Activation of Insect Immunity by Gram-negative Bacteria

描述（由申请人提供）：先天免疫是一种古老的防御反应，与最早的后生动物一起进化，是抵御微生物感染的第一道防线。这些反应依赖于生殖细胞编码的受体对微生物的立即识别，并驱动许多化学，生物和细胞反应的产生以抵御感染。面对不断的微生物攻击，先天免疫对几乎所有多细胞生物的生存至关重要。另一方面，过度旺盛或不适当的先天免疫应答是与许多感染性、自身免疫性和自身炎性疾病相关的发病率和死亡率的根本原因。因此，对先天免疫的彻底机制理解在下一代疗法的开发中具有许多潜在的应用。这项建议使用果蝇作为模型的先天免疫的研究。苍蝇为先天免疫的研究提供了许多优势，包括实验易处理性和没有适应性免疫反应复杂性的模型系统。果蝇的免疫反应是媒介昆虫物种的一个很好的模型，在苍蝇中的发现正在转化为控制媒介传播疾病的新方法。此外，先天免疫反应的许多方面在哺乳动物中是高度保守的，并且在苍蝇中的发现可以转化为哺乳动物中重要的范式转变发现。特别相关的这一建议是保守的NF-？在昆虫和哺乳动物中，B和MAPK信号通路驱动对感染的立即反应。 在果蝇，系统性微生物感染是由两个不同的NF-？B信号通路、Toll和免疫缺陷（IMD）通路。这两种途径都是由微生物细胞壁触发的，并驱动抗菌肽和其他免疫保护分子的产生。特别地，IMD途径由来自某些细菌的细胞壁的DAP型肽聚糖触发。该提案的长期目标是从分子上详细了解IMD途径触发有效免疫反应的机制。该提案的具体目标是解决IMD信号转导中涉及的分子机制。目的1着重于多聚泛素链控制IMD信号转导的机制，特别强调泛素化的靶点和类型以及这些多聚泛素链的功能。目的2研究果蝇I？B激酶（IKK）调节NF-κ B的活化。B前体调味剂IMD途径的一个新发现的组分，称为RYBP，是目标3中遗传和分子分析的重点。RYBP是高度保守的，并且Aim 3另外研究了小鼠和人RYBP同系物在哺乳动物先天免疫信号传导中的作用。

DESCRIPTION (provided by applicant): Innate immunity is an ancient defense response that evolved with the earliest metazoan creatures, and is the first line of defense against microbial infection. These responses rely on the immediate recognition of microbes by germline-encoded receptors, and drive the production of numerous chemical, biological, and cellular responses to defend against infection. In the face of constant microbial assault, innate immunity is essential for the survival of nearly all multicellular organisms. On the other hand, over-exuberant or inappropriate innate immune responses are the underlying cause of morbidity and mortality associated with many infectious, autoimmune, and autoinflammatory diseases. Thus, a thorough mechanistic understanding of innate immunity has many potential applications in the development of the next generation of therapeutics. This proposal uses the fruit fly Drosophila melanogaster as a model for the study of innate immunity. Flies offer many advantages for the study of innate immunity, including experimental tractability and a model system without the complexity of the adaptive immune response. The Drosophila immune response is an excellent model for vector insect species, and discoveries made in flies are being translated into new approaches to control vector-borne diseases. Furthermore, many aspects of the innate immune responses are highly conserved with mammals, and discoveries made in flies can be translated into important, paradigm shifting, findings in mammals. Particularly relevant for this proposal are the conserved NF-?B and MAPK signaling pathways that drive the immediate response to infection, in both insects and mammals. In Drosophila, systemic microbial infections are recognized by two distinct NF-?B signaling pathways, the Toll and immune deficiency (IMD) pathways. Both of these pathways are triggered by microbial cell walls and drive the production of antimicrobial peptides and other immuno-protective molecules. In particular, the IMD pathway is triggered by DAP-type peptidoglycan from the cell wall of certain bacteria. The long-term objective of this proposal is to understand in molecular detail the mechanisms used by the IMD pathway to trigger effective immune responses. The specific aims of this proposal address the molecular mechanisms involved in IMD signal transduction. Aim 1 focuses on the mechanisms by which polyubiquitin chains control IMD signal transduction, with particular emphasis on the targets and types of ubiquitination as well as the function of these polyubiquitin chains. Aim 2 investigates the dual mechanisms utilized by the Drosophila I?B kinase (IKK) to regulate activation of the NF-?B precursor Relish. A newly identified component of the IMD pathway, known as RYBP, is the focus of genetic and molecular analysis in Aim 3. RYBP is highly conserved, and Aim 3 additionally investigates the role of mouse and human RYBP homologs in mammalian innate immune signaling.