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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对感染的先天免疫反应的关键参与者。髓样细胞发育、募集、活化和杀微生物活性受I型和II型干扰素（IFN？和IFN？）调节。IFN和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？激活巨噬细胞杀微生物活性并通常降低宿主对细胞内微生物的易感性。相反，IFN抑制骨髓细胞活化并增加宿主对某些细胞内细菌的易感性。IFN？？加剧细菌感染的机制仍然知之甚少。在这项探索性的R21资助申请中，我们测试了IFN由于其抑制骨髓细胞免疫的能力而增加对细菌感染的易感性的假设。在第一个目标中，我们确定是否下调髓系细胞IFNGR表达的IFN <$削弱髓系细胞活化，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ifngr 1基因表达的新型非经典IFN？应答途径是否也损害了对骨髓细胞活化重要的其他基因的表达，以及抑制该途径是否增加了宿主对感染的抵抗力。来自这些研究的信息将提供对IFN的非典型应答增加宿主对微生物感染的易感性的机制的深入了解。