The innate immune system is the first line of defense against pathogens. Innate immune cells lack the exquisite specificity of the adaptive immune system, yet in order to respond in a measured way, they must be able to tailor their activity to the specific pathogen. These cells have therefore evolved pattern recognition receptors (PRRs) that recognize conserved molecules characteristic of the microbe, which are not found within the host. The Toll-like receptors (TLRs) are the archetypal PRRs. The innate immune response to viruses occurs principally by inducing type I interferons (IFN). It has recently been appreciated that IFN also functions in the response to bacteria, although its role here is poorly defined. We have shown that 25-HC, an oxysterol which is derived enzymatically from cholesterol by Ch25h, has a role in regulating the inflammatory response and immunity. Ch25h is strongly induced by both TLR2-activation and by IFN, and we have further demonstrated that 25-HC reciprocally impacts both of these pathways: It amplifies and sustains a subset of the TLR-induced inflammatory genes while simultaneously suppressing expression of a subset of interferon- stimulated genes. Therefore, Ch25h is an immune modulator situated at the intersection of these two major pathways, the precise regulation of which is crucial to controlling viral and bacterial infections such as Listeria monocytogenes and Mycobacterium tuberculosis. We propose to identify the molecular mechanisms by which 25-HC impacts TLR and IFN responses and determine the role of these interactions in control of bacterial infections. We will first define the mechanism by which 25-HC amplifies TLR2 signaling in macrophages by examining the mechanism by which 25-HC suppresses IL-10 production and determining the role of 25-HC- mediated epigenetic regulation in altering expression of TLR2 induced genes. Next we will determine the mechanisms by which 25-HC regulates crosstalk between interferon and inflammatory signaling. Here we shall determine the mechanism by which 25-HC mediates the suppression of IFN-stimulated genes. We shall then determine the role of 25-HC in cross-regulation between innate immune pathways. Finally, we will determine the role of 25-HC in macrophage control of Listeria monocytogenes in vitro and in vivo.
The molecules being investigated in this proposal have a pivotal role in regulating the human immune response. They instruct the body to effectively combat infectious disease, and an understanding of their function will permit us to make better vaccines and drugs.
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