Neutrophil IFN-gamma in host defense and inflammation

中性粒细胞 IFN-γ 在宿主防御和炎症中的作用

基本信息

批准号：
9106433
负责人：
Felix Yarovinsky
金额：
$ 44.99万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-03-01 至 2021-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9106433
关键词：
Address Animals Blood Bone Marrow Cells Cytoplasmic Granules Development Disease Event Goals Health Host Defense Host resistance Human Human Genome Immune Immune response Immune system Immunity Infection Inflammation Interferon Type II Interferons Interleukin-12 Knowledge Lymphoid Cell Mediating Microbe Modeling Mus Mycobacterium tuberculosis Natural Killer Cells Neuraxis Parasites Phase Physiological Play Population Production Pseudogenes Recruitment Activity Regulation Resistance to infection Risk Role Salmonella typhimurium Site Source Streptococcus pneumoniae T-Lymphocyte Testing Toll-like receptor 11 Toll-like receptors Toxoplasma gondii Toxoplasmosis adaptive immunity arm cytokine innovation insight macrophage microbial neutrophil novel novel strategies pathogen precursor cell profilin response seropositive transcription factor

项目摘要

DESCRIPTION (provided by applicant): IFN- is a key cytokine that mediates host resistance to a variety of intracellular pathogen. Until recently, it was largely acknowledged that lymphoid cells are the sole sources for IFN-. We have recently established that neutrophils are an emerging cellular source of IFN-, a key cytokine that mediates host defense to Toxoplasma gondii and other intracellular pathogens. Production of IFN-by neutrophils, in contrast to lymphoid cells, is Toll-like receptor (TLR) and IL-12-independent and the events associated with IFN- production by neutrophils are not understood. We have also observed that neutrophils express IFN-during their lineage development in the bone marrow niche independently of microbes. IFN- accumulates in neutrophilic granules and is released upon induction of neutrophil degranulation. We propose to build upon these findings to gain a deeper understanding of how neutrophil-derived IFN- expression is regulated, and to investigate the physiological significance of neutrophil-derived IFN- in mouse and human models of toxoplasmosis. In Aim 1, we will identify neutrophil precursors involved in IFN- production in naïve and Toxoplasma gondii-infected mice and determine the transcription factors that regulate IFN- production in human and mouse neutrophil. In Aim 2, we will use mice harboring neutrophil-specific IFN- deficiency to test the hypothesis that neutrophil-derived IFN-coordinates innate and adaptive immune responses to Toxoplasma gondii. These studies will advance our understanding of how human and mouse innate immune systems

描述（由适用提供）：IFN-是一种关键的细胞因子，可介导宿主对各种细胞内病原体的抗性。直到最近，人们在很大程度上承认淋巴样细胞是IFN-的唯一来源。我们最近确定，中性粒细胞是IFN-的新兴细胞来源，IFN-是一种关键的细胞因子，可介导宿主的防御剂对弓形虫弓形虫和其他细胞内病原体。与淋巴样细胞相比，嗜中性粒细胞的产生是Toll样接收器（TLR）和IL-12独立的，并且不了解与中性粒细胞与IFN-产生有关的事件。我们还观察到，中性粒细胞表达了IFN-在骨髓细分市场中独立于微生物中的谱系发育。 IFN-积聚在中性粒细胞中，并在诱导中性粒细胞脱粒后释放。我们建议建立这些发现，以更深入地了解中性粒细胞衍生的IFN-表达，并研究中性粒细胞衍生的IFN-在小鼠和人类弓形虫病模型中的物理意义。在AIM 1中，我们将鉴定出在幼稚和弓形虫感染的小鼠中与IFN-产生有关的中性粒细胞前体，并确定调节人和小鼠中性粒细胞中IFN-产生的转录因子。在AIM 2中，我们将使用带有中性粒细胞特异性IFN-缺乏症的小鼠来测试中性粒细胞衍生的IFN-的假设，即对毒素gondii的先天和适应性免疫调查。这些研究将促进我们对人类和老鼠先天免疫系统如何的理解