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

线虫模型中白色念珠菌感染的先天免疫识别

• 批准号: 8969859
• 负责人: Read Pukkila-Worley
• 金额: $ 8.06万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8969859
• 关键词: Innate; Immune; Recognition; Candida; albicans

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.

描述（由申请人提供）：白色念珠菌是最常见的人类真菌病原体，但其毒力机制尚不完全清楚。在此，我提交了一份K08奖的修订申请，该申请提出了一种研究白色念珠菌发病机制的新方法。自我最初提交以来，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（Eukaryotic Cell，封面），参与了另一项研究（Journal of Experimental Medicine），并以第一作者身份发表了一篇综述文章。此外，我还获得了癌症研究所Irvington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拨款的资助。这些经历和成功表明了我想从事学术医学事业的愿望，并表明我有潜力成为一名独立的科学家。支持这一申请的教师是学术界最受认可的导师之一，每一位都在培养独立研究者方面有着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），各自为这个项目带来了互补的专业领域。我还成立了一个科学顾问小组，由我的共同导师Stephen B. Calderwood博士（Morton N. Swartz教授兼系主任）和Joseph Heitman博士（James B. Duke教授兼系主任）组成，以监督我的进展。因此，研究环境特别适合于促进拟议的职业发展计划的完成。在这些研究中，我将使用模型宿主秀丽隐杆线虫来确定白色念珠菌激活上皮免疫的机制。在自然界中，线虫会遇到许多来自摄取病原体的威胁，这为维持协调的防御反应提供了强大的选择压力。我是第一个证明秀丽隐杆线虫可以用来准确地模拟人类念珠菌病的关键方面的人。我还发现线虫在全基因组转录分析中产生了靶向抗真菌反应。在这里，我使用这些数据来表征对线虫免疫至关重要的两种毒力途径的信号机制（目的1）。我还概述了我在新的先天免疫受体筛选中发现的一个基因的深入表征（Aim 2）。最后，我提出了一种独特的筛选新型免疫反应基因的工具，该工具将最大限度地提高未表征的先天免疫反应元件的产量（目标3）。这些实验首次评估了秀丽隐杆线虫对肠道真菌病原体的先天免疫反应，并解决了宿主-病原体相互作用的基本问题。白色念珠菌存在于几乎所有健康人的肠道中。然而，这种真菌可引起危及生命的感染，特别是在危重病人或免疫系统受损的个体中。拟议的研究使用模型宿主秀丽隐杆线虫来检查先天免疫系统防御白色念珠菌感染的机制。