Inborn errors of type I IFN immunity in patients with life-threatening COVID-19

Clinical outcome upon infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ranges from silent infection to lethal coronavirus disease 2019 (COVID-19). We have found an enrichment in rare variants predicted to be loss-of-function (LOF) at the 13 human loci known to govern Toll-like receptor 3 (TLR3)– and interferon regulatory factor 7 (IRF7)–dependent type I interferon (IFN) immunity to influenza virus in 659 patients with life-threatening COVID-19 pneumonia relative to 534 subjects with asymptomatic or benign infection. By testing these and other rare variants at these 13 loci, we experimentally defined LOF variants underlying autosomal-recessive or autosomal-dominant deficiencies in 23 patients (3.5%) 17 to 77 years of age. We show that human fibroblasts with mutations affecting this circuit are vulnerable to SARS-CoV-2. Inborn errors of TLR3- and IRF7-dependent type I IFN immunity can underlie life-threatening COVID-19 pneumonia in patients with no prior severe infection.

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Inborn errors of TLR3- or MDA5-dependent type I IFN immunity in children with enterovirus rhombencephalitis

Journal of Experimental Medicine ◽

10.1084/jem.20211349 ◽

2021 ◽

Vol 218 (12) ◽

Author(s):

Jie Chen ◽

Huie Jing ◽

Andrea Martin-Nalda ◽

Paul Bastard ◽

Jacques G. Rivière ◽

...

Keyword(s):

Poly I:C ◽

Compound Heterozygous ◽

Late Time ◽

Type I ◽

Type I Ifn ◽

Loss Of Function ◽

Inborn Errors ◽

Viral Susceptibility ◽

Life Threatening ◽

The Central Nervous System

Enterovirus (EV) infection rarely results in life-threatening infection of the central nervous system. We report two unrelated children with EV30 and EV71 rhombencephalitis. One patient carries compound heterozygous TLR3 variants (loss-of-function F322fs2* and hypomorphic D280N), and the other is homozygous for an IFIH1 variant (loss-of-function c.1641+1G>C). Their fibroblasts respond poorly to extracellular (TLR3) or intracellular (MDA5) poly(I:C) stimulation. The baseline (TLR3) and EV-responsive (MDA5) levels of IFN-β in the patients’ fibroblasts are low. EV growth is enhanced at early and late time points of infection in TLR3- and MDA5-deficient fibroblasts, respectively. Treatment with exogenous IFN-α2b before infection renders both cell lines resistant to EV30 and EV71, whereas post-infection treatment with IFN-α2b rescues viral susceptibility fully only in MDA5-deficient fibroblasts. Finally, the poly(I:C) and viral phenotypes of fibroblasts are rescued by the expression of WT TLR3 or MDA5. Human TLR3 and MDA5 are critical for cell-intrinsic immunity to EV, via the control of baseline and virus-induced type I IFN production, respectively.

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Inherited IFNAR1 deficiency in otherwise healthy patients with adverse reaction to measles and yellow fever live vaccines

Journal of Experimental Medicine ◽

10.1084/jem.20182295 ◽

2019 ◽

Vol 216 (9) ◽

pp. 2057-2070 ◽

Cited By ~ 29

Author(s):

Nicholas Hernandez ◽

Giorgia Bucciol ◽

Leen Moens ◽

Jérémie Le Pen ◽

Mohammad Shahrooei ◽

...

Keyword(s):

Yellow Fever ◽

Measles Virus ◽

Severe Illness ◽

Compound Heterozygous ◽

Type I ◽

Loss Of Function ◽

Inborn Errors ◽

Iranian Patient ◽

Brazilian Patient ◽

Life Threatening

Vaccination against measles, mumps, and rubella (MMR) and yellow fever (YF) with live attenuated viruses can rarely cause life-threatening disease. Severe illness by MMR vaccines can be caused by inborn errors of type I and/or III interferon (IFN) immunity (mutations in IFNAR2, STAT1, or STAT2). Adverse reactions to the YF vaccine have remained unexplained. We report two otherwise healthy patients, a 9-yr-old boy in Iran with severe measles vaccine disease at 1 yr and a 14-yr-old girl in Brazil with viscerotropic disease caused by the YF vaccine at 12 yr. The Iranian patient is homozygous and the Brazilian patient compound heterozygous for loss-of-function IFNAR1 variations. Patient-derived fibroblasts are susceptible to viruses, including the YF and measles virus vaccine strains, in the absence or presence of exogenous type I IFN. The patients’ fibroblast phenotypes are rescued with WT IFNAR1. Autosomal recessive, complete IFNAR1 deficiency can result in life-threatening complications of vaccination with live attenuated measles and YF viruses in previously healthy individuals.

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

Journal of Experimental Medicine ◽

10.1084/jem.20180628 ◽

2018 ◽

Vol 215 (10) ◽

pp. 2567-2585 ◽

Cited By ~ 54

Author(s):

Nicholas Hernandez ◽

Isabelle Melki ◽

Huie Jing ◽

Tanwir Habib ◽

Susie S.Y. Huang ◽

...

Keyword(s):

Influenza A ◽

Respiratory Viruses ◽

Type I ◽

Loss Of Function ◽

Inborn Errors ◽

Life Threatening ◽

Gene Transcripts ◽

Syncytial Virus

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 IRF9 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.

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Faculty Opinions recommendation of Inborn errors of type I IFN immunity in patients with life-threatening COVID-19.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.738725362.793578991 ◽

2020 ◽

Author(s):

Elizabeth Hartland

Keyword(s):

Type I ◽

Type I Ifn ◽

Inborn Errors ◽

Life Threatening

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Faculty Opinions recommendation of Inborn errors of type I IFN immunity in patients with life-threatening COVID-19.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.738725362.793586118 ◽

2021 ◽

Author(s):

Brian Eley

Keyword(s):

Type I ◽

Type I Ifn ◽

Inborn Errors ◽

Life Threatening

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Failure to replicate the association of rare loss-of-function variants in type I IFN immunity genes with severe COVID-19

10.1101/2020.12.18.20248226 ◽

2020 ◽

Author(s):

Gundula Povysil ◽

Guillaume Butler-Laporte ◽

Ning Shang ◽

Chen Weng ◽

Atlas Khan ◽

...

Keyword(s):

Candidate Genes ◽

Type I ◽

Whole Genome ◽

Type I Ifn ◽

Loss Of Function ◽

Mild Disease ◽

Whole Exome ◽

Immunity Genes ◽

Population Controls ◽

Dependent Type

AbstractA recent report found that rare predicted loss-of-function (pLOF) variants across 13 candidate genes in TLR3- and IRF7-dependent type I IFN pathways explain up to 3.5% of severe COVID-19 cases. We performed whole-exome or whole-genome sequencing of 1,934 COVID-19 cases (713 with severe and 1,221 with mild disease) and 15,251 ancestry-matched population controls across four independent COVID-19 biobanks. We then tested if rare pLOF variants in these 13 genes were associated with severe COVID-19. We identified only one rare pLOF mutation across these genes amongst 713 cases with severe COVID-19 and observed no enrichment of pLOFs in severe cases compared to population controls or mild COVID-19 cases. We find no evidence of association of rare loss-of-function variants in the proposed 13 candidate genes with severe COVID-19 outcomes.

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