C. elegans to study organismal control of recovery from bacterial infections

 描述(由申请人提供)本提案描述了旨在了解控制细菌感染恢复的机制的实验。为了从感染中恢复并恢复到动态平衡，宿主必须激活能够控制病原体毒力因子、炎症和潜在有毒抗生素暴露所造成的损害的机制。未能从感染症状中正确恢复 反复感染、伤口愈合不当、自身免疫性疾病和慢性炎症性疾病。病原体识别和免疫激活的机制已经得到了很好的研究，但感染清除后参与恢复的细胞和系统反应还没有很好的定义。我们建立了秀丽隐杆线虫急性感染和抗生素治疗的模型，用于研究感染缓解阶段的生物学变化。我们发现，作为先天免疫标志的基因在康复后下调，而参与异物解毒、氧化还原调节和细胞动态平衡的基因上调。利用基因表达谱、电子分析和反向遗传学方法，我们已经将控制感染恢复与保守的转录因子的功能联系在一起，包括TH GATA转录因子ELT-2、FOXO转录因子DAF-16和NRF转录因子SKN-1。拟议的实验将探索一个普遍的假设，即来自不同神经元的神经GPCR和细胞非自主信号可能作用于非神经组织，在生物水平上调节感染后的恢复。鉴于GPCR介导的信号的保守性和参与恢复控制的转录因子的保守性，拟议的研究应该能够在整个动物水平上更好地理解后生动物用于控制细菌感染恢复的机制。

 DESCRIPTION (provided by applicant) This proposal describes experiments designed to understand the mechanisms involved in the control of recovery from bacterial infections. To recover from an infection and return to homeostasis, the host must activate mechanisms capable of controlling the damage caused by pathogen virulence factors, inflammation, and a potentially toxic antibiotic exposure. Failure to properly recover from infections manifests in the form of recurrent infections, inappropriate wound healing, autoimmune diseases, and chronic inflammatory disorders. The mechanisms involved in pathogen recognition and immune activation have been very well studied, but the cellular and systemic responses involved in recovery after an infection is cleared are not well defined. We have established a Caenorhabditis elegans model of acute infection and antibiotic treatment for studying biological changes during the resolution phase of an infection. We found that genes that are markers of innate immunity are downregulated upon recovery, while genes involved in xenobiotic detoxification, redox regulation, and cellular homeostasis are upregulated. Using gene expression profiling, in silico analysis, and reverse genetic approaches, we have linked to the control of recovery from infection to the function of conserved transcription factors, including th GATA transcription factor ELT-2, the FOXO transcription factor DAF-16, and the Nrf transcription factor SKN-1. The proposed experiments will explore the general hypothesis that neural GPCRs and cell non-autonomous signals from different neurons may act on non-neural tissues to regulate recovery from infection at the organismal level. Given the conserved nature of GPCR-mediated signaling and the conservation of the transcription factors involved in the control of recovery, the proposed studies should lead to a better understanding of the mechanisms used by metazoans to control recovery from bacterial infection at the whole animal level.