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-微生物的相互作用来改善传染病患者的健康。我的短期目标是完善和增加我作为一名独立调查员的技能，并开始我作为威斯康星大学麦迪逊分校初级教员的终身教职，在有保护的时间和资源的情况下，加快我的研究计划的发展。与这项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之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被膜感染的先天免疫反应。我将用这些新的知识、技能和培训来消除阻碍最佳感染治疗的无数关键知识空白。 研究项目。留置静脉导管等医疗设备的患者有患由念珠菌引起的侵袭性疾病的风险，念珠菌是人类最常见的真菌病原体之一。在这些患者中，念珠菌附着在设备表面，以生物膜的形式增殖，弹性细胞被包裹在生物体来源的细胞外基质中。由于宿主免疫系统和传统的抗真菌药物无法根除念珠菌的生物被膜，这些感染可能是毁灭性的。向生物膜生活方式的转变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。 在检查念珠菌设备相关生物被膜感染的患者和动物模型时，我被缺乏宿主免疫细胞，包括中性粒细胞所震惊。我的初步观察表明，这些免疫细胞招募不力，缺乏有效的杀灭念珠菌生物被膜的活性。细胞外生物膜基质似乎是造成这种现象的原因。拟议的实验旨在确定支持中性粒细胞对念珠菌生物被膜反应受损的具体机制。 职业发展计划。我建议的指导和培训活动将集中在(1)通过指导、动手实验室工作和课程工作获得免疫学专业知识；(2)发展领导技能，以便在独立实验室进行研究；(3)展示和发布数据；以及(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R01。 研究环境。我将在威斯康星大学的医学系和医学微生物学与免疫学系得到很好的支持。此外，我将受益于我们机构出色的协作生物科学研究基础设施以及最先进的显微镜、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.