Life-threatening viral disease in a novel form of autosomal recessive IFNAR2 deficiency in the Arctic

Abstract

Type I interferons (IFN-I) play a critical role in human antiviral immunity, as demonstrated by the exceptionally rare deleterious variants of IFNAR1 or IFNAR2. We investigated five children from Greenland, Canada, and Alaska presenting with viral diseases, including life-threatening COVID-19 or influenza, in addition to meningoencephalitis and/or hemophagocytic lymphohistiocytosis following live-attenuated viral vaccination. The affected individuals bore the same homozygous IFNAR2 c.157T>C, p.Ser53Pro missense variant. Although absent from reference databases, p.Ser53Pro occurred with a minor allele frequency of 0.034 in their Inuit ancestry. The serine to proline substitution prevented cell surface expression of IFNAR2 protein, small amounts of which persisted intracellularly in an aberrantly glycosylated state. Cells exclusively expressing the p.Ser53Pro variant lacked responses to recombinant IFN-I and displayed heightened vulnerability to multiple viruses in vitro—a phenotype rescued by wild-type IFNAR2 complementation. This novel form of autosomal recessive IFNAR2 deficiency reinforces the essential role of IFN-I in viral immunity. Further studies are warranted to assess the need for population screening.

Respiratory viral infections in otherwise healthy humans with inherited IRF7 deficiency

“…The intact type III IFN activity in IFNAR1-deficient patients with critical COVID-19 pneumonia suggests that the poor induction of type I IFN impairs host defense against SARS-CoV-2 in the respiratory tract of IRF7-deficient patients ( Zhang et al, 2020 ). By contrast, critical influenza has been reported in only two of the 25 patients with IFNAR1 or IFNAR2 deficiency, suggesting that type III IFN may help to protect against influenza in most cases, accounting for the occurrence of critical influenza in IRF7-deficient patients, who have impaired production of both type I and III IFNs ( Abolhassani et al, 2022 ; Bastard et al, 2022 ; Bastard et al, 2021 ; Duncan et al, 2015 ; Duncan et al, 2022 ; Gothe et al, 2020 ; Hernandez et al, 2019 ; Zhang et al, 2020 ).…”

“…It is also surprising that IRF7-deficient patients are not prone to other viral infections repeatedly seen in many of the 25 patients with IFNAR1 or IFNAR2 deficiency reported to date, such as disseminated disease following MMR or YFV-17D vaccination and HSV-1 encephalitis ( Abolhassani et al, 2022 ; Bastard et al, 2022 ; Bastard et al, 2021 ; Duncan et al, 2015 ; Duncan et al, 2022 ; Gothe et al, 2020 ; Hernandez et al, 2019 ). These viral susceptibilities, and predisposition to severe disease from additional human herpesviruses, are also common to patients with other core deficiencies of the type I IFN response, such as STAT1, STAT2, and IRF9 deficiencies ( Duncan et al, 2021 ; Meyts and Casanova, 2021 ).…”

“…Ifnar1 or Ifnar2 knockout mice that lack the type I IFN receptor are susceptible to many experimental infections, but an unexpected pattern is emerging in humans, with the corresponding deficits seeming to confer vulnerability to a narrower range of viruses ( Duncan et al, 2021 ; Meyts and Casanova, 2021 ). Autosomal recessive (AR) IFNAR1 and IFNAR2 deficiencies have been reported in 16 and 9 patients, respectively ( Abolhassani et al, 2022 ; Bastard et al, 2022 ; Bastard et al, 2021 ; Duncan et al, 2015 ; Duncan et al, 2022 ; Gothe et al, 2020 ; Hernandez et al, 2019 ; Zhang et al, 2020 ). Patients with inherited STAT2 or IRF9 deficiency lack ISG factor 3 (ISGF-3)—a transcription factor complex consisting of STAT1, STAT2, and IRF9 that normally induces ISG expression in response to type I and type III IFNs—but these patients have a similarly narrower range of viral susceptibility ( Alosaimi et al, 2019 ; Hambleton et al, 2013 ; Hernandez et al, 2018 ; Moens et al, 2017 ).…”

“…Patients with an apparent complete absence of type I IFN immunity (IFNAR1, IFNAR2) or of ISGF-3 (STAT2, IRF9) are prone to adverse reactions to live attenuated viral vaccines, such as yellow fever virus 17D (YFV-17D) and the measles, mumps, and rubella virus (MMR) vaccine, and are also susceptible to HSV-1, encephalitis, and critical influenza or COVID-19 pneumonia ( Abolhassani et al, 2022 ; Alosaimi et al, 2019 ; Bastard et al, 2021 ; Bastard et al, 2022 ; Duncan et al, 2015 ; Duncan et al, 2022 ; Hambleton et al, 2013 ; Hernandez et al, 2019 ; Hernandez et al, 2018 ; Moens et al, 2017 ; Zhang et al, 2020 ). The clinical penetrance of such infections in patients with type I IFN deficiencies remains unclear.…”

Recessive inborn errors of type I IFN immunity in children with COVID-19 pneumonia

“…These disorders (or, by inference from their milder, dominant form, for autosomal disorders, underlined) are associated with severe viral diseases, including influenza pneumonia ( TLR3 , IRF7, IRF9, STAT1, STAT2; Alosaimi et al, 2019 ; Ciancanelli et al, 2015 ; Hernandez et al, 2018 ; Le Voyer et al, 2021 ), COVID-19 pneumonia ( TLR3 , UNC93B1 , TBK1 , TRIF , IRF3 , IRF7, IFNAR1, IFNAR2 , TLR7; Abolhassani et al, 2022 ; Asano et al, 2021 ; Schmidt et al, 2021 ; Solanich et al, 2021 ; van der Made et al, 2020 ; Zhang et al, 2020b ), rhinovirus or respiratory syncytial virus pneumonia (MDA5, encoded by IFIH1 ; Asgari et al, 2017 ; Lamborn et al, 2017 ), herpes simplex virus encephalitis (IFNAR1, STAT1, TLR3, TRIF, TYK2, UNC93B1; Bastard et al, 2021c ; Casrouge et al, 2006 ; Dupuis et al, 2003 ; Guo et al, 2011 ; Kreins et al, 2015 ; Minegishi et al, 2006 ; Sancho-Shimizu et al, 2011 ), adverse reactions to measles, mumps, and rubella (MMR) or yellow fever virus (YFV) vaccines (IFNAR1, IFNAR2, STAT1, STAT2; Bastard et al, 2022 ; Burns et al, 2016 ; Duncan et al, 2015 ; Duncan et al, 2022 ; Hambleton et al, 2013 ; Hernandez et al, 2019 ; Moens et al, 2017 ), enterovirus encephalitis ( TLR3 , MDA5; Chen et al, 2021 ), EBV viremia (MYD88; Chiriaco et al, 2019 ), and human herpesvirus-6 (HHV6) infection (IRAK4; Nishimura et al, 2021 ). Over the last two decades, 105 children with these disorders have been reported, and many more were probably diagnosed.…”