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

I型干扰素(IFNA蛋白和IFNp家族)和II型干扰素(IFNy)发挥核心和关键作用 在促进对各种病毒、细菌和寄生虫的先天免疫方面的作用。《IFN》 不仅诱导保护宿主细胞免受病原体感染的细胞内在机制，而且还激活 导致NK细胞、巨噬细胞、中性粒细胞活化的多种细胞-外在机制 破坏受感染细胞的白细胞和T细胞。我们对干扰素生物学的了解很大程度上源于 在干扰素应答细胞和无应答细胞上进行的体外实验以及在体内的方法 通过使用中和或封闭的单抗，小鼠的干扰素反应性被全局消融 或者通过破坏编码干扰素物种本身或其各自受体的基因。 这些研究的生理学相关性已经被发现的人类所证实 在产生或对各种形式的干扰素反应方面存在明显的缺陷。然而，由于受体 由于IFNA/p或IFNy在几乎所有细胞上都有表达，我们仍然对细胞特有的功能知之甚少 这些细胞因子在体内。由于IFN在先天免疫中扮演着如此关键的角色，因此获得了更详细的 不仅需要了解它们对不同细胞群体的共同和独特的影响，而且 如果我们想要故意激发先天免疫，无论是预防还是治疗，都是必不可少的 保护我们免受自然发生的(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。具备(1)Schreiber实验室对干扰素生物学的广泛了解 从过去28年进行的分子和基因实验中获得(2)全面的 联合国大学实验室内关于单核细胞增多性李斯特菌免疫生物学的知识 感染，以及(3)对病毒学的特别广泛和深入的理解 将MRCE计划引入这一应用，我们建议在稳定的C57BL/6上培育和研究小鼠 遗传背景，在特定细胞类型中缺乏对IFNA/p或IFNy的反应性来定义组织 IFN对优先病原体感染的具体作用。

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.