Targeted Disruption of the Mouse Stat1 Gene Results in Compromised Innate Immunity to Viral Disease

TLDR

The STAT1 transcription factor is activated by many cytokines and growth factors. The authors disrupted the Stat1 gene in embryonic stem cells and mice to investigate STAT1’s in vivo role. Stat1−/− ES cells were unresponsive to interferon but retained LIF responsiveness; Stat1−/− mice were born normally yet failed to thrive, were highly susceptible to viral disease, and remained responsive to other cytokines, indicating STAT1’s essential role in IFN‑mediated antiviral immunity.

Abstract

The STAT1 transcription factor is activated in response to many cytokines and growth factors. To study the requirement for STAT1 in vivo, we disrupted the Stat1 gene in embryonic stem (ES) cells and in mice. Stat1−/− ES cells were unresponsive to interferon (IFN), but retained responsiveness to leukemia inhibitory factor (LIF) and remained LIF dependent for undifferentiated growth. Stat1−/− animals were born at normal frequencies and displayed no gross developmental defects. However, these animals failed to thrive and were extremely susceptible to viral disease. Cells and tissues from Stat1−/− mice were unresponsive to IFN, but remained responsive to all other cytokines tested. Thus, STAT1 appears to be specific for IFN pathways that are essential for viability in the face of otherwise innocuous pathogens.