Slfn proteins in innate immunity

描述（由申请方提供）：宿主生物体对入侵病原体的快速识别对于建立有效的免疫应答至关重要。被称为PAMP的病原体上的保守结构特征被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。我们以前已经确定了干扰素调节因子3（IRF 3）的激活和随后的干扰素刺激基因（ISG）的诱导作为一种新的信号传导途径，由TLR配体启动。我们已经将该途径表征为脓毒性休克综合征的主要贡献者，但也发现IRF-3激活级联是细菌毒素如炭疽杆菌致死因子的靶点。最近，我们研究了一个新的家庭LPS和干扰素诱导的核酸结合蛋白（schlafen = slfn），其成员似乎改变IRF 3，但不NF：B介导的转录反应对TLR配体。该研究旨在研究Slfn蛋白在IRF 3介导的先天免疫应答中的功能。 我们推测，较长的成员的Slfn家族的行为，无论是作为外源核酸的细胞质传感器直接，或可能作为辅助因子，这样的感觉蛋白，而中，短细胞Slfn亚型以及病毒Slfn蛋白的功能，以减弱先天性免疫反应。实验提出了表征的特异性Slfn功能，定义其点的作用在IRF 3激活级联，并确定Slfn相互作用的蛋白质。 这些研究的结果不仅有助于我们理解IRF 3激活的机制，而且还将揭示Slfn蛋白作为生理和病理过程下先天免疫应答的新型调节剂的作用。 公共卫生相关性：IRF 3是TLR诱导反应的关键介质之一。缺乏IRF 3激活导致免疫应答的固定化，但该途径的减弱在脓毒症过程中可能是有益的。因此，详细了解的因素，如Slfn蛋白，可以调节IRF 3激活可能提供新的目标，在感染性疾病的过程中进行药物干预。

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.