Activation of Insect Immunity by Gram-negative Bactria

描述（由申请人提供）：先天免疫系统是抵御入侵微生物的第一道防线。当先天免疫系统不能被激活时，致命的感染就会出现。相反，先天免疫的不适当激活可导致多种疾病，包括败血症、类风湿性关节炎和狼疮。 昆虫完全依靠先天免疫反应来对抗病原体。果蝇是一种遗传学上易于处理的生物体，有先进的遗传学方法可用于其先天免疫的研究，这使得在没有适应性免疫应答的混杂影响的情况下先天免疫研究能够快速进展。果蝇免疫的研究对我们理解人类免疫做出了重要贡献，例如Toll受体的鉴定。该提案的长期目标是阐明负责识别革兰氏阴性菌的分子机制，以及随后激活的信号转导途径，最终在果蝇中表达抗菌肽基因。IMD信号转导通路对于革兰氏阴性菌感染后的免疫激活和存活至关重要。所提出的实验将表征被受体PGRP-LC识别的革兰氏阴性细菌产物，并揭示PGRP-LC激活IMD细胞内信号通路的机制。该途径需要激酶dTAK 1和果蝇IKK以及半胱天冬酶Dredd，并最终通过半胱天冬酶介导的切割激活果蝇NF-κ B同源物Relish。我们拟研究IKK介导的磷酸化作用控制Relish裂解的机制。我们将表征一个平行的信号转导通路，也通过PGRP-LC激活，涉及JNK激酶激活，并导致可能参与宿主防御的一些新基因的表达。我们相信，我们的目标的成功完成可能会导致更好地了解人类和苍蝇的先天免疫反应。这种理解对于我们设计更有效的炎症性疾病治疗方法的能力至关重要。

DESCRIPTION (provided by applicant): The innate immune system is the first line of defense against invading microorganisms. When the innate immune system fails to be activated, lethal infection ensues. Conversely, the inappropriate activation of innate immunity can lead to a variety of illnesses, including sepsis, rheumatoid arthritis and lupus. Insects rely solely on an innate immune response to combat pathogens. The study of innate immunity in Drosophila, a genetically tractable organism for which advanced genetic methods are available, allows for the rapid progress in the study of innate immunity in the absence of the confounding influence of the adaptive immune response. The study of Drosophila immunity has resulted in important contributions to our understanding of immunity in humans, such as the identification of Toll receptors. The long-term goal of this proposal is to elucidate the molecular mechanisms responsible for the recognition of gram-negative bacteria and the subsequent activation of the signal transduction pathways which culminate in the expression of antimicrobial peptide genes in Drosophila. The IMD signal transduction pathway is critical for immune activation and survival following gram-negative infection. The proposed experiments will characterize the gram-negative bacterial products that are recognized by the receptor PGRP-LC, and uncover the mechanisms by which PGRP-LC activates the IMD intracellular signaling pathway. This pathway requires the kinases dTAK1 and Drosophila IKK as well as the caspase Dredd, and culminates in the activation, by caspase-mediate cleavage, of the Drosophila NF-kB homolog Relish. We propose to investigate the mechanism(s) by which the cleavage of Relish is controlled by IKK-mediated phosphorylation. We will characterize a parallel signal transduction pathway, also activated via PGRP-LC, that involves JNK kinas activation, and results in the expression of a number of novel genes likely to be involved in host defense. We believe that the successful completion of our Aims is likely to lead to a better understanding of the innate immune response, in humans and flies. Such an understanding is critical to our ability to devise more effective therapies against inflammatory disease.