type I and type III interferon production, although there is some residual IFN-beta (IFNB1; 147640) production, which may explain the relatively narrow susceptibility to critical infections with respiratory viruses (Campbell et al., 2022).

Ciancanelli et al. (2015) reported a French girl, born of unrelated parents, who developed life-threatening acute respiratory distress during infection with H1N1 influenza A at age 2.5 years. She had no detectable immunologic abnormalities suggesting any T- or B-cell defects, and had a normal vaccination response to typical childhood immunizations. She also had laboratory evidence of antibodies against other viruses, including cytomegalovirus, varicella zoster, respiratory syncytial virus, adenovirus, and parainfluenza viruses 1, 2, and 3, but had no other clinical viral infections at age 7 years. The patient's parents were unaffected.

Zhang et al. (2020) reported 2 unrelated adults who developed life-threatening SARS-CoV-2 infections: a 49-year-old woman of Belgian/Italian descent (P1) and a 50-year-old man of Turkish descent (P3). The authors stated that neither had a prior history of hospitalization for other life-threatening viral illnesses. Clinical details were limited, but both survived. P1 was seropositive for several common viruses, including influenza A and B; she also had low levels of serum IFN-alpha (IFNA1; 147660).

Campbell et al. (2022) reported clinical details of the patients reported by Zhang et al. (2020). The Belgian woman (P2), who was born of consanguineous Italian parents (kindred B), had a complex medical history, including infection with mumps, varicella, and measles as a child (unclear whether she was vaccinated), recurrent upper respiratory infections and flu-like illnesses since childhood, tonsillectomy at age 9, recurrent bronchitis, asthma, hepatitis with gastrointestinal symptoms, obesity, type 2 diabetes mellitus, and traumatic brain injury. Her acute SARS-CoV-2 infection was complicated by hypoxemia requiring extracorporeal membrane oxygenation (ECMO), subglottic edema necessitating tracheostomy, pulmonary superinfection with E. coli and Staphylococcus aureus, urinary tract infection, elevated liver enzymes, and multidrug-resistant Enterococcus faecium. Family history was notable for 2 sibs who underwent tonsillectomy; these sibs were heterozygous for the IRF7 mutation. P2 had 3 healthy daughters. The 50-year-old Turkish man (P3, kindred C) was admitted due to severe respiratory infection with SARS-CoV-2 and responded well to treatment. He had no comorbidities (no asthma, recurrent infections, immunodeficiency, or hypogammaglobulinemia).

Campbell et al. (2022) reported 4 newly described patients (P4-P7) from 3 unrelated families (kindreds D, E, and F) with life-threatening viral respiratory infections. P4, born of consanguineous Iranian parents (kindred D), was a 29-year-old man who presented with severe SARS-CoV-2 infection requiring mechanical ventilation and resulting in death 20 days after admission. He was overweight, but had no other comorbid conditions. Two brothers (P5 and P6) of Swedish/Finnish descent (kindred E) presented in their thirties with severe SARS-CoV-2 infections. P5 required mechanical ventilation and later had transient heart palpitations. He reported lingering fatigue for several months, but showed full recovery. P6 had recurrent ear infections in early childhood and had 2 severe infections requiring hospitalization in his teens (influenza and Streptococcus). He showed rapid recovery from his SARS-CoV-2 infection as an adult. A year later, he developed acute neurologic symptoms after receiving several tick bites. Although he had received TBE (tick-born encephalitis) vaccination prior to the onset of symptoms, serologic tests for the TBE virus were positive in serum and CSF. He recovered fully from this infection. P7 was a Belgian girl (kindred F) who was admitted at 6 months of age with RSV bronchiolitis. She continued to have recurrent severe infections, including influenza A pneumonia at 7 months, culture-negative sepsis and metabolic acidosis at 8 months, otitis media, periorbital cellulitis, and lymphadenitis at 21 months, and scarlet fever with positive adenovirus and Streptococcus pyogenes testing at 33 months. Immunologic workup showed normal antibody levels and immunophenotyping, but weak response to pneumococcal vaccine. At 3 years, 9 months of age, she was hospitalized again for bronchopneumonia due to influenza A, and showed a full recovery. Repeat immunologic workup was normal, and she received MMR and COVID19 vaccines with no adverse events. Detailed immunologic studies showed that adaptive antiviral T-cell immunity and B-cell immunity were intact in the patients studied. Both P5 and P6 had increased frequencies of SARS-CoV-2-responding CD4+ and CD8+ memory T cells. Immunologic studies of all patients, including the patients reported by Ciancanelli et al. (2015) and Zhang et al. (2020), showed that they were able to form antibodies after vaccination, including to mRNA vaccines and MMR, and after exposure to common pathogens, including viruses.

The transmission pattern of IMD39 in the families reported by Ciancanelli et al. (2015) and Campbell et al. (2022) was consistent with autosomal recessive inheritance. There is evidence of incomplete penetrance toward some viruses.

In a 7-year-old French girl with immunodeficiency-39 manifest as life-threatening H1N1 influenza A infection, Ciancanelli et al. (2015) identified compound heterozygous mutations in the IRF7 gene (F410V, 605047.0001 and Q421X, 605047.0002). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the family. In vitro studies and studies of patient cells showed impaired type I and type III interferon responses to influenza virus, as well as increased virus replication.

In 2 unrelated individuals with IMD39 (P1 and P3) who presented in adulthood with life-threatening SARS-CoV-2 respiratory infection, Zhang et al. (2020) identified biallelic loss-of-function mutations in the IRF7 gene. A 49-year-old Italian/Belgian woman (P1) carried a homozygous frameshift (605047.0003), and a 50-year-old Turkish man (P3) carried compound heterozygous missense variants (D117N and M371V). The mutations were found by whole-exome or whole-genome gene sequencing; segregation studies were not performed. Western blot analysis of patient T cells showed decreased IRF7 protein levels at baseline and after stimulation with IFN-alpha-2 (IFNA2; 147562), and plasmacytoid dendritic cells from P1 produced no type I or type III interferon in response to infection with SARS-CoV-2 or influenza A. However, there was some residual production of IFN-beta. Fibroblasts derived from the patient reported by Ciancanelli et al. (2015) showed higher SARS-CoV-2 infection levels in vitro compared to controls, which could be rescued with transduction of wildtype IRF7. The findings indicated that defects in IRF7-dependent type I immunity predispose to severe critical SARS-CoV-2 infection, consistent with its previously documented role in pulmonary immunity to influenza virus. Zhang et al. (2020) noted that these genotypes were silent until infection with SARS-CoV-2 in their 2 patients with biallelic mutations, who presented with severe COVID at 49 and 50 years of age and had no prior history of life-threatening infections. The patients were part of a cohort of 659 patients who were hospitalized for life-threatening pneumonia caused by SARS-CoV-2 who underwent genetic studies.

In 4 patients (P4-P7) from 3 unrelated families (kindreds D, E, and F), with IMD39, Campbell et al. (2022) identified homozygous or compound heterozygous mutations in the IRF7 gene (see, e.g., 605047.0004 and 605047.0005). The mutations, which were found by whole-exome or whole-genome sequencing, segregated with the disorder in kindreds E and F; DNA from other family members of the proband in kindred D was not studied. P4 carried compound heterozygous missense variants (E28Q and A62T), whereas sibs P5 and P6 and unrelated P7 carried homozygous frameshift or nonsense mutations. Expression of the frameshift and nonsense mutations in HEK293 cells showed that they resulted in impaired IRF7 transcriptional activity as demonstrated by a lack of IFNB induction when exposed to the Sendei virus. Plasmacytoid dendritic cells (pDC) derived from these patients did not produce IFN-alpha in response to TLR7 (300365) or TLR9 (605474) agonists, consistent with a loss of IRF7 function. The patients had severe infections with respiratory viruses, including influenza A, SARS-CoV-2, and RSV, all of which are single-stranded RNA viruses. Of note, P6 also had an episode of acute encephalitis after a tick bite due to the TBE ('tick-borne encephalitis') virus, a flavivirus that is also a single-stranded RNA virus, despite his being vaccinated prior to symptom onset.

Honda et al. (2005) generated mice deficient in Irf7 by targeted disruption. Using Irf7-null mice, they showed that the transcription factor IRF7 is essential for the induction of IFN-alpha (see 147660)/beta (see 147640) genes via the virus-activated, MYD88 (602170)-independent pathway and the toll-like receptor (TLR)-activated, MYD88-dependent pathway. Viral induction of Myd88-independent Ifn-alpha/beta genes is severely impaired in Irf7-null fibroblasts. Irf7-null mice were consistently more vulnerable than Myd88-null mice to viral infection, and this correlated with marked decrease in serum interferon levels, indicating the importance of the IRF7-dependent induction of systemic interferon responses for innate antiviral immunity. Furthermore, robust induction of interferon production by activation of the Tlr9 (605474) subfamily in plasmacytoid dendritic cells was entirely dependent on Irf7, and this Myd88-Irf7 pathway governed the induction of CD8(+) T-cell responses. Honda et al. (2005) concluded that all elements of interferon responses, whether the systemic production of interferon in innate immunity or the local action of interferon from plasmacytoid dendritic cells in adaptive immunity, are controlled by IRF7.