Excessive negative regulation of type I interferon disrupts viral control in individuals with Down syndrome

Louise Malle, Marta Martin-Fernandez, Sofija Buta, Ashley Richardson, Douglas Bush, Dusan Bogunovic

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Down syndrome (DS) is typically caused by triplication of chromosome 21. Phenotypically, DS presents with developmental, neurocognitive, and immune features. Epidemiologically, individuals with DS have less frequent viral infection, but when present, these infections lead to more severe disease. The potent antiviral cytokine type I Interferon (IFN-I) receptor subunits IFNAR1 and IFNAR2 are located on chromosome 21. While increased IFNAR1/2 expression initially caused hypersensitivity to IFN-I, it triggered excessive negative feedback. This led to a hypo-response to subsequent IFN-I stimuli and an ensuing viral susceptibility in DS compared to control cells. Upregulation of IFNAR2 expression phenocopied the DS IFN-I dynamics independent of trisomy 21. CD14+ monocytes from individuals with DS exhibited markers of prior IFN-I exposure and had muted responsiveness to ex vivo IFN-I stimulation. Our findings unveil oscillations of hyper- and hypo-response to IFN-I in DS, predisposing individuals to both lower incidence of viral disease and increased infection-related morbidity and mortality.

Original languageEnglish
Pages (from-to)2074-2084.e5
JournalImmunity
Volume55
Issue number11
DOIs
StatePublished - 8 Nov 2022

Keywords

  • Down syndrome
  • IFN-I
  • USP
  • antiviral defense
  • negative feedback
  • trisomy 21
  • type I interferon
  • viral susceptibility

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