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：
8430416
负责人：
Laurel L Lenz
金额：
$ 23.78万
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 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8430416
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（由适用提供）：巨噬细胞和其他髓样细胞类型是对感染的先天免疫反应中的关键参与者。髓样细胞的发育，募集，激活和微生物活性受I型和II干扰素（IFN？和IFN？）调节。 ifn¿和ifn？在微生物感染期间同时产生，但对髓样细胞具有不同的作用。 ifn？激活巨噬细胞微生物活性，通常会降低宿主对细胞内微生物的敏感性。相反，IFNC抑制髓样细胞的激活，并增加宿主对某些细胞内细菌的敏感性。加剧细菌感染的机制仍然很少了解。在此探索性R21赠款应用中，我们检验了以下假设：IFN``ifn''由于抑制髓样细胞免疫的能力而增加了对细菌感染的敏感性。在第一个目标中，我们确定通过IFN损害髓样细胞激活的髓样细胞IFNGR表达的下调并增加了宿主感染的敏感性。在第二个目标中，我们测试了抑制IFNGR1基因表达的新型非规范IFN“响应途径是否会损害其他对髓样细胞活化重要的基因的表达，以及抑制该途径的新基因是否会增加宿主对感染的抵抗力。来自这些研究的信息将洞悉对IFN的非传统反应提高宿主对微生物感染的敏感性的机制。