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

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(-1-)ES cells were unresponsive to interferon (IFN), but retained responsiveness to leukemia inhibitory factor (LIF) and remained LIF dependent for undifferentiated growth. Stat1(-1-1) 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(-1-) 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.

Local activation of STAT‐1 and STAT‐3 in the inflamed synovium during zymosan‐induced arthritis: Exacerbation of joint inflammation in STAT‐1 gene–knockout mice

“…STAT-1 expression and activation were restricted to the chronic phase of ZIA (days [14][15][16][17][18][19][20][21]. In IL-6 Ϫ/Ϫ mice, continuous STAT-3 activation was not observed even though these animals exhibited the expected acute inflammation.…”

“…The animals were studied at the age of 8-10 weeks. STAT-1 ؊/؊ mice were originally developed by Dr. D. Levy (New York, NY) (16). Breeding pairs of STAT-1 ؊/؊ mice and their WT controls were kept at the Institute for Agrobiotechnology.…”

Divergent roles of STAT1 and STAT5 in malignancy as revealed by gene disruptions in mice

“…Stat1-mutant mice were created that expressed either a truncated and crippled Stat1 protein that displayed no activity (Meraz et al, 1996) or that expressed no detectable Stat1 protein (Durbin et al, 1996). Results obtained with theses two mutant strains thus far have been entirely consistent, with the major defect associated with the null phenotype being unresponsiveness to both type I and type II IFN.…”

Fish virus-induced interferon exerts antiviral function through Stat1 pathway

“…The key role of Stat1 in IFN signaling cascade was further delineated by two reports in which Stat1 null mice exhibit a complete lack of responsiveness to either type I IFN or type II IFN and are highly sensitive to infection by microbial pathogens and viruses (Durbin et al, 1996;Meraz et al, 1996). Stat1␤, a natural splice variant that lacks 38 C-terminal amino acids of Stat1(␣), is sufficient for full function of type I IFN signaling (Shuai et al, 1993;Wen et al, 1995).…”