Tissue specific role of IFNalpha/beta and IFNgamma in innate immuniy to prio path

IFNα/β 和 IFNγ 在先天免疫中的组织特异性作用

• 批准号: 8234935
• 负责人: ROBERT DAVID SCHREIBER
• 金额: $ 36.23万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8234935
• 关键词: Bacteria; Biology; Bioterrorism; C57BL/6 Mouse; Cells; Collaborations; Defect; Engineering; Family; Family member; Francisella tularensis; Genes; Genetic; Goals; Human; Immune; Immunobiology; In Vitro; Individual; Infection; Infection Control; Infectious Agent; Interferon Type I; Interferon-alpha; Interferons; Knowledge; Laboratories; Learning; Listeria monocytogenes; Molecular Genetics; Molecular and Cellular Biology; Monoclonal Antibodies; Mus; NK Cell Activation; Natural Immunity; Parasites; Physiological; Play; Population; Protein Family; Proteins; Reagent; Resistance; Resistance to infection; Role; T-Lymphocyte; Therapeutic; Tissues; Viral; Virus; Virus Diseases; Yersinia pestis; arm; biodefense; cell type; cytokine; in vivo; macrophage; member; neutrophil; novel; pandemic disease; pathogen; programs; receptor; research study; stem; virology

Type I Interferons (the family of IFNa proteins and IFNp) and Type II IFN (IFNy) play central and essential roles in promoting innate immunity against a wide variety of viruses, bacteria and parasites. The IFNs induce not only cell-intrinsic mechanisms that protect host cells against pathogen infection but also activate a variety of cell-extrinsic mechanisms leading to activation of NK cells, macrophages, polymorphonuclear leukocytes and T cells that destroy infected cells. Our knowledge of IFN biology has stemmed largely from in vitro experiments performed on IFN-responsive versus unresponsive cells and in vivo approaches in which IFN responsiveness is globally ablated in mice through use of neutralizing or blocking monoclonal antibodies or through disruption of genes encoding either the IFN species themselves or their respective receptors. The physiologic relevance of these studies have been validated by the discovery of humans who have distinct defects in either producing or responding to the various forms of IFN. However, since the receptors for IFNa/p or IFNy are expressed on nearly all cells, we still know very little about the cell-specific functions of these cytokines in vivo. Since the IFNs play such a key role in innate immunity, obtaining a more detailed understanding of their common and unique effects on different cell populations is not only needed but essential if we wish to intentionally stimulate innate immunity, either prophylactically or therapeutically, to protect us against naturally-occurring (e.g. pandemic viral infections) or intentionally-produced (e.g., bioterrorism) infections. Armed with (1) an extensive understanding of IFN biology that the Schreiber lab has gained from molecular and genetic experiments conducted over the last 28 years (2) a comprehensive knowledge that exists within the Unanue laboratory about the immunobiology of Listeria monocytogenes infection, and (3) the particularly broad and deep understanding of virology that the other members of this MRCE program bring to this application, we propose to produce and study mice on a stabilized C57BL/6 genetic background that lack responsiveness to IFNa/p or IFNy in specific cell types to define the tissue specific actions of the IFNs to infection with priority pathogens.

I型干扰素（IFNA蛋白质和IFNP的家族）和II型IFN（IFNY）发挥着中心和必不可少的作用 促进对各种病毒，细菌和寄生虫的先天免疫的作用。 IFNS 不仅诱导保护宿主细胞免受病原体感染的细胞中性机制，还激活A 各种细胞 - 肢体机制，导致NK细胞，巨噬细胞，多形核的激活 白细胞和破坏感染细胞的T细胞。我们对IFN生物学的了解主要来自 在IFN响应性与无反应性细胞和体内方法上进行的体外实验在其中进行 通过使用中和或阻断单克隆抗体，在小鼠中全球反应能力在全球范围内消除 或通过破坏编码IFN物种本身或其各自受体的基因。 这些研究的生理相关性已通过发现具有的人类 产生或响应各种形式的IFN的不同缺陷。但是，由于受体 对于IFNA/P或IFNY几乎在所有细胞上表达，我们仍然对细胞特异性功能知之甚少 这些细胞因子在体内。由于IFN在先天免疫中起着如此关键的作用，因此获得了更详细的 了解它们对不同细胞群体的共同和独特影响，不仅需要 如果我们希望故意刺激先天免疫，无论是预防或治疗，都必须 保护我们免受天然发生的（例如大流行病毒感染）或故意产生的（例如， 生物恐怖主义）感染。拥有（1）对IFN生物学的广泛了解，Schreiber Lab具有 从过去28年中进行的分子和遗传实验中获得（2） 关于李斯特菌的免疫生物学的统一实验室中存在的知识 感染，以及（3）对病毒学的特别广泛而深刻的理解 MRCE计划带给该应用程序，我们建议在稳定的C57BL/6上生产和研究小鼠 在特定细胞类型中缺乏对IFNA/P或IFNY响应的遗传背景以定义组织 IFN对具有优先病原体感染的特定作用。