Dysregulation of antimicrobial peptide gene expression

这项研究解决了人体表面上皮细胞的抗菌反应，特别是这些防御系统的失败如何导致机会性细菌感染的发展。细菌性肺炎是造成牛肉生产经济损失的重要原因，也是研究宿主、病原菌和环境之间复杂相互作用的一个范例。这项拟议的研究调查了抗菌肽对一系列牛呼吸道病原体的活性，以及增加这些天然抗菌产品生产的刺激因素。我们以前观察到，皮质类固醇和病毒感染损害了这些抗菌肽的合成，这种作用可能介导了应激相关的细菌感染易感性。这一效应将在体内得到证实，并将阐明相关的细胞内信号通路。人工刺激这些反应作为预防细菌性肺炎的新方法的潜力将得到测试。最后，在合并孢菌病的背景下研究了同样的反应，合并孢霉病是一种新出现的青蛙真菌疾病，是全球两栖动物物种减少和灭绝的原因之一。有人认为，抗菌肽合成的应激相关失败是全球气候变化、局部环境条件变化以及这种皮肤感染性疾病易感性增加之间的联系。这些研究将阐明抗菌肽基因表达失败是否以及如何导致两种似乎有许多相似之处的重要疾病--肉牛的细菌性肺炎和青蛙的壶菌病。这些发现有望改进控制肉牛这种常见疾病的战略，并更好地理解环境影响是否以及如何影响青蛙种群对这种新出现的传染病的易感性。

The research addresses antibacterial responses of epithelial cells at body surfaces, and particularly how failure of these defences leads to development of opportunistic bacterial infections. Bacterial pneumonia is an important cause of economic loss in beef production, and a paradigm for studying the complex interactions among host, pathogens, and the environment. The proposed research investigates the activity of antimicrobial peptides against a range of bovine respiratory pathogens, and the stimuli that increase production of these natural antibacterial products. We previously observed that corticosteroids and viral infection impair the synthesis of these antimicrobial peptides, and this effect may mediate stress-related susceptibility to bacterial infection. This effect will be confirmed in vivo, and the intracellular signalling pathways responsible will be elucidated. The potential for artificial stimulation of these responses as a novel method to prevent bacterial pneumonia will be tested. Finally, the same response is investigated in the context of chytridiomycosis, an emerging fungal disease of frogs that is one reason for global declines and extinction of amphibian species. It is proposed that stress-related failure of antimicrobial peptide synthesis is a link between global climate change, local alteration of environmental conditions, and increased predisposition to this cutaneous infectious disease. These studies will elucidate whether and how a failure of antimicrobial peptide gene expression leads to two important diseases that appear to share many similarities--bacterial pneumonia in beef cattle, and chytridiomycosis in frogs. These findings are expected to lead to improved strategies to control this common disease in beef cattle, as well as an improved understanding of whether and how environmental influences affect susceptibility of frog populations to this emerging infectious disease.