Respiratory viral infections in otherwise healthy humans with inherited IRF7 deficiency

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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.
Funding Information
  • Swedish Research Council
  • Göran Gustafsson Foundation
  • Karolinska Institute
  • Center for Innovative Medicine
  • Stockholm County Council
  • Swedish Society for Medical Research
  • Howard Hughes Medical Institute
  • Rockefeller University
  • St. Giles Foundation
  • National Institutes of Health (R01AI088364, R01AI63029)
  • National Center for Advancing Translational Sciences
  • National Institutes of Health (UL1 TR001866)
  • Fast Grant from Emergent Ventures
  • Mercatus Center at George Mason University
  • National Human Genome Research Institute (UM1HG006504, U24HG008956)
  • Fisher Center for Alzheimer’s Research Foundation
  • JPB Foundation
  • Meyer Foundation
  • French National Research Agency (ANR-10-IAHU-01)
  • Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID)
  • Foundation for Medical Research (EQU201903007798)
  • ANR GenMISC (ANR-21-COVR-039)
  • ANRS-COV05 (ANR-20-CE93-003)
  • ANR GENVIR (ANR-20-CE93-003)
  • ANR AABIFNCOV (ANR-20-CO11-0001)
  • European Union’s Horizon 2020 Research and Innovation Program (824110)
  • Square Foundation
  • SCOR Corporate Foundation for Science
  • French Ministry of Higher Education
  • Institut National de la Santé et de la Recherche Médicale
  • University of Paris
  • Imagine Institute
  • CSL Behring
  • KU Leuven (C16/18/007)
  • Vlaams Instituut voor Biotechnologie
  • Research Foundation - Flanders (G0C8517N, G0B5120N, G0E8420N)
  • Jeffrey Modell Foundation
  • Fonds Erasme
  • National Institute of Allergy and Infectious Diseases
  • Grandir – Fonds de Solidarité pour l’Enfance
  • Fondation du Souffle
  • ERN-RITA

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