Inducible, dose-adjustable and time-restricted reconstitution of STAT1 deficiency in vivo

PLoS One. 2014 Jan 29;9(1):e86608. doi: 10.1371/journal.pone.0086608. eCollection 2014.

Abstract

Signal transducer and activator of transcription (STAT) 1 is a key player in interferon (IFN) signaling, essential in mediating host defense against viruses and other pathogens. STAT1 levels are tightly regulated and loss- or gain-of-function mutations in mice and men lead to severe diseases. We have generated a doxycycline (dox) -inducible, FLAG-tagged Stat1 expression system in mice lacking endogenous STAT1 (i.e. Stat1(ind) mice). We show that STAT1 expression depends on the time and dose of dox treatment in primary cells and a variety of organs isolated from Stat1(ind) mice. In bone marrow-derived macrophages, a fraction of the amount of STAT1 present in WT cells is sufficient for full expression of IFN-induced genes. Dox-induced STAT1 established protection against virus infections in primary cells and mice. The availability of the Stat1(ind) mouse model will enable an examination of the consequences of variable amounts of STAT1. The model will also permit the study of STAT1 dose-dependent and reversible functions as well as of STAT1's contributions to the development, progression and resolution of disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Marrow Cells / immunology
  • Bone Marrow Cells / virology
  • Cardiovirus Infections / genetics*
  • Cardiovirus Infections / immunology
  • Cardiovirus Infections / virology
  • Doxycycline / pharmacology*
  • Encephalomyocarditis virus / immunology
  • Founder Effect
  • Gene Expression Regulation / drug effects*
  • Gene Expression Regulation / immunology
  • Genetic Engineering
  • Interferons / genetics
  • Interferons / immunology
  • Macrophages / immunology
  • Macrophages / virology
  • Male
  • Mice
  • Mice, Transgenic
  • Primary Cell Culture
  • STAT1 Transcription Factor / deficiency*
  • STAT1 Transcription Factor / genetics
  • STAT1 Transcription Factor / immunology
  • Signal Transduction
  • Time Factors
  • Vesicular Stomatitis / genetics*
  • Vesicular Stomatitis / immunology
  • Vesicular Stomatitis / virology
  • Vesicular stomatitis Indiana virus / immunology

Substances

  • STAT1 Transcription Factor
  • Stat1 protein, mouse
  • Interferons
  • Doxycycline

Grants and funding

This work was supported by the Austrian Science Fund SFB-F28 “JAK-STAT” and the Austrian Genome Research Programme GEN-AU II and III “Austromouse.” The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.