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

2019 ◽  
Vol 216 (9) ◽  
pp. 2057-2070 ◽  
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.

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

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.

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

Science ◽  
2020 ◽  
Vol 370 (6515) ◽  
pp. eabd4570 ◽  
Author(s):  
Qian Zhang ◽  
Paul Bastard ◽  
Zhiyong Liu ◽  
Jérémie Le Pen ◽  
Marcela Moncada-Velez ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Rare Variants ◽  
Human Fibroblasts ◽  
Severe Infection ◽  
Type I ◽  
Type I Ifn ◽  
Loss Of Function ◽  
Inborn Errors ◽  
Life Threatening ◽  
Dependent Type

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.

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

2018 ◽  
Vol 215 (10) ◽  
pp. 2567-2585 ◽  
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.

scholarly journals Preexisting autoantibodies to type I IFNs underlie critical COVID-19 pneumonia in patients with APS-1

2021 ◽  
Vol 218 (7) ◽  
Author(s):  
Paul Bastard ◽  
Elizaveta Orlova ◽  
Leila Sozaeva ◽  
Romain Lévy ◽  
Alyssa James ◽  
...  
Keyword(s):  
Intensive Care Unit ◽  
Type I Interferons ◽  
Type I ◽  
Syndrome Type ◽  
Loss Of Function ◽  
Type I Ifns ◽  
Autoimmune Polyendocrine Syndrome ◽  
Life Threatening ◽  
Very High

Patients with biallelic loss-of-function variants of AIRE suffer from autoimmune polyendocrine syndrome type-1 (APS-1) and produce a broad range of autoantibodies (auto-Abs), including circulating auto-Abs neutralizing most type I interferons (IFNs). These auto-Abs were recently reported to account for at least 10% of cases of life-threatening COVID-19 pneumonia in the general population. We report 22 APS-1 patients from 21 kindreds in seven countries, aged between 8 and 48 yr and infected with SARS-CoV-2 since February 2020. The 21 patients tested had auto-Abs neutralizing IFN-α subtypes and/or IFN-ω; one had anti–IFN-β and another anti–IFN-ε, but none had anti–IFN-κ. Strikingly, 19 patients (86%) were hospitalized for COVID-19 pneumonia, including 15 (68%) admitted to an intensive care unit, 11 (50%) who required mechanical ventilation, and four (18%) who died. Ambulatory disease in three patients (14%) was possibly accounted for by prior or early specific interventions. Preexisting auto-Abs neutralizing type I IFNs in APS-1 patients confer a very high risk of life-threatening COVID-19 pneumonia at any age.

scholarly journals Severe viral respiratory infections in children with IFIH1 loss-of-function mutations

2017 ◽  
Vol 114 (31) ◽  
pp. 8342-8347 ◽  
Author(s):  
Samira Asgari ◽  
Luregn J. Schlapbach ◽  
Stéphanie Anchisi ◽  
Christian Hammer ◽  
Istvan Bartha ◽  
...  
Keyword(s):  
Respiratory Infections ◽  
In Vitro Assays ◽  
Severe Illness ◽  
Healthy Children ◽  
Loss Of Function ◽  
Life Threatening ◽  
Syncytial Virus ◽  
Viral Respiratory Infections ◽  
Viral Respiratory

Viral respiratory infections are usually mild and self-limiting; still they exceptionally result in life-threatening infections in previously healthy children. To investigate a potential genetic cause, we recruited 120 previously healthy children requiring support in intensive care because of a severe illness caused by a respiratory virus. Using exome and transcriptome sequencing, we identified and characterized three rare loss-of-function variants in IFIH1, which encodes an RIG-I-like receptor involved in the sensing of viral RNA. Functional testing of the variants IFIH1 alleles demonstrated that the resulting proteins are unable to induce IFN-β, are intrinsically less stable than wild-type IFIH1, and lack ATPase activity. In vitro assays showed that IFIH1 effectively restricts replication of human respiratory syncytial virus and rhinoviruses. We conclude that IFIH1 deficiency causes a primary immunodeficiency manifested in extreme susceptibility to common respiratory RNA viruses.

scholarly journals Negative selection on human genes underlying inborn errors depends on disease outcome and both the mode and mechanism of inheritance

2021 ◽  
Vol 118 (3) ◽  
pp. e2001248118
Author(s):  
Franck Rapaport ◽  
Bertrand Boisson ◽  
Anne Gregor ◽  
Vivien Béziat ◽  
Stéphanie Boisson-Dupuis ◽  
...  
Keyword(s):  
Negative Selection ◽  
Evolutionary Process ◽  
Integrative Approach ◽  
Loss Of Function ◽  
Inborn Errors ◽  
Complete Penetrance ◽  
Human Genes ◽  
Monogenic Diseases ◽  
Life Threatening ◽  
Better Than

Genetic variants underlying life-threatening diseases, being unlikely to be transmitted to the next generation, are gradually and selectively eliminated from the population through negative selection. We study the determinants of this evolutionary process in human genes underlying monogenic diseases by comparing various negative selection scores and an integrative approach, CoNeS, at 366 loci underlying inborn errors of immunity (IEI). We find that genes underlying autosomal dominant (AD) or X-linked IEI have stronger negative selection scores than those underlying autosomal recessive (AR) IEI, whose scores are not different from those of genes not known to be disease causing. Nevertheless, genes underlying AR IEI that are lethal before reproductive maturity with complete penetrance have stronger negative selection scores than other genes underlying AR IEI. We also show that genes underlying AD IEI by loss of function have stronger negative selection scores than genes underlying AD IEI by gain of function, while genes underlying AD IEI by haploinsufficiency are under stronger negative selection than other genes underlying AD IEI. These results are replicated in 1,140 genes underlying inborn errors of neurodevelopment. Finally, we propose a supervised classifier, SCoNeS, which predicts better than state-of-the-art approaches whether a gene is more likely to underlie an AD or AR disease. The clinical outcomes of monogenic inborn errors, together with their mode and mechanisms of inheritance, determine the levels of negative selection at their corresponding loci. Integrating scores of negative selection may facilitate the prioritization of candidate genes and variants in patients suspected to carry an inborn error.

scholarly journals Auto-antibodies to type I IFNs can underlie adverse reactions to yellow fever live attenuated vaccine

2021 ◽  
Vol 218 (4) ◽  
Author(s):  
Paul Bastard ◽  
Eleftherios Michailidis ◽  
Hans-Heinrich Hoffmann ◽  
Marwa Chbihi ◽  
Tom Le Voyer ◽  
...  
Keyword(s):  
Yellow Fever ◽  
Yellow Fever Virus ◽  
Previous History ◽  
Type I ◽  
Live Attenuated Vaccine ◽  
Attenuated Vaccine ◽  
Type I Ifns ◽  
Individual Type ◽  
Life Threatening

Yellow fever virus (YFV) live attenuated vaccine can, in rare cases, cause life-threatening disease, typically in patients with no previous history of severe viral illness. Autosomal recessive (AR) complete IFNAR1 deficiency was reported in one 12-yr-old patient. Here, we studied seven other previously healthy patients aged 13 to 80 yr with unexplained life-threatening YFV vaccine–associated disease. One 13-yr-old patient had AR complete IFNAR2 deficiency. Three other patients vaccinated at the ages of 47, 57, and 64 yr had high titers of circulating auto-Abs against at least 14 of the 17 individual type I IFNs. These antibodies were recently shown to underlie at least 10% of cases of life-threatening COVID-19 pneumonia. The auto-Abs were neutralizing in vitro, blocking the protective effect of IFN-α2 against YFV vaccine strains. AR IFNAR1 or IFNAR2 deficiency and neutralizing auto-Abs against type I IFNs thus accounted for more than half the cases of life-threatening YFV vaccine-associated disease studied here. Previously healthy subjects could be tested for both predispositions before anti-YFV vaccination.

scholarly journals Autoantibodies against type I IFNs in patients with life-threatening COVID-19

Science ◽  
2020 ◽  
Vol 370 (6515) ◽  
pp. eabd4585 ◽  
Author(s):  
Paul Bastard ◽  
Lindsey B. Rosen ◽  
Qian Zhang ◽  
Eleftherios Michailidis ◽  
Hans-Heinrich Hoffmann ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
B Cell ◽  
Immunoglobulin G ◽  
The Other ◽  
Type I ◽  
Healthy Individuals ◽  
Inborn Errors ◽  
Type I Ifns ◽  
Life Threatening

Interindividual clinical variability in the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is vast. We report that at least 101 of 987 patients with life-threatening coronavirus disease 2019 (COVID-19) pneumonia had neutralizing immunoglobulin G (IgG) autoantibodies (auto-Abs) against interferon-ω (IFN-ω) (13 patients), against the 13 types of IFN-α (36), or against both (52) at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs. The auto-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. These auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were present in only 4 of 1227 healthy individuals. Patients with auto-Abs were aged 25 to 87 years and 95 of the 101 were men. A B cell autoimmune phenocopy of inborn errors of type I IFN immunity accounts for life-threatening COVID-19 pneumonia in at least 2.6% of women and 12.5% of men.

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