A human gain-of-function STING mutation causes immunodeficiency and gammaherpesvirus-induced pulmonary fibrosis in mice

Brock G. Bennion, Harshad Ingle, Teresa L. Ai, Cathrine A. Miner, Derek J. Platt, Amber M. Smith, Megan T. Baldridge, Jonathan J. Miner

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

Abstract

We previously generated STING N153S knock-in mice that have a human disease-associated gain-of-function mutation in STING. Patients with this mutation (STING N154S in humans) develop STING-associated vasculopathy with onset in infancy (SAVI), a severe pediatric autoinflammatory disease characterized by pulmonary fibrosis. Since this mutation promotes the upregulation of antiviral type I interferon-stimulated genes (ISGs), we hypothesized that STING N153S knock-in mice may develop more severe autoinflammatory disease in response to a virus challenge. To test this hypothesis, we infected heterozygous STING N153S mice with murine gammaherpesvirus 68 (HV68). STING N153S mice were highly vulnerable to infection and developed pulmonary fibrosis after infection. In addition to impairing CD8 T cell responses and humoral immunity, STING N153S also promoted the replication of HV68 in cultured macrophages. In further support of a combined innate and adaptive immunodeficiency, HV68 infection was more severe in Rag1 -/- STING N153S mice than in Rag1 -/- littermate mice, which completely lack adaptive immunity. Thus, a gain-of-function STING mutation creates a combined innate and adaptive immunodeficiency that leads to virus-induced pulmonary fibrosis.

Original languageEnglish
Article numbere0180618
JournalJournal of virology
Volume93
Issue number4
DOIs
StatePublished - Feb 1 2019

Keywords

  • Adaptive immunity
  • Autoimmunity
  • Gammaherpesvirus
  • Innate immunity
  • MHV68
  • Pulmonary fibrosis
  • STING
  • Vasculopathy

Fingerprint

Dive into the research topics of 'A human gain-of-function STING mutation causes immunodeficiency and gammaherpesvirus-induced pulmonary fibrosis in mice'. Together they form a unique fingerprint.

Cite this