Non-canonical responses to IFNab in the suppression of macrophage immunity

IFNab 抑制巨噬细胞免疫的非典型反应

基本信息

批准号：
8882969
负责人：
Laurel L Lenz
金额：
$ 16.62万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8882969
关键词：
Acute Anti-Inflammatory Agents Anti-inflammatory Antigens Antiviral Agents Applications Grants Autoimmune Diseases Autoimmune Process Bacteria Bacterial Infections Binding Bone Marrow Cell Surface Receptors Cell physiology Cell surface Cells Chronic Complex Data Development Down-Regulation Francisella tularensis Gene Expression Profile Genes Genetic Transcription Genome Host resistance Human IFNAR1 gene IFNGR1 gene Immune Immune response Immunity Incidence Infection Infectious Agent Inflammatory Inflammatory Response Interferon Type I Interferons Intestines Knockout Mice Lead Life Listeria monocytogenes Malignant Neoplasms Maps Mediating Meningitis Microbe Multiple Sclerosis Mus Mycobacterium tuberculosis Myelogenous Myeloid Cell Activation Myeloid Cells Pathway interactions Patients Phosphotransferases Predisposition Process Production Protein Binding Proteins Receptor Down-Regulation Regimen Resistance Rest Role STAT protein STAT1 gene Safety Sepsis Signal Pathway Signal Transduction Somatic Cell Stimulus Testing Transcription Repressor/Corepressor Viral Virulence Virus Virus Diseases Work bacterial resistance bactericide clinical efficacy cytokine immune resistance improved in vivo inhibitor/antagonist insight macrophage microbial microbicide mouse model novel pathogenic bacteria promoter research study response tool

项目摘要

Project Summary: Macrophages and other myeloid cells are key players in the innate immune response to infection. Myeloid cell development, recruitment, activation, and microbicidal activity are regulated by type I and II interferons (IFN�� and IFN�). IFN�� and IFN� are concurrently produced during microbial infections but have different - and in some cases opposing - effects on myeloid cell function. IFN� activates microbicidal activity of macrophages and typically reduces host susceptibility to intracellular microbes. Conversely, IFN�� suppresses myeloid cell activation by IFN� and increases host susceptibility to certain bacteria. The mechanisms by which IFN�� suppresses myeloid cell activation remain incompletely understood. Our prior studies showed that IFN�� triggers down regulation of the receptor for IFN�, IFNGR1, specifically in myeloid cells. This down regulation occurs at the transcriptional level and is independent of STAT proteins important for other, "canonical," responses to type I IFNs. We have begun to investigate the mechanisms for ifngr1 down regulation and have identified inhibitors of this process and obtained evidence that two specific host proteins not previously associated with type I IFN responses are important for IFNGR down regulation. In this exploratory R21 grant application we propose experiments to further dissect how these proteins intersect the type I IFN signaling pathway in macrophages and to evaluate their impact on global myeloid cell gene expression patterns in resting and IFN�-stimulated states. Information from these studies will provide insight into immune-suppressive non-canonical responses to IFN�� and their effects on host susceptibility to microbial infections.

项目概要：巨噬细胞和其他骨髓细胞是对感染的先天免疫反应的关键参与者。发育、募集、激活和杀菌活性受 I 型和 II 型干扰素 (IFN�� 和 IFN�）。 IFN�� 和 IFN� 在微生物感染过程中同时产生，但有不同 - 并且在有些情况相反 - 干扰素对骨髓细胞功能的影响会激活巨噬细胞的杀菌活性。 IFNα 会抑制骨髓细胞，通常会降低宿主对细胞内微生物的敏感性。 IFNα 的激活并增加宿主对某些细菌的敏感性。 IFNα 的机制。我们之前的研究表明 IFN�� 抑制骨髓细胞活化的作用尚不完全清楚。触发 IFNα、IFNGR1 受体的下调，特别是在骨髓细胞中。发生在转录水平，并且独立于对其他“规范”很重要的 STAT 蛋白。对 I 型 IFN 的反应我们已经开始研究 ifngr1 下调的机制并已取得进展。确定了该过程的抑制剂，并获得了两种特定宿主蛋白以前未发现的证据与 I 型 IFN 反应相关的 IFNGR 下调非常重要。我们提出实验来进一步剖析这些蛋白质如何与 I 型 IFN 信号传导相交叉巨噬细胞中的通路并评估其对全球骨髓细胞基因表达模式的影响这些研究的信息将提供对免疫抑制的深入了解。对 IFNα 的非典型反应及其对宿主对微生物感染易感性的影响。