Mechanisms of Candida Biofilm Immune Evasion

描述（由申请人提供）： 候选人我的职业目标是通过研究宿主-微生物相互作用来改善感染性疾病患者的健康。我的短期目标是完善和增加我的技能作为一个独立的调查员和开始我的终身职位的任命作为一个初级教员在威斯康星大学麦迪逊分校的加速轨迹与保护的时间和资源，以充分发展我的研究计划。与此建议相关的具体教育是在免疫学领域，这将使我能够补充我以前在微生物发病机制方面的培训，并开发一种创新的方法来研究念珠菌生物膜感染的先天免疫反应。我将使用这些新知识、技能和培训来剖析阻碍感染最佳治疗的许多关键知识差距。 研究项目。使用留置医疗器械（如静脉导管）的患者存在由念珠菌（最常见的人类真菌病原体之一）引起的侵袭性疾病的风险。在这些患者中，念珠菌粘附在器械表面，并作为包裹在生物体来源的细胞外基质中的弹性细胞生物膜增殖。由于宿主免疫系统和常规抗真菌药物无法根除念珠菌生物膜，这些感染可能是毁灭性的。过渡到生物膜生活方式如何保护念珠菌免受免疫清除的问题仍然是一个谜，答案将对患者护理产生影响。 在检查念珠菌器械相关生物膜感染的患者和动物模型时，我对缺乏宿主免疫细胞（包括中性粒细胞）感到震惊。我的初步观察表明，这些免疫细胞招募不足，缺乏对念珠菌生物膜的有效杀伤活性。细胞外生物膜基质似乎是造成这种现象的原因。所提出的实验旨在定义支持受损的中性粒细胞对念珠菌生物膜的反应的具体机制。 职业发展计划。我建议的指导和培训活动将侧重于（1）通过指导，动手实验室工作和课程获得免疫学专业知识;（2）发展领导技能，在独立实验室进行调查;（3）展示和发布数据;（4）继续和扩大专业合作。我的研究将与我的培训活动密切协调，并将在该奖项的第四年成功申请R 01。 研究环境。我将在威斯康星州大学医学系、医学微生物学和免疫学系得到很好的支持。此外，我将受益于我们机构杰出的合作生物科学研究基础设施和最先进的显微镜，生物技术和动物设施。

DESCRIPTION (provided by applicant): Candidate. My career goal is to improve the health of people with infectious diseases through investigation of host-microbial interactions. My short-term objective is to refine and add to my skills as an independent investigator and begin my tenure-track appointment as a junior faculty member at the University of Wisconsin-Madison on an accelerated trajectory with the protected time and resources to fully develop my research program. The specific education linked to this proposal is in the area of immunology, which will enable me to complement my prior training in microbial pathogenesis and develop an innovative approach to study of the innate immune response to Candida biofilm infection. I will use this new knowledge, skill, and training to dissec numerous critical knowledge gaps impeding optimal therapy of infections. Research Project. Patients with indwelling medical devices, such as venous catheters, are at risk for invasive disease caused by Candida, one of the most common human fungal pathogens. In these patients, Candida sticks to the device surface and proliferates as a biofilm of resilient cells encased in an organism- derived extracellular matrix. As the host immune system and conventional antifungals are not capable of eradicating Candida biofilms, these infections can be devastating. The question of how transition to the biofilm lifestyle protects Candida from immune clearance remains a mystery, and the answer will have implications for patient care. When examining patient and animal models of Candida device-associated biofilm infection, I was struck by the lack of host immune cells, including neutrophils. My preliminary observations suggest these immune cells are both poorly recruited and lack effective killing activity against Candida biofilms. The extracellular biofilm matrix appears to be responsible for this phenomenon. The proposed experiments are designed to define the specific mechanism underpinning impaired neutrophil responses to Candida biofilm. Career Development Plan. My proposed mentoring and training activities will focus on (1) attaining expertise in immunology through mentoring, hands-on laboratory work, and coursework; (2) developing leadership skills to pursue investigations in an independent laboratory; (3) presenting and publishing data; and (4) continuing and expanding professional collaborations. My research will be closely coordinated with my training activities and will build toward a successful R01 application in the fourth year of this award. Research Environment. I will be well-supported within the Departments of Medicine and Medical Microbiology & Immunology at the University of Wisconsin. In addition, I will benefit from the outstanding collaborative biological sciences research infrastructure at our institution and state-of-the-art microscopy, biotechnology, and animal facilities.