Abstract
Type I interferons (IFN-I) broadly control innate immunity and are typically transcriptionally induced by Interferon Regulatory Factors (IRFs) following stimulation of pattern recognition receptors within the cytosol of host cells. For bacterial infection, IFN-I signaling can result in widely variant responses, in some cases contributing to the pathogenesis of disease while in others contributing to host defense. In this work, we addressed the role of type I IFN during Yersinia pestis infection in a murine model of septicemic plague. Transcription of IFN-β was induced in vitro and in vivo and contributed to pathogenesis. Mice lacking the IFN-I receptor, Ifnar, were less sensitive to disease and harbored more neutrophils in the later stage of infection which correlated with protection from lethality. In contrast, IRF-3, a transcription factor commonly involved in inducing IFN-β following bacterial infection, was not necessary for IFN production but instead contributed to host defense. In vitro, phagocytosis of Y. pestis by macrophages and neutrophils was more effective in the presence of IRF-3 and was not affected by IFN-β signaling. This activity correlated with limited bacterial growth in vivo in the presence of IRF-3. Together the data demonstrate that IRF-3 is able to activate pathways of innate immunity against bacterial infection that extend beyond regulation of IFN-β production.
Highlights
Type I interferons (IFN-I) are expressed by macrophages and epithelial cells as part of the first line of defense against infection, and the IFN-I receptor (IFNAR) is expressed by most cells [1]
We show that the respiratory pathogen, Yersinia pestis, the causative agent of plague, activates Interferon Regulatory Factors (IRFs)-3 and the IFN-I response and that these two events cause opposite outcomes in the host
While Interferon Regulatory Factor-3 (IRF-3) is necessary for an early stage of phagocytosis, IFN-ab receptor (IFNAR) signaling promotes the infection and may directly contribute to neutrophil depletion during infection
Summary
Type I interferons (IFN-I) are expressed by macrophages and epithelial cells as part of the first line of defense against infection, and the IFN-I receptor (IFNAR) is expressed by most cells [1]. IFN-I signaling following bacterial infection leads to the production of pro-inflammatory cytokines and chemokines and promotes apoptosis of infected cells [2]. IRF-3P is found in the nucleus where it forms a complex with p300 which can act as a potent transcription factor, binding to interferon stimulated response elements (ISREs) on target genes, including Ifnb [6,7]. Secreted IFN-b binds IFNAR and signaling through STAT-1 and STAT-2 (signal transducers and activators of transcription) induces transcription of hundreds of ISRE-containing genes including many pro-inflammatory cytokines and chemokines. Further amplification of IFN-b expression occurs through an autocrine loop that requires IFNAR, IRF-3 and a second transcription factor IRF-7 and all three proteins play key roles in the expression of IFN-I [8]
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