Innate Immune Recognition of Candida albicans Infection in a C. elegans Model

描述（由申请人提供）：C。白色念珠菌是最常见的人类真菌病原体，但其毒力机制尚未完全了解。在这里，我提交了一份修改后的K 08奖申请，为C的研究提供了一种新的方法。白色念珠菌发病机制自从我最初提交以来，我在马萨诸塞州总医院（MGH）的Eleftherios Mylonakis博士和Frederick Ausubel博士的实验室进行了15个月的全职研究。在此期间，我发表了一篇第一作者原创研究论文（真核细胞，封面），为另一项研究（实验医学杂志）做出了贡献，并且是一篇评论文章的第一作者。此外，我还获得了癌症研究所的欧文顿研究所奖学金计划，MGH医学发现研究基金执行委员会，NIH贷款偿还计划和NIH T32赠款的资助。这些经历和成功证明了我对学术医学事业的渴望，并表明我有潜力发展成为一名独立的科学家。支持这项申请的教师是学术界最受认可的导师之一，每个人都有促进独立调查人员发展的令人印象深刻的记录。我的共同导师，Mylonakis博士（医学助理教授）和Ausubel博士（遗传学教授），每个人都为这个项目带来了互补的专业领域。我还成立了一个由我的共同导师Stephen B博士组成的科学顾问小组。Calderwood（Morton N.斯沃茨教授和部门负责人）和约瑟夫海特曼博士（詹姆斯B。杜克教授和系主任）来监督我的进展。因此，研究环境特别适合于促进完成拟议的职业发展计划。对于这些研究，我将使用模式宿主秀丽隐杆线虫来确定C。白色念珠菌激活上皮免疫。在自然界中，线虫面临着来自摄入病原体的众多威胁，这些病原体提供了强大的选择压力来维持协调的防御反应。我是第一个证明C。秀丽隐杆线虫可用于精确模拟人类念珠菌病的关键方面。我还发现，线虫在全基因组转录谱分析中产生了靶向抗真菌反应。在这里，我用这些数据来表征两个毒力的信号传导机制的核心重要性线虫免疫（目的1）。我还概述了一个基因，我确定在屏幕上的新的先天免疫受体（目标2）的深入表征。最后，我提出了一个独特的屏幕新的免疫反应基因使用的工具，将最大限度地提高产量的先天免疫反应元件（目标3）。这些实验提供了对C. elegans先天性免疫反应的肠道真菌病原体和解决问题的根本重要性宿主-病原体的相互作用。白色念珠菌存在于几乎所有健康人的肠道中。然而，这种真菌可能导致危及生命的感染，特别是在重症患者或免疫系统受损的个体中。这项研究使用模式宿主秀丽隐杆线虫来研究先天免疫系统防御C。白色念珠菌感染

DESCRIPTION (provided by applicant): C. albicans is the most common human fungal pathogen yet its virulence mechanisms are not fully understood. Here, I submit a revised application for a K08 award that presents a novel approach for the study of C. albicans pathogenesis. Since my original submission, I have conducted full-time research for 15 months in the laboratories of Dr. Eleftherios Mylonakis and Dr. Frederick Ausubel at Massachusetts General Hospital (MGH). During this time, I have published a first-author original research paper (Eukaryotic Cell, cover), contributed to another study (Journal of Experimental Medicine) and was first-author on a review article. Additionally, I have obtained grant support from the Irvington Institute Fellowship Program of the Cancer Research Institute, the MGH Executive Committee on Research Fund for Medical Discovery, the NIH Loan Repayment Program and a NIH T32 grant. These experiences and successes demonstrate my desire to have a career in academic medicine and indicate that I have the potential to develop into an independent scientist. The faculty who support this application are among the most recognized mentors in academia, each with an impressive record of fostering the development of independent investigators. My co-mentors, Dr. Mylonakis (Assistant Professor of Medicine) and Dr. Ausubel (Professor of Genetics), each bring complementary areas of expertise to this project. I have also formed a Scientific Advisory Panel composed of my co-mentors, Dr. Stephen B. Calderwood (Morton N. Swartz Professor and Division Chief) and Dr. Joseph Heitman (James B. Duke Professor and Department Chair) to monitor my progress. The research environment is therefore uniquely suited to facilitate the completion of the proposed career development plan. For these studies, I will use the model host Caenorhabditis elegans to determine the mechanisms by which C. albicans activates epithelial immunity. In nature, nematodes encounter numerous threats from ingested pathogens, which have provided a strong selection pressure to maintain a coordinated defense response. I was the first to show that C. elegans can be used to accurately model key aspects of human candidiasis. I also found that the nematode mounts a targeted antifungal response in a genome-wide transcription profiling analysis. Here, I use these data to characterize the signaling mechanisms of two virulence pathways of central importance to nematode immunity (Aim 1). I also outline an in-depth characterization of a gene I identified in a screen for novel innate immune receptors (Aim 2). Lastly, I propose a unique screen for novel immune response genes using a tool that will maximize the yield for uncharacterized innate immune response elements (Aim 3). These experiments offer the first assessment of the C. elegans innate immune response to an intestinal fungal pathogen and address questions of fundamental importance to host-pathogen interactions. Candida albicans is found in the intestine of virtually all healthy humans. However, this fungus can cause life- threatening infections, particularly in critically ill patients or in individuals with compromised immune systems. The proposed studies use the model host Caenorhabditis elegans to examine the mechanisms employed by the innate immune system to defend against C. albicans infection.