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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：
9433503
负责人：
Felix Yarovinsky
金额：
$ 45.76万
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/9433503
关键词：
Address Animals Blood Bone Marrow Cells Cytoplasmic Granules Development Disease Event Goals Host Defense Host resistance Human Human Genome Immune Immune response Immune system Immunity Infection Inflammation Innate Immune System Interferon Type II Interferon-alpha Interferons Interleukin-12 Knowledge Lymphoid Cell Mediating Microbe Mus Mycobacterium tuberculosis Natural Killer Cells Neuraxis Parasites Phase Physiological Play Population Production Pseudogenes Regulation Resistance to infection Risk Role Salmonella typhimurium Site Source Streptococcus pneumoniae T-Lymphocyte TLR6 gene Testing Toll-like receptor 11 Toll-like receptors Toxoplasma gondii Toxoplasmosis adaptive immune response arm cytokine human model innovation insight macrophage microbial mouse model neutrophil novel novel strategies pathogen precursor cell profilin public health relevance recruit 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（由申请人提供）：IFN-γ是介导宿主对多种细胞内病原体抗性的关键细胞因子。直到最近，人们才普遍认识到淋巴细胞是IFN-γ的唯一来源。我们最近已经确定中性粒细胞是IFN-γ的一种新兴的细胞来源，IFN-γ是介导宿主防御弓形虫和其他细胞内病原体的关键细胞因子。与淋巴样细胞相反，嗜中性粒细胞产生IFN-γ是Toll样受体（TLR）和IL-12非依赖性的，并且与嗜中性粒细胞产生IFN-γ相关的事件尚不清楚。我们还观察到，中性粒细胞在其骨髓小生境中的谱系发育过程中表达IFN-γ，与微生物无关。IFN-γ在嗜中性粒细胞颗粒中积累，并在诱导嗜中性粒细胞脱粒时释放。我们建议建立在这些研究结果，以获得更深入的了解如何调节嗜中性粒细胞衍生的IFN-γ的表达，并调查的生理意义，嗜中性粒细胞衍生的IFN-γ在小鼠和人类模型的弓形虫病。在目标1中，我们将鉴定参与幼稚和刚地弓形虫感染小鼠中IFN-γ产生的中性粒细胞前体，并确定调节人和小鼠中性粒细胞中IFN-γ产生的转录因子。在目标2中，我们将使用携带嗜中性粒细胞特异性IFN-γ缺陷的小鼠来测试嗜中性粒细胞衍生的IFN-γ协调对弓形虫的先天性和适应性免疫应答的假设。这些研究将推进我们对人类和小鼠先天免疫系统如何