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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：
8646881
负责人：
Laurel L Lenz
金额：
$ 2.81万
依托单位：
NATIONAL JEWISH HEALTH
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-15 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8646881
关键词：
Acute Affect Apigenin Applications Grants Bacteria Bacterial Infections Cell Surface Receptors Cell surface Chronic Data Development Disease Down-Regulation Engineering Francisella tularensis Gene Expression Gene Targeting Genes Genetic Transcription Host resistance Human IFNAR1 gene IFNGR1 gene Immune Immune response Immunity Incidence Infection Inflammatory Interferon Type I Interferons Intestines Lead Learning Life Ligation Listeria monocytogenes Macrophage Activation Mediating Meningitis Microbe Multiple Sclerosis Mus Mycobacterium tuberculosis Myeloid Cell Activation Myeloid Cells Pathway interactions Patients Phosphotransferases Predisposition Production Protein Binding Proteins Publishing RNA Interference Resistance Resistance to infection STAT1 gene STAT2 gene Sepsis Signal Pathway Signal Transduction Somatic Cell Stimulus Streptococcus Testing Therapeutic Transgenic Mice Viral Virulence Virus bacterial resistance cell type congenic cytokine immune resistance improved in vivo inhibitor/antagonist insight killings macrophage microbial microbicide novel pathogen pathogenic bacteria prevent promoter public health relevance response

项目摘要

DESCRIPTION (provided by applicant): Macrophages and other myeloid cell types 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 effects on myeloid cells. IFN? activates macrophage microbicidal activity and typically reduces host susceptibility to intracellular microbes. Conversely, IFN¿¿ suppresses myeloid cell activation and increases host susceptibility to certain intracellular bacteria. The mechanisms by which IFN¿¿ exacerbates bacterial infections remain poorly understood. In this exploratory R21 grant application we test the hypothesis that IFN¿¿ increases susceptibility to bacterial infections due to its ability to suppress myeloid cell immunity. In the first Aim, we determine whether down regulation of myeloid cell IFNGR expression by IFN¿¿ impairs myeloid cell activation and increases host susceptibility to infection. In the second Aim, we test whether the novel non- canonical IFN¿¿ response pathway that suppresses ifngr1 gene expression also impairs expression of other genes important for myeloid cell activation and whether inhibiting this pathway increases host resistance to infection. Information from these studies will provide insight into the mechanisms by which non-canonical responses to IFN¿¿ increase host susceptibility to microbial infections.

描述（由申请人提供）：巨噬细胞和其他骨髓细胞类型是针对感染的先天免疫反应的关键参与者。骨髓细胞的发育、募集、激活和杀菌活性受 I 型和 II 型干扰素（IFN¿和 IFN?）的调节。干扰素（IFN）和干扰素（IFN）？在微生物感染过程中同时产生，但对骨髓细胞有不同的影响。干扰素？激活巨噬细胞杀菌活性，通常会降低宿主对细胞内微生物的敏感性。相反，干扰素抑制骨髓细胞活化并增加宿主对某些细胞内细菌的敏感性。干扰素加剧细菌感染的机制仍知之甚少。在这个探索性的 R21 拨款申请中，我们测试了这样的假设：干扰素由于其抑制骨髓细胞免疫的能力而增加了对细菌感染的易感性。在第一个目标中，我们确定IFN-γ下调骨髓细胞IFNGR表达是否会损害骨髓细胞活化并增加宿主对感染的易感性。在第二个目标中，我们测试了抑制 ifngr1 基因表达的新型非经典 IFN¿ 反应途径是否也会损害对骨髓细胞激活重要的其他基因的表达，以及抑制该途径是否会增加宿主对感染的抵抗力。这些研究的信息将深入了解干扰素的非典型反应增加宿主对微生物感染的易感性的机制。