IFN-beta in antibacterial immunity

Type I interferons (IFN) are cytokines best known for their vital importance in innate immune responses to virus. We have recently shown that one of these, IFN-beta, is produced during infection of macrophages with the intracellular bacterium Listeria monocytogenes. We found that the cytokine is needed as a signaling intermediate for the synthesis of antibacterial gene products. Moreover, IFN-beta increases the sensitivity of macrophages to cell death induced by intracellular L.monocytogenes. Death induction and the sensitizing activity of IFN-beta do not require the expression of toll-like receptors on the macrophage surface. Here we propose to further investigate the significance of IFN-beta synthesis for the innate immune response to L. monocytogenes. We will investigate the clearance of L. monocytogenes infection from organs of mice deficient for the IFN-beta gene and examine the occurrence of cell death in infected mouse livers. We will thus determine the contribution of IFN-beta`s death-sensitizing activity to the decrease in innate immunity to the intracellular pathogen. Using mice with a disrupted type I IFN receptor (IFNAR1) gene in either macrophages or hepatocytes we will study the importance of these cell types` interferon response to the increase in the sensitivity of mice to L. monocytogenes infection. A second goal is to identify the genes and their products that are involved in L. monocytogenes-induced macrophage death. Macrophages will be isolated from several mouse strains, each deficient for a particular candidate `death` gene. These include Fas and FasL, TNF receptor I, and the apoptosis-inducing factor (AIF). In addition to this candidate gene approach we will carry out biochemical studies testing an involvement of caspases or other mediators of apoptotic and /or necrotic cell death. Finally, gene induction stimulated by L. monocytogenes in infected macrophages will be examined. Our studies will address the role of interferon regulatory factors (IRF) and signal transducers and activators of transcription (STAT) in inducing the expression of a group of interferon-stimulated genes (ISGs). Furthermore, we will investigate the cooperative activity of bacteria-derived signals and IFN-beta in causing the expression of the gene encoding inducible nitric oxide synthase (iNOS). We will assess the changes occurring in iNOS promoter chromatin and their dependence on the binding of Stat, IRF and NFkB transcription factors.

Type I interferons (IFN) are cytokines best known for their vital importance in innate immune responses to virus. We have recently shown that one of these, IFN-beta, is produced during infection of macrophages with the intracellular bacterium Listeria monocytogenes. We found that the cytokine is needed as a signaling intermediate for the synthesis of antibacterial gene products. Moreover, IFN-beta increases the sensitivity of macrophages to cell death induced by intracellular L.monocytogenes. Death induction and the sensitizing activity of IFN-beta do not require the expression of toll-like receptors on the macrophage surface. Here we propose to further investigate the significance of IFN-beta synthesis for the innate immune response to L. monocytogenes. We will investigate the clearance of L. monocytogenes infection from organs of mice deficient for the IFN-beta gene and examine the occurrence of cell death in infected mouse livers. We will thus determine the contribution of IFN-beta`s death-sensitizing activity to the decrease in innate immunity to the intracellular pathogen. Using mice with a disrupted type I IFN receptor (IFNAR1) gene in either macrophages or hepatocytes we will study the importance of these cell types` interferon response to the increase in the sensitivity of mice to L. monocytogenes infection. A second goal is to identify the genes and their products that are involved in L. monocytogenes-induced macrophage death. Macrophages will be isolated from several mouse strains, each deficient for a particular candidate `death` gene. These include Fas and FasL, TNF receptor I, and the apoptosis-inducing factor (AIF). In addition to this candidate gene approach we will carry out biochemical studies testing an involvement of caspases or other mediators of apoptotic and /or necrotic cell death. Finally, gene induction stimulated by L. monocytogenes in infected macrophages will be examined. Our studies will address the role of interferon regulatory factors (IRF) and signal transducers and activators of transcription (STAT) in inducing the expression of a group of interferon-stimulated genes (ISGs). Furthermore, we will investigate the cooperative activity of bacteria-derived signals and IFN-beta in causing the expression of the gene encoding inducible nitric oxide synthase (iNOS). We will assess the changes occurring in iNOS promoter chromatin and their dependence on the binding of Stat, IRF and NFkB transcription factors.