Adaptation in the Drosophila innate immune response

描述（由申请人提供）：本提案的目标是确定苍蝇先天免疫反应中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接触时比第一次接触时更强、更迅速的免疫反应。免疫学家通常将免疫系统分为两部分，先天免疫系统和适应性免疫系统。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固有免疫范式。我们发现果蝇的先天免疫反应在最初的挑战之后会发生变化，并且免疫反应会在果蝇的一生中保留这种变化的记忆。这第二种免疫反应是特异性的，比初次免疫反应更具保护性。两种不同的苍蝇病原体能够引发启动反应：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苍蝇产生抗菌肽（AMPs），我们就会发现对大肠杆菌的类似但隐蔽的反应。我们把这些保护作用称为微生物诱导的启动反应。这些启动反应是特异性的：肺炎链球菌不会启动球孢杆菌或大肠杆菌，反之亦然。我们目前的假设是，由于血细胞的特异性激活，微生物诱导了启动。在这里，我们提出了实验来定义果蝇中这种现象背后的分子途径，这提供了一个简单的和遗传上可处理的系统。这一建议阐明了目前最容易在苍蝇中研究的先天免疫描述中的一个漏洞。通过在苍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，并为我们提供操纵先天免疫系统的方法，以提高其对抗病原体的效率或降低其引起发病机制的潜力。如果我们有办法稳定而有针对性地增加人体内的先天免疫反应，我们就能开发出阻止感染的新方法。具体目标：1；在启动反应期间测量血细胞活性的变化，并确定抗菌肽诱导对启动的贡献。2. 确定候选分子在何时何地需要免疫肺炎链球菌。（Toll信令，JAK/STAT信令和Dscam）识别在启动反应中发生的转录变化。

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.