Adaptation in the Drosophila innate immune response

描述(申请人提供)：这项建议的目标是确定果蝇先天免疫反应中适应所需的信号转导途径和效应器。我们在这里将适应定义为一种免疫反应，在第二次暴露期间比第一次暴露时更强烈和更迅速。免疫学家通常将免疫系统分为两部分，即先天免疫系统和后天免疫系统。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先天免疫范例。我们已经发现，果蝇的先天免疫反应在最初的挑战之后会发生变化，这种免疫反应会在果蝇的一生中保持对这种变化的记忆。第二种免疫反应是特异的，比单纯的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：革兰氏阳性细菌肺炎链球菌和真菌球孢白僵菌。如果我们从基因上阻止苍蝇产生抗菌肽(AMP)，我们就会发现对大肠杆菌的类似但神秘的反应。我们将这些保护作用称为微生物诱导的启动反应。这些启动的反应是特定的：肺炎链球菌不会对球孢杆菌或大肠杆菌启动，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这种现象背后的分子途径，这提供了一个简单和遗传上容易处理的系统。这一提议揭示了目前对先天性免疫的描述中的一个漏洞，这是最容易在苍蝇身上研究的。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，对先天免疫的更多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，以提高其对抗病原体的效率或降低其引起发病的可能性。如果我们有方法稳定并特别地增加人类的先天免疫反应，我们就可以开发出阻止感染的新方法。具体目标：1.测定启动反应过程中血细胞活性的变化，确定抗菌肽诱导对启动的贡献。2.确定对肺炎链球菌免疫所需的候选分子的位置和时间。(Toll信号、JAK/STAT信号和DSCAM)3.识别在启动反应过程中发生的转录变化。

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.