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，由最早的后生动物进化而来，是抵御微生物感染的第一道防线。这些反应依赖于种系编码受体对微生物的即时识别，并驱动大量化学、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，过度活跃或不适当的先天免疫反应是与许多感染性、自身免疫性和自身炎症性疾病相关的发病率和死亡率的潜在原因。因此，对先天免疫机制的透彻理解在下一代治疗方法的开发中具有许多潜在的应用。这一建议使用果蝇黑腹果蝇作为研究先天免疫的模型。果蝇为先天免疫的研究提供了许多优势，包括实验的可追溯性和一个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，在果蝇身上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都是高度保守的，在苍蝇身上的发现可以转化为在哺乳动物身上重要的、改变范式的发现。与这个建议特别相关的是保守的NF-？B和MAPK信号通路驱动昆虫和哺乳动物对感染的即时反应。在果蝇中，系统性微生物感染是由两种不同的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。特别是，IMD途径是由来自某些细菌细胞壁的dap型肽聚糖触发的。本提案的长期目标是了解IMD途径触发有效免疫反应的分子细节机制。本提案的具体目的是解决涉及IMD信号转导的分子机制。Aim 1关注多泛素链控制IMD信号转导的机制，特别强调泛素化的目标和类型以及这些多泛素链的功能。目的2研究果蝇I？B激酶（IKK）调节NF-？B前体味。IMD通路的一个新发现的成分，被称为RYBP，是Aim 3遗传和分子分析的重点。RYBP是高度保守的，Aim 3进一步研究了小鼠和人类RYBP同源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.