Adaptation in the Drosophila innate immune response

描述（由申请人提供）：本提案的目的是确定果蝇先天免疫应答适应所需的信号转导途径和效应物。我们在这里将适应定义为在第二次暴露期间比第一次暴露更强烈和更迅速的免疫反应。免疫学家通常将免疫系统分为两部分，先天性和适应性。根据定义，先天免疫系统不被认为是适应性的。我们的实验有可能改变目前将先天免疫定义为非适应性的先天免疫范式。我们发现果蝇的先天免疫反应在最初的攻击后发生了变化，并且免疫反应在果蝇的一生中保留了这种变化的记忆。这种第二免疫应答是特异性的，并且比初始免疫应答更具保护性。两种不同的苍蝇病原体能够引起引发反应：肺炎链球菌，一种革兰氏阳性细菌和白僵菌，一种真菌。如果我们从基因上阻止果蝇产生抗菌肽（AMP），我们就会发现一种类似但神秘的抗大肠杆菌反应。我们将这些保护作用称为微生物诱导的引发反应。这些引发的反应是特定的：S。pneumoniae不会对B起作用。或大肠杆菌，反之亦然。 我们目前的假设是，微生物诱导启动由于血细胞的特异性激活。在这里，我们提出了实验来定义这种现象的果蝇，这提供了一个简单的和遗传上易于处理的系统的分子途径。这一提议阐明了目前对先天免疫的描述中的一个漏洞，而先天免疫是最容易在苍蝇中研究的。通过在果蝇中定义这种生物学，我们可以直接识别脊椎动物中保守的同源途径。总的来说，对先天免疫的更深入了解应该有助于我们设计新的疫苗佐剂，并可以为我们提供操纵先天免疫系统的方法，以提高其对病原体的效率或降低其导致发病的可能性。如果我们有稳定和特异性地增加人体先天免疫反应的方法，我们就可以开发出阻断感染的新方法。具体目标：1。测量预激反应期间血细胞活性的变化，并确定抗菌肽诱导对预激的贡献。2.确定在何处以及何时需要候选分子以获得抗沙门氏菌的免疫力。肺炎。(Toll信号传导、JAK/STAT信号传导和Dscam）3.识别启动反应期间发生的转录变化。

DESCRIPTION (provided by applicant): The goal of this proposal is to identify the signal transduction pathways and effectors required for adaptation in the innate immune response in the fly. We define adaptation here as an immune response that is stronger and more rapid during a second exposure than a first. Immunologists typically divide the immune system into two parts, innate and adaptive. By definition, the innate immune system is not considered to be adaptive. Our experiments have the potential to change the current innate immunity paradigm that defines innate immunity as being non-adaptive. We've found that the innate immune response of a fruit fly changes following an initial challenge and that the immune response retains a memory of this change for the life of the fly. This second immune response is specific and more protective than a naive immune response. Two different fly pathogens are able to elicit a primed response: Streptococcus pneumoniae, a Gram-positive bacterium and Beauveria bassiana, a fungus. If we genetically prevent the fly from making antimicrobial peptides (AMPs), we uncover a similar but cryptic response against E.coli. We refer to these protective effects as microbe-induced primed responses. These primed responses are specific: S. pneumoniae will not prime for B. bassiana or E.coli and vice versa. Our current hypothesis is that microbes induce priming due to the specific activation of hemocytes. Here we propose experiments to define the molecular pathways underlying this phenomenon in the fruit fly, which provides a simple and genetically tractable system. This proposal illuminates a hole in the current description of innate immunity that is most easily studied in the fly. By defining this biology in the fly, we can directly identify homologous pathways conserved in vertebrates. In general, a greater understanding of innate immunity should help us design new vaccine adjuvants and could provide us with methods of manipulating the innate immune system to increase its efficiency against pathogens or decrease its potential to cause pathogenesis. If we had methods of stably and specifically increasing the innate immune response in people we could develop new methods of blocking infections. Specific Aims: 1. Measure changes in hemocyte activity during the priming response and determine the contribution of antimicrobial peptide induction to priming. 2. Determine where and when candidate molecules are required for immunity against S. pneumoniae. (Toll signaling, JAK/STAT signaling and Dscam) 3. Identify transcriptional changes occurring during a priming response.