Cellular Response to Infectious Triggers

描述（由申请人提供）：我们研究的长期目标是描述调节免疫防御抵抗入侵病原体的分子机制。本研究旨在探讨干扰素调节因子（IRF）家族转录因子在病毒感染的先天性和获得性应答中的作用。这些因子被证明不仅参与I型IFN基因的诱导，而且参与其他细胞因子、趋化因子和直接参与抗病毒和抗炎反应的基因的诱导。在过去的几年中，我们已经连续分离IRF-3，IRF-7和IRF-5，并已表明，这些因素作为病毒诱导的信号的直接转运。这些因子的功能不是多余的，因为这些因子在不同的细胞类型中表达，并刺激不同基因的谱。在这三种因子中，IRF-7在IFNa的诱导中起限制作用，IFNa被证明对于先天性和适应性免疫应答都是重要的。我们的假设是，这三个IRF，特别是IRF-7，调节这两种免疫反应。本申请的主要目的是验证这一假设，并确定IRF激活靶基因以响应病原体的分子机制。 这项研究有三个目的。 在目标#1中，我们将研究IRF-7介导的抗病毒基因激活中涉及的分子机制。 在目标#2中，我们将确定Toll 3和Toll 9分别对dsRNA和CpG DNA的应答是否导致IRF-3、IRF-5和IRF-7的活化。 在目标#3中，我们将确定病毒、dsRNA和CpG DNA对巨噬细胞和树突细胞的刺激是否靶向相似或不同的抗病毒基因组。 我们相信，对IRF因子在病原体诱导的细胞反应中的作用的基本认识将为免疫和炎症性疾病的治疗提供新的治疗平台。

DESCRIPTION (provided by applicant): The long time goal of our studies is to delineate the molecular mechanism that regulates the immune defense against invading pathogens. The study proposed is focused on the role of the family transcription factors of interferon regulatory factors (IRF) in the innate and acquired responses to viral infection. These factors were shown to participate not only in the induction of Type I IFN genes but also in the induction of other cytokines, chemokines and genes directly involved in the antiviral and anti-inflammatory responses. Over the past years we have sequentially isolated IRF-3, IRF-7 and IRF-5 and have shown that these factors serve as direct transporters of virus induced signaling. The function of these factors is not redundant since these factors are expressed in different cell types and stimulate a profile of distinct genes. Among these three factors IRF-7 plays a limiting role in the induction of IFNa that was shown to be important both for the innate and adaptive immune responses. It is our hypothesis that these three IRFs, especially then IRF-7, are regulating both of these immune responses. The key objective of this application is to validate this hypothesis and to determine the molecular mechanism by which IRFs activates the targeted genes in response to pathogens. The study has three aims. In Aim#1 we shall examine the molecular mechanism involved in the IRF-7 mediated activation of antiviral genes. In Aim#2 we shall determine whether Toll 3 and Toll 9 responses to dsRNA and CpG DNA respectively results in the activation of IRF-3, IRF-5 and IRF-7. In Aim #3 we shall determine whether the stimulation of macrophages and dendritic cells by virus, dsRNA and CpG DNA targets similar or distinct set of antiviral genes. We believe that the basic understanding of the role of IRF factors in pathogen induced cellular responses will provide a new therapeutic platform for the treatment of the immune and inflammatory disease.