Slfn proteins in innate immunity

描述（由申请人提供）：宿主生物对入侵病原体的快速识别对于建立有效的免疫反应至关重要。被称为PAMPs的病原体的保守结构特征被toll样细胞表面受体识别，toll样细胞表面受体是进化保守的先天免疫系统的一部分。我们之前已经确定干扰素调节因子3 （IRF3）的激活以及随后干扰素刺激基因（ISGs）的诱导是由TLR配体启动的一种新的信号通路。我们已经将这一途径定性为脓毒性休克综合征的主要因素，但也发现IRF-3激活级联是细菌毒素（如炭疽芽孢杆菌致死因子）的靶标。最近，我们研究了一个新的脂多糖和干扰素诱导的核酸结合蛋白家族（schlafen = slfn），其成员似乎改变了IRF3，而不是NF:B介导的对TLR配体的转录反应。本研究旨在探讨Slfn蛋白在irf3介导的先天免疫应答中的功能。我们假设Slfn家族的较长成员要么直接作为外源核酸的细胞质传感器，要么可能作为这些感觉蛋白的辅助因子，而中等和较短的细胞Slfn异构体以及病毒Slfn蛋白起减弱先天免疫反应的作用。我们提出了实验来表征Slfn功能的特异性，确定它们在IRF3激活级联中的作用点，并鉴定Slfn相互作用蛋白。这些研究的结果不仅有助于我们理解IRF3激活的机制，而且还将揭示Slfn蛋白在生理和病理过程中作为先天免疫反应的新调节剂的作用。

DESCRIPTION (provided by applicant): Rapid recognition of invading pathogens by the host organism is crucial in mounting an effective immune response. Conserved structural features on pathogens termed PAMPs are recognized by the Toll-like cell surface receptors, which are part of the evolutionary conserved innate immune system. We had previously identified the activation of Interferon Regulatory Factor 3 (IRF3) and the subsequent the induction of Interferon Stimulated Genes (ISGs) as a novel signaling pathway that is initiated by TLR ligands. We have characterized this pathway as a major contributor to septic shock syndrome, but also found that the IRF-3 activation cascade is a target for bacterial toxins such a Bacillus anthracis Lethal Factor. Recently, we studied a novel family of LPS and interferon-induced nucleic acid binding proteins (schlafen = slfn) whose members appear to alter IRF3, but not NF:B mediated transcriptional responses towards TLR ligands. The proposed research is aimed towards investigating the function of the Slfn proteins in IRF3-mediated innate immune responses. We hypothesize that the longer members of the Slfn family act either as cytoplasmic sensors of foreign nucleic acids directly, or possibly as cofactors to such sensory proteins, whereas the medium and short cellular Slfn isoforms as well as the viral Slfn proteins function to attenuate the innate immune response. Experiments are proposed to characterize the specificity of Slfn function, to define their point-of-action in the IRF3 activation cascade, and to identify Slfn-interacting proteins. Results from these proposed studies will not only facilitate our understanding of the mechanism of IRF3 activation, but will also shed light on the role of Slfn proteins as novel modulators of the innate immune response under physiological and pathological processes. PUBLIC HEALTH RELEVANCE: IRF3 is one of the key mediators of TLR-induced responses. Lack of IRF3-activation leads to an immobilization of the immune response, yet attenuation of this pathway can be beneficial during septic processes. Thus, a detailed understanding of factors such as Slfn proteins that can modulate IRF3 activation is likely to provide novel targets for pharmacological intervention during infectious disease processes.